Monocyte class switch and hyperinflammation characterise severe COVID-19 in type 2 diabetes

Background: Early in the COVID-19 pandemic type 2 diabetes (T2D) was marked as a risk factor of severe disease and mortality. Inflammation is central to the aetiology of both conditions where variations in immune responses have the potential to mitigate or aggravate disease course. Identifying at risk groups based on immuno-inflammatory signatures is valuable in directing personalised care and developing potential targets for precision therapy. Methods: This study characterised immunophenotypic variation associated with COVID-19 severity in type 2 diabetes. Broad-spectrum immunophenotyping quantified 15 leukocyte populations in peripheral circulation from a cohort of 45 hospitalised COVID-19 patients with and without type 2 diabetes. Results: Morphological anomalies in the monocyte pool, monocytopenia specific to quiescent monocytes, and a decreased frequency of cytotoxic lymphocytes were associated with severe COVID-19 in patients with type 2 diabetes requiring intensive care. An aggravated inflammatory gene expression profile, reminiscent of the type-1 interferon pathway, underlaid the immunophenotype associated with severe disease in T2D. Conclusion: Shifts in T-cell and monocyte dynamics underpin a maladaptive response to SARS-CoV-2. These alterations may impact type-1 interferon signalling which is the likely source of the hyperinflammation that increases voracity of COVID-19. These findings allow the identification of type 2 diabetic patients at risk of severe disease as well as providing evidence that the type-1 interferon pathway may be an actionable therapeutic target for future studies.