Drug-associated cytokine release syndrome: a FAERS pharmacovigilance study with complementary transcriptomic analysis

Cytokine release syndrome (CRS) is a potentially severe systemic inflammatory toxicity associated with immunotherapies such as CAR-T cells, monoclonal antibodies, and immune checkpoint inhibitors. However, its real-world reporting landscape across different drug classes remains incompletely characterized. We conducted a pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) from 2004 to 2024, focusing on reports coded as CRS. Disproportionality analyses were used to identify drugs associated with disproportionate CRS reporting, and temporal patterns were assessed using time-to-onset analyses and Weibull modeling. Logistic regression was used to explore factors associated with reported fatal outcomes among CRS cases. To provide complementary mechanistic context, exploratory transcriptomic and immune infiltration analyses were performed using the GEO dataset GSE255323. A total of 12,941 CRS reports were linked to 58 drugs, with CAR-T therapies and bispecific antibodies representing the most frequently reported triggers. Female-predominant reporting patterns were more commonly observed with conventional treatments, whereas male-predominant reporting patterns were more often observed with newer immunotherapies. CRS was typically reported within 3 days of drug administration, with a modest but statistically significant earlier onset in women. Factors associated with reported fatal outcomes included male sex, hematologic malignancies, and exposure to specific agents such as tisagenlecleucel. Complementary exploratory transcriptomic analyses suggested immune dysregulation involving myeloid and T-cell-related pathways, and immune deconvolution analyses indicated a pro-inflammatory effector-dominant profile in CRS samples. This study characterizes the real-world reporting landscape of drug-associated CRS and highlights sex-specific reporting patterns, early-onset clinical trajectories, and factors associated with reported fatal outcomes in FAERS. Complementary exploratory transcriptomic analyses suggest potential involvement of myeloid and T-cell dysregulation in CRS, providing additional context for future mechanistic and clinical studies.