Respiratory Viral Infections Following CAR-T Cell Therapy for Lymphoma and Myeloma: Severity and Immune Correlates

Infectious complications are a major cause of morbidity and non-relapse mortality after CAR-T cell therapy. Respiratory viral infections (RVIs) are frequent, yet their incidence, timing, and immune correlates remain incompletely defined.

We retrospectively analyzed laboratory-confirmed RVIs in 563 commercial CAR-T recipients (2018-2024). Episodes were classified as URTI or LRTI and graded by CTCAE v5.0 and additionally characterized by respiratory-support requirement. Immune reconstitution markers were assessed as time-dependent covariates in all patients. Recurrent events were quantified using mean cumulative function estimates, and multivariable Andersen-Gill models assessed risk factors.

Among 563 CAR-T recipients (82% CD19, 18% BCMA; median age 65), 446 laboratory-documented RVI episodes occurred in 259 patients (46%), predominantly beyond day 100. The expected cumulative number of RVIs per patient reached 1.15 by 2 years, with severe (grade ≥3) events reaching 0.25. SARS-CoV-2 (41%) and rhinovirus (27%) predominated; LRTI developed in 18% of episodes, with 10 infection-related deaths. ALC below 0.5 × 10⁹/L was associated with increased risk of recurrent and severe RVI. Lower CD19⁺ B-cell counts and mantle cell lymphoma were independently associated with severe disease.

Laboratory-documented RVIs are frequent late complications after CAR-T therapy. Impaired immune reconstitution, particularly lymphopenia, is associated with increased risk, with an ALC <0.5 × 10⁹/L emerging as a clinically relevant threshold.