Monocytopenia, monocyte morphological anomalies and hyperinflammation characterise severeCOVID-19 in type 2 diabetes

Early in theCOVID-19 pandemic, type 2 diabetes (T2D) was marked as a risk factor for severe disease and mortality. Inflammation is central to the aetiology of both conditions where variations in immune responses can mitigate or aggravate disease course. Identifying at-risk groups based on immunoinflammatory signatures is valuable in directing personalised care and developing potential targets for precision therapy. This observational study characterised immunophenotypic variation associated withCOVID-19 severity in T2D. Broad-spectrum immunophenotyping quantified 15 leucocyte populations in peripheral circulation from a cohort of 45 hospitalisedCOVID-19 patients with and without T2D. Lymphocytopenia and specific loss of cytotoxicCD8(+)lymphocytes were associated with severeCOVID-19 and requirement for intensive care in both non-diabetic and T2D patients. A morphological anomaly of increased monocyte size and monocytopenia restricted to classicalCD14(Hi)CD16(-)monocytes was specifically associated with severeCOVID-19 in patients with T2D requiring intensive care. Increased expression of inflammatory markers reminiscent of the type 1 interferon pathway (IL6,IL8,CCL2,INFB1) underlaid the immunophenotype associated with T2D. These immunophenotypic and hyperinflammatory changes may contribute to increased voracity ofCOVID-19 in T2D. These findings allow precise identification of T2D patients with severeCOVID-19 as well as provide evidence that the type 1 interferon pathway may be an actionable therapeutic target for future studies.