HHV-6 reactivation in the era of CAR T-cell therapy: A systematic review of emerging challenges

Human herpesvirus-6 (HHV-6) infection is a known complication of allogeneic hematopoietic stem cell transplantation, but its incidence and clinical impact following chimeric antigen receptor T-cell (CAR-T) therapy remain unclear.

A systematic review was conducted according to PRISMA 2020 guidelines to evaluate HHV-6 infection or reactivation after CAR-T therapy in adults. Searches of PubMed Central, Embase, and the Cochrane Library identified 50 records, of which 10 studies (five case reports, three case series, and two cohort studies) met inclusion criteria. Data on patient characteristics, timing, clinical manifestations, treatment, and outcomes were extracted and analyzed descriptively.

Among 728 CAR-T recipients, HHV-6 infection or reactivation was reported in 22 patients (3.0%; 95% CI, 1.9%-4.5%) over a median follow-up of 2.8 months (range, 0.6-33.8). The median age was 56 years (range, 18-74), and 53.8% were male. HHV-6 infection occurred a median of 21 days (range, 16-84) after CAR-T infusion. Reported complications included encephalitis (n = 10), myelitis (n = 1), pancolitis (n = 1), and disseminated infection (n = 1). Antiviral therapy was administered in seven patients. Among 19 patients with available mortality data, 8 patients died from any cause (42.1%); 4 of these 8 deaths were attributed to HHV-6, corresponding to an HHV-6-attributable mortality of 21.1% among evaluable patients. Cytokine release syndrome was reported in all evaluable cases, and immune effector cell-associated neurotoxicity syndrome occurred in 11 of 17 patients.

Although infrequent, HHV-6 infection or reactivation following CAR-T therapy is associated with substantial morbidity, particularly involving the central nervous system, and overlaps with CAR-T-related toxicities, underscoring the need for heightened clinical awareness.