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. 2020 Sep 15;202(6):812-821.
doi: 10.1164/rccm.202005-1583OC.

Characterization of the Inflammatory Response to Severe COVID-19 Illness

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  3   2 , 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  3   2 , Noel G McElvaney  1   2
Affiliations

Characterization of the Inflammatory Response to Severe COVID-19 Illness

Oliver J McElvaney et al. Am J Respir Crit Care Med. .

Abstract

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 (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.

Keywords: COVID-19; alpha-1 antitrypsin; cytokines; immunometabolism; neutrophils.

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Figures

Figure 1.
Figure 1.
The coronavirus disease (COVID-19) cytokinemia. (A) Plasma was obtained from healthy control (HC) subjects (n = 15), patients with COVID-19 infection who required hospitalization but were stable at ward level (COVIDstable patients; n = 20), severely unwell patients with COVID-19 requiring intubation and mechanical ventilation (COVIDICU patients; n = 20), and patients with severe community-acquired pneumonia in ICU (CAPICU patients; n = 15). IL-1β levels were elevated in COVIDstable patients compared with HC subjects, with an increase observed between the COVIDstable and COVIDICU groups. IL-1β levels were higher in COVIDICU than in CAPICU patients. (B) IL-6 levels were elevated in COVIDstable patients compared with HC subjects, with an additional increase in COVIDICU patients. IL-6 levels were higher in CAPICU than in COVIDstable patients but significantly lower than in COVIDICU patients. (C) IL-10 was higher in COVIDstable patients than in HC subjects. IL-10 in CAPICU patients was higher than in both COVID-19 groups. (D) IL-6:IL-10 was higher in COVIDICU patients than in COVIDstable and CAPICU patients. (E) IL-8 was increased in COVIDstable plasma, with a further rise in COVIDICU patients. No difference between COVIDICU and CAPICU patients was observed. (F) Levels of sTNFR1 were higher in COVIDstable than in HC subjects, with a further increase in COVIDICU patients. Levels were higher in COVIDICU than in CAPICU patients. *P < 0.05 and **P < 0.001. ns = not significant; sTNFR1 = soluble tumor necrosis factor receptor 1.
Figure 2.
Figure 2.
Neutrophil immunometabolism is altered in severe coronavirus disease (COVID-19) illness. (A) Neutrophils were isolated from the peripheral blood of healthy control (HC) subjects (n = 8) and patients with severe COVID-19 illness requiring intubation and mechanical ventilation (COVIDICU patients; n = 8), and cytosolic fractions were obtained. PKM2 (pyruvate kinase M2) was significantly increased in COVIDICU neutrophil cytosols compared with HC neutrophil cytosols (P < 0.0001). (B) Cytosolic levels of phosphorylated PKM2, indicative of PKM2 dimer formation, were also significantly increased in COVIDICU patients compared with HC subjects (P < 0.0001). (C) Cytosolic succinate levels were higher in COVIDICU than in HC neutrophils (fold increase 10.41 ± 1.97; P < 0.0001). (D) Cytosolic HIF-1α (hypoxia-inducible factor-1α) was higher in COVIDICU neutrophils than in HC neutrophil cytosols (P < 0.0001). Nuclear levels of HIF-1α and PKM2 were also increased in neutrophils from the same infected patients (both P < 0.0001). (E) Cytosolic lactate was higher in circulating COVIDICU neutrophils than in HC neutrophils (P < 0.0001). (F) Cytosolic lactate:pyruvate ratio was similarly increased (P < 0.0001). **P < 0.001. DU = densitometric units; LP = lactate:pyruvate; Phos. PKM2 = phosphorylated PKM2.
Figure 3.
Figure 3.
The acute phase response of AAT (alpha-1 antitrypsin) is overwhelmed in severe coronavirus disease (COVID-19) illness. AAT is a 52 kD glycosylated protein synthesized primarily in the liver. (A) Immunofixation of plasma from patients with COVID-19 after isoelectric focusing gel electrophoresis demonstrated the presence of the highly sialylated M0 and M1 AAT glycoforms indicative of an attempt to mount a response to inflammation. (B) Plasma IL-6:AAT ratios were significantly higher in patients who required ICU support (COVIDstable: 19.00 ± 8.41; COVIDICU: 92.05 ± 35.61; CAPICU: 35.26 ± 13.77; P = 0.0002). (C) Sequential plasma samples were obtained from 16 COVIDICU patients (indicated in red), 8 of whom resolved sufficiently within 10 days of entering ICU to be discharged to the ward, and 8 of whom had a poor outcome (death or prolonged ICU stay). A progressive increase in IL-6:AAT was observed in COVIDICU patients who had a poor outcome, whereas a decrease in IL-6:AAT was seen in COVIDICU patients who recovered. By comparison, CAPICU patients (indicated in blue; good outcome: n = 8, poor outcome: n = 7) did not exhibit the same trend. **P < 0.001. CAPICU = patients with severe community-acquired pneumonia requiring ICU support; COVIDICU = patients with COVID-19 requiring ICU admission; COVIDstable = hospitalized but stable patients with COVID-19; HC = healthy control subjects.
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Comment in

  • Rewiring the Immune Response in COVID-19.
    Chalmers JD, Chotirmall SH. Chalmers JD, et al. Am J Respir Crit Care Med. 2020 Sep 15;202(6):784-786. doi: 10.1164/rccm.202007-2934ED. Am J Respir Crit Care Med. 2020. PMID: 32755507 Free PMC article. No abstract available.
  • Is IL-6 the Right Target in COVID-19 Severe Pneumonia?
    Blot M, Bourredjem A, Binquet C, Piroth L; LYMPHONIE Study Group. Blot M, et al. Am J Respir Crit Care Med. 2021 Jan 1;203(1):139-140. doi: 10.1164/rccm.202007-2924LE. Am J Respir Crit Care Med. 2021. PMID: 32955921 Free PMC article. No abstract available.
  • Reply to Blot et al. and to Inoue et al.
    McElvaney OJ, McEvoy NL, McElvaney NG, Curley GF. McElvaney OJ, et al. Am J Respir Crit Care Med. 2021 Jan 1;203(1):141-142. doi: 10.1164/rccm.202008-3169LE. Am J Respir Crit Care Med. 2021. PMID: 32955924 Free PMC article. No abstract available.
  • Role of IL-6 in Severe Inflammation.
    Inoue KI, Sagawa T, Takano H. Inoue KI, et al. Am J Respir Crit Care Med. 2021 Jan 1;203(1):140-141. doi: 10.1164/rccm.202007-3001LE. Am J Respir Crit Care Med. 2021. PMID: 32955926 Free PMC article. No abstract available.

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