Characterization of the Inflammatory Response to Severe COVID-19 Illness.

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-1ß, 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-1ß, 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-1ß, 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.

Immunocompromise among vaccinated versus unvaccinated COVID-19 cases admitted to critical care in Ireland, July to October 2021.

As the COVID-19 pandemic progressed, so too did the proportion of cases admitted to critical care in Ireland who were fully vaccinated. Reporting of this observation has public health implications as incorrect interpretation may affect public confidence in COVID-19 vaccines. A potential explanation is the reduced ability of those who are immunocompromised to produce an adequate, sustained immune response to vaccination. We conducted an analysis of the association between COVID-19 vaccination status and underlying degree of immunocompromise among a cohort of critical care patients all with a confirmed diagnosis of COVID-19 admitted to critical care between July and October 2021. Multinomial logistic regression was used to estimate an odds ratio of immunocompromise among vaccinated COVID-19 cases in critical care compared to unvaccinated cases. In this study, we found a statistically significant association between the vaccination status of severe COVID-19 cases requiring critical care admission and underlying immunocompromise. Fully vaccinated patients were significantly more likely to be highly (OR = 19.3, 95 % CI 7.7-48.1) or moderately immunocompromised (OR = 9.6, 95 % CI 5.0-18.1) compared to unvaccinated patients with COVID-19. These findings support our hypothesis, that highly immunocompromised patients are less likely to produce an adequate and sustained immune response to COVID-19 vaccination, and are therefore more likely to require critical care admission for COVID-19 infection.