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.
【초록키워드】 COVID-19, Critical illness, Cytokines, Health care, Neutralizing antibodies, T cells, IL-6, CXCL10, GM-CSF, Influenza, SARS-COV-2 infection, disease severity, health care workers, Infection, Intervention, cytokine, Proteins, chemokines, CD8, immune, ICU, serum, T cell, Immunophenotyping, Viral, Critically ill, COVID-19 infection, cells, T cell responses, Patient, death, pathway, ECMO, target, ICU Patients, Critical, critically ill patients, RNA-sequencing, COVID-19 patients, T cell activation, IFNα, Potential biomarker, Inflammatory response, Critically ill patient, dysfunction, elements, Viral antigen, Activation, Serum protein, serum proteins, 95% CI, CCL2, influenza infection, in-depth analysis, measure, shift, pro-inflammatory response, cell activation, hierarchy, Single-cell RNA-sequencing, fatal COVID-19, abnormality, element, prognostic indicator, controls, ICU patient, independent, identify, performed, examined, healthy, elevated, unique, demonstrated, correlated, reveal, driven by, death in COVID-19, driver, 【제목키워드】 outcome, COVID-19 patient, identification, immune correlate,