Complement activation induces excessive T cell cytotoxicity in severe COVID-19

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathogenesis, and it remains unclear if T cells also contribute to disease pathology. Here, we combined single-cell transcriptomics and proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated, CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Age-dependent generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. The proportion of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a correlated with clinical outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.

Adjusting preoperative risk models of post heart transplant survival to a European cohort in the age of a new cardiac allocation score in Europe.

Background Several risk models target the issue of posttransplant survival, but none of them have been validated in a large European cohort. This aspect is important, in a time of the planned change of the Eurotransplant allocation system to a scoring system. Material and Methods Data of 761 heart transplant recipients from the Eurotransplant region with a total follow up of 5027 patient-years were analyzed. We assessed 30-day to 10-year freedom from graft failure. Existing post-transplant mortality risk models, IMPACT, Meld-XI and Columbia Risk Stratification Score were (RSS) were evaluated. A new risk model was created and the predictive accuracy was compared with the existing risk scores, with a focus on LVAD patients. Results Thirty-day, 1-year, 5-year and 10-year rates of freedom from graft failure were 78.3±1.5%, 68.8±1.71%, 59.1±1.8% and 44.1±1.9. The 1-year incidence of graft failure varied from 14.1% to 50% (RSS), from 22.9% to 57.1 (IMPACT) and from 24.9% to 42.6% using MELD-XI. Our newly adjusted risk score showed an improved area under the curve (AUC) of 0.69 (95% CI 0.64-0.72) with better discrimination in the intermediate to moderate risk cohort (CABDES Score). Conclusion IMPACT, Meld-XI and RSS were suitable to predict posttransplant graft failure only in a high and low risk cohort. CABDES Score, might be an alternative scoring system, with donor age and eGFR beeing the strongest predictors. Implementation of the IMPACT score within the new Eurotransplant Cardiac Allocation Score for patient prioritization for heart transplantation, should be reevaluated.