Abstract
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.
Highlights
The disease course of COVID-19 is highly variable between individuals: approximately 15% of patients develop severe disease requiring intensive care unit (ICU) admission, and, of these, approximately 50% will require invasive mechanical ventilation [1]
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 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
Summary
The disease course of COVID-19 is highly variable between individuals: approximately 15% of patients develop severe disease requiring intensive care unit (ICU) admission, and, of these, approximately 50% will require invasive mechanical ventilation [1]. Type I interferon (IFN) responses, for example, are attenuated in those patients with the most severe disease and the presence of anti-IFN auto-antibodies or genetic defects in type I IFN pathways result in worse outcomes in a subset of patients [5,6,7,8,9]. One area that has remained relatively unexplored is an understanding of the immunological factors associated with death in critically ill COVID-19 patients, i.e. those requiring mechanical ventilation, in whom mortality remains as high as 30–40% [1,10]. Most immunology studies have been underpowered to study these responses in the context of fatal disease [2,3], limiting our understanding of how immune responses contribute or protect from fatal outcomes
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