Characterization of the Inflammatory Response to Severe COVID-19 Illness

Abstract

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 (http://creativecommons.org/licenses/by-nc-nd/4.0/).