Characterization of the Inflammatory Response to Severe COVID-19 Illness

McElvaney, Oliver J.; McEvoy, Natalie L.; McElvaney, Oisín F.; Carroll, Tomás P.; Murphy, Mark P.; Dunlea, Danielle M.; Ní Choileáin, Orna; Clarke, Jennifer; O’Connor, Eoin; Hogan, Grace; Ryan, Daniel; Sulaiman, Imran; Gunaratnam, Cedric; Branagan, Peter; O’Brien, Michael E.; Morgan, Ross K.; Costello, Richard W.; Hurley, Killian; Walsh, Seán; de Barra, Eoghan; McNally, Cora; McConkey, Samuel; Boland, Fiona; Galvin, Sinead; Kiernan, Fiona; O’Rourke, James; Dwyer, Rory; Power, Michael; Geoghegan, Pierce; Larkin, Caroline; O’Leary, Ruth Aoibheann; Freeman, James; Gaffney, Alan; Marsh, Brian; Curley, Gerard F.; McElvaney, Noel G.

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood. Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness. Methods: Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVID(stable) patients), patients with COVID-19 requiring ICU admission (COVID(ICU) patients), and patients with severe community-acquired pneumonia requiring ICU support (CAP(ICU) patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated. Measurements and Main Results: IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVID(ICU) patients could be clearly differentiated from COVID(stable) patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAP(ICU) patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001). Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.