Characterization of the Inflammatory Response to Severe COVID-19 Illness

Oliver J McElvaney, Natalie 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, Noel G McElvaney
American Journal of Respiratory and Critical Care Medicine 2020 June 25

RATIONALE: Coronavirus disease 2019 (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 interleukin (IL)-1β, IL-6, IL-8, IL-10 and soluble TNF receptor 1 (sTNFR1) were assessed in plasma from healthy volunteers, hospitalized-but-stable COVID-19 patients (COVIDstable), COVID-19 patients requiring intensive care unit (ICU) admission (COVIDICU) and individuals with severe community-acquired pneumonia requiring ICU support (CAPICU). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of alpha-1 antitrypsin (AAT) to COVID-19 was also evaluated.

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, and demonstrated higher levels of IL-1β, IL-6 and sTNFR1 - but lower IL-10 - than CAPICU. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2, phosphorylated PKM2, HIF-1α and lactate. The production and sialylation of AAT increased in COVID-19, but this anti-inflammatory 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 COVID-19 patients, increases in IL-6:AAT predicted prolonged ICU stay and mortality, while 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. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (

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