Innate Immune Response in COVID-19 Pneumonia During the Pandemic: A Prospective Cohort Study

Background Dysregulated innate immunity contributes to COVID-19 severity, but its evolution over the periods of the pandemic is undefined. The aim of the study was to compare ex vivo innate immune responses in COVID-19 and non-COVID-19 community-acquired pneumonia (CAP) and assess associations with pandemic period, severe respiratory failure (SRF), mortality, and circulating microRNA patterns. Methods In this prospective cohort study conducted at 2 tertiary hospitals in Athens, Greece, 102 hospitalized patients with COVID-19 pneumonia and 28 with non-COVID-19 community-acquired pneumonia were enrolled. Peripheral blood mononuclear cells were isolated during the first 24 hours before any immune intervention other than dexamethasone and stimulated for cytokine production. SRF was defined as a PaO₂/FiO₂ ratio <150 mmHg necessitating invasive or non-invasive ventilation. Exploratory serum microRNA sequencing was performed in a small subset. Results On Day 1, release of TNFα and IL-6 was higher by the PBMCs of patients with COVID-19 pneumonia than non-COVID-19 CAP; the opposite was found for IL-1RA. Patients infected by the Omicron variant had higher production of TNFα and lower of IL-6. Using multivariate logistic regression analysis, it was confirmed that over-time decrease of the production of IL-6 by the PBMCs of patients with COVID-19 was a risk factor for progression into SRF and 28-day mortality. Conclusion COVID-19 pneumonia and non-COVID-19 CAP exhibited distinct patterns of ex vivo PBMC responsiveness, characterized by higher TNF-α and IL-6 production in COVID-19. Functional cytokine responses also varied across pandemic periods.