Severity of cytokine release syndrome and its association with infections after T-cell replete haploidentical related donor transplantation.

An increased risk of infections has been described after T-cell-replete haploidentical transplantation (haploHCT). Cytokine release syndrome (CRS) after haploHCT is a known phenomenon but the impact of CRS severity on the risk of infections remains unexplored. We retrospectively evaluated 78 consecutive adult haploHCT recipients from 2012 to 2018 for the development of CRS (graded by Lee et al. criteria) and examined the incidence and mortality due to infections in correlation with CRS severity. Eighty percent of patients developed infections within 180 days of HCT in our study cohort that was stratified by severity of CRS into 3 groups. A significantly higher proportion of patients with CRS grades 2 (89%) and ≥3 (90%) had at least one infection, compared to grade 0-1 (68%) in the first 100 days (p=0.04). Bloodstream infections (BSI) were seen more frequently in CRS grades 2 and ≥3 in the first 6 months. Multivariable analysis for time-to-infection showed that CRS grade ≥3 was independently associated with a higher risk of any infection, compared to grade 0-1 (HR 3.05, p=0.007). CRS grade ≥3 was also associated with a higher hazard of viral (HR 3.42, p=0.04) and bacterial infections (HR 2.83, p=0.03) compared to CRS grade 0-1. After adjusting for time-to-neutrophil engraftment as a time-dependent covariate, CRS grade ≥3 still had a significant effect on viral infections (HR 2.49, p=0.03), but not on bacterial infections (HR 1.32, p=0.57). CRS grade was also a significant predictor for infection density (overall, bacterial, and viral). The incidence of infection-related mortality by day+100 was higher in patients with severe CRS. Severe CRS developing after PTCy-based haploHCT is independently associated with viral infections and increased the risk of bacterial infections likely through delayed neutrophil engraftment.