Oliver J. McElvaney 1 , 2 , Natalie L. McEvoy 3 , Oisín F. McElvaney 1 , 2 , Tomás P. Carroll 1 , Mark P. Murphy 1 , Danielle M. Dunlea 1 , Orna Ní Choileáin 2 , Jennifer Clarke 2 , 3 , Eoin O’Connor 2 , Grace Hogan 3 , Daniel Ryan 2 , Imran Sulaiman 2 , Cedric Gunaratnam 1 , 2 , Peter Branagan 2 , Michael E. O’Brien 2 , Ross K. Morgan 2 , Richard W. Costello 2 , Killian Hurley 2 , Seán Walsh 2 , Eoghan de Barra 4 , Cora McNally 2 , Samuel McConkey 4 , Fiona Boland 5 , Sinead Galvin 2 , Fiona Kiernan 2 , James O’Rourke 2 , Rory Dwyer 2 , Michael Power 2 , Pierce Geoghegan 2 , Caroline Larkin 2 , Ruth Aoibheann O’Leary 2 , James Freeman 2 , Alan Gaffney 2 , Brian Marsh 6 , Gerard F. Curley , 2 , 3 , Noel G. McElvaney 1 , 2
15 September 2020
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.