Background: Infectious complications are the leading cause of non-relapse mortality following CAR-T cell therapy. Respiratory viral infections (RVIs) are frequent, but the contribution of patient- and treatment-related factors to their incidence and severity remains unclear. Defining the timing, burden, and immune determinants of RVIs is essential to prevention and management strategies. We investigated the clinical course of RVIs after CAR-T therapy and identified predictors of progression to lower respiratory tract infection (LRTI), with a focus on immune vulnerabilities.

Methods: We retrospectively identified laboratory-confirmed RVIs (influenza, human metapneumovirus, coronavirus, adenovirus, parainfluenza, rhinovirus, SARS-CoV-2, and respiratory syncytial virus) in patients who received commercial CAR-T therapy between 2018–2024 at a large tertiary cancer center. Infections occurring from day –5 before infusion through next treatment or death were included. Severity was graded using CTCAE v5.0 and BMT-CTN criteria. Immune markers, including absolute lymphocyte count (ALC), absolute neutrophil count (ANC), CD4⁺ T cells and CD19⁺ B cells, and immunoglobulin levels (IgG, IgA, IgM) were extracted longitudinally for each patient as time-dependent covariates. Upper and lower respiratory tract infections (URTI/ LRTI) were classified per EBMT definitions (Pinana et al., 2024). For recurrent infections, we applied the BMT-CTN recurrence interval (90 days). RVI incidence was assessed by time to first event and by recurrent episodes. Cumulative incidence of first and first severe (grade ≥3) RVI was estimated at 100, 365, and 730 days post-infusion, with death or next treatment as competing risks. Risk factors for recurrent RVIs were analyzed using multivariable proportional hazards models incorporating time-dependent covariates.

Results: Among 563 CAR-T recipients, 82% were treated for lymphoma with CD19 CAR-T and 18% for multiple myeloma with BCMA CAR-T. The median age was 65 years (IQR 57-73), and 83% had received bridging therapy. We identified 445 viral infection episodes among 260 patients (46%). The cumulative incidence of RVI was 15% at day 100, 30% at day 365 and 38% at day 730. The cumulative incidence of first severe RVI was 4% at day 100, 10% at day 364 and 14% at day 730. Median time from infusion to first RVI was 5 months (IQR 2–12). A majority of infections, 69%, occurred after day 100. Most infections were mild (40%), moderate (37%), with 18% classified as severe, 2% as life-threatening and 2% as fatal. Of the 10 fatal RVIs, 9 were due to SARS-CoV-2 and 1 to influenza A. The most common RVIs were SARS-CoV-2 (41%), rhinovirus (28%), influenza (9%), RSV (9%) and parainfluenza (6%). Presentation with or progression to LRTI occurred in 18% of episodes, most frequently in RSV (26%), parainfluenza (25%), SARS-CoV-2 (25%), and influenza (18%). Recurrence was common for SARS-CoV-2 (20%), and rhinovirus (19%), but rare for other RVIs, occurring in only 0-3% of cases.

Performance status, LDH pre-lymphodepletion, CD4+ T cells or immunoglobulin levels were not associated with RVI incidence or severity in the univariable models.

In multivariable models accounting for repeated measures, ALC <0.5 k/μL was independently associated with an increased risk of RVI (HR = 1.39, p = 0.012), as was increasing age at CAR-T infusion (HR = 0.99 per year, p = 0.024). The risk of acquiring an RVI was lower during the COVID-19 pandemic (HR = 0.57, p = 0.017).

In a separate model examining predictors of severe RVI (grade ≥3), independent risk factors included ALC <0.5 k/μL (HR = 1.69, p = 0.043), lower CD19+ B-cell counts (HR = 0.67, p < 0.001), and a diagnosis of mantle cell lymphoma (HR = 2.64, p = 0.002).

Conclusions: In this largest analysis to date, involving nearly 600 CAR-T recipients, RVIs remained a significant source of morbidity during long term follow-up. Nearly half the patients experienced ≥1 RVI, with most infections occurring after day 100. Approximately 20% progressed to lower respiratory tract infection, although severity varied by viral pathogen. Markers of immune reconstitution, particularly ALC, were independently associated with both the incidence and severity of infection. These findings underscore the central role of immune recovery in infection susceptibility and highlight the need to study both preventive and therapeutic strategies in this vulnerable population.

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2025
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