• Oliver J McElvaney, Natalie L McEvoy, Oisín F McElvaney, Tomás P Carroll, Mark P Murphy, Danielle M Dunlea, Orna Ní Choileáin, Jennifer Clarke, Eoin O'Connor, Grace Hogan, Daniel Ryan, Imran Sulaiman, Cedric Gunaratnam, Peter Branagan, Michael E O'Brien, Ross K Morgan, Richard W Costello, Killian Hurley, Seán Walsh, Eoghan de Barra, Cora McNally, Samuel McConkey, Fiona Boland, Sinead Galvin, Fiona Kiernan, James O'Rourke, Rory Dwyer, Michael Power, Pierce Geoghegan, Caroline Larkin, Ruth Aoibheann O'Leary, James Freeman, Alan Gaffney, Brian Marsh, Gerard F Curley, and Noel G McElvaney.
• Department of Medicine.
• Am. J. Respir. Crit. Care Med. 2020 Sep 15; 202 (6): 812821812-821.

AbstractRationale: 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 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU 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. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAPICU 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.

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