Assessment of longitudinal changes in immune responses in critically ill adults with COVID-19

Clinically, COVID-19 is often a mild or asymptomatic illness. However, in a subset of patients, a more severe illness with one or more organ dysfunction requiring intensive care (ICU) admission occurs (stated as critical COVID-19). Most studies assessing the immune responses in COVID-19 focus on patients with non-critical COVID-19, often assessing single biological domain (such as cytokines, leukocytes, proteomics, or transcriptomics) at single time point in patient’s illness. In this context, our cohort study of patients with critical COVID-19 with demographically similar pre-pandemic controls, characterised the longitudinal changes in multiple biological domains (28 plasma cytokines, 30 immune cell subsets identified using mass cytometry and pan-leukocyte transcriptome) at four clinically relevant timepoints between ICU admission and discharge. When compared with controls, on ICU admission day, patients with critical COVID-19, had altered cytokine/chemokine profile (high interleukin-6 (IL-6), IL-10, IL-13, CXCL10, with low CCL17, and CXCL5)), raised histones (H3.1, H3R8), robust plasmablast response despite lymphopenia, with enrichment of immunoglobulin production and interferon pathways in the transcriptome. Analyses of longitudinal transcriptome data highlights three immunologically distinct clusters that were discordant to clinical time points, indicating that the clinical time points do capture immune response trajectory. Complete integration of this multi-domain longitudinal data indicated that ~ 70% of immunological heterogeneity is explained by the transcriptome.