Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients
Youngs J., Provine NM., Lim N., Sharpe HR., Amini A., Chen Y-L., Luo J., Edmans MD., Zacharopoulou P., Chen W., Sampson O., Paton R., Hurt WJ., Duncan DA., McNaughton AL., Miao VN., Leaver S., Wyncoll DLA., Ball J., Hopkins P., Skelly DT., Barnes E., Dunachie S., Ogg G., Lambe T., Pavord I., Shalek AK., Thompson CP., Xue L., Macallan DC., Goulder P., Klenerman P., Bicanic T.
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.