Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients
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by Jonathan Youngs, Nicholas M. Provine, Nicholas Lim, Hannah R. Sharpe, Ali Amini, Yi-Ling Chen, Jian Luo, Matthew D. Edmans, Panagiota Zacharopoulou, Wentao Chen, Oliver Sampson, Robert Paton, William J. Hurt, David A. Duncan, Anna L. McNaughton, Vincent N. Miao, Susannah Leaver, Duncan L. A. Wyncoll, Jonathan Ball, Philip Hopkins, Oxford Immunology Network Covid-19 response T cell Consortium , Oxford Protective T cell Immunology for COVID-19 (OPTIC) Clinical team , Donal T. Skelly, Eleanor Barnes, Susanna Dunachie, Graham Ogg, Teresa Lambe, Ian Pavord, Alex K. Shalek, Craig P. Thompson, Luzheng Xue, Derek C. Macallan, Philip Goulder, Paul Klenerman, Tihana Bicanic
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.