Respiratory Syncytial Virus After CAR T-cell therapy: Risk Factors and Outcomes in a Multicenter Retrospective Cohort

Abstract

Among 667 CAR-T recipients, the 2-year cumulative incidence of RSV was 7%, with 29% of diagnosed cases progressing to LRTI. Older age and lymphopenia were associated with severity. Most infections (74%) occurred beyond day +100 (median 8 months). No RSV-attributable deaths occurred. Clinical vigilance is warranted, especially during RSV season.

Visual abstract:

Visual abstract summarizing a multicenter retrospective cohort of adult CD19- or BCMA-directed CAR T-cell recipients (United States and Israel, 2018–2024) with RSV confirmed by RT-PCR and classified using EBMT criteria. Key findings: 7% developed RSV within 2 years after CAR T-cell therapy; 74% of infections occurred beyond day +100; 29% of diagnosed RSV progressed to lower respiratory tract infection. Older age and profound lymphopenia were associated with progression; severe cases required hospitalization and supplemental oxygen, and no RSV-attributable deaths were reported.

In 667 CAR-T recipients, two-year cumulative incidence of RSV was 7%. Among diagnosed cases, 29% progressed to lower respiratory tract infection. Older age and lymphopenia predicted severity. Most infections occurred beyond day 100, and no RSV-attributable deaths were observed.

Introduction

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed outcomes in relapsed or refractory B-cell malignancies but confers unique and challenging infectious risks related to prolonged B-cell aplasia, hypogammaglobulinemia, protracted hematotoxicity and delayed T-cell recovery (1, 2). Importantly, infections represent the main driver of non-relapse mortality in CAR-T recipients (3) and beyond the early post–CAR-T period, respiratory viral infections (RVIs) account for a substantial proportion of infectious complications (4). In hematopoietic cell transplantation (HCT), respiratory syncytial virus (RSV) can rapidly progress from upper respiratory tract infection (URTI) to lower respiratory tract infection (LRTI) with substantial clinical impact in the peri-transplant period (5–7). The epidemiology and determinants of RSV severity after CAR-T remain poorly defined (1, 4, 8). Our aim was to define the burden of RSV after CAR-T, identify immunologic and clinical predictors of progression to LRTI, and describe the real-world experience on management and outcomes.

Methods

We identified RT-PCR confirmed RSV infections among adults who received commercial CD19- or BCMA directed-CAR-T between 2018 and 2024 at two international centers, in the US and Israel. Eligible infections occurred from start of lymphodepletion until initiation of subsequent antineoplastic therapy or death, whichever came first. RSV was diagnosed by RT-PCR from respiratory specimens and classified as URTI or LRTI according to European Blood and Marrow Transplantation (EBMT) definitions for community-acquired respiratory viral (CARV) infection severity (9). URTI was defined by symptoms limited to the upper respiratory tract (e.g., rhinorrhea, sore throat, cough without dyspnea), while LRTI required evidence of lower airway involvement, including new pulmonary infiltrates and/or hypoxia (9). Severity of all infections was further graded using CTCAE v5.0 criteria.

We extracted demographics, underlying disease, CAR-T product, prior HCT, bridging therapy, lymphodepleting regimen, maximal cytokine release syndrome (CRS) and Immune Effector Cell Associated Encephalopathy (ICANS) grade, hospitalization, intensive care admission, and ventilation (mechanical vs supplemental oxygen when available). Immunologic parameters within 30 days of infection onset included absolute lymphocyte count (ALC), absolute neutrophil count (ANC), CD4⁺ and CD19⁺ lymphocyte subsets, and immunoglobulins (IgG, IgA, IgM). No primary immunoglobulin replacement therapy (IGRT) prophylaxis was given at either center during the study period. We recorded IGRT given within 12 weeks before infection diagnosis, RSV directed therapy (oral ribavirin ± IGRT), and RSV vaccination status. RSV attributable mortality was prespecified as death from respiratory failure within 28 days of RSV diagnosis in a patient with proven or probable LRTI. Group comparisons used Fisher’s exact and Wilcoxon rank sum tests (two-sided p<0.05). Institutional review boards at both centers approved the study.

Results

Among 667 CAR-T recipients, the 2-year cumulative incidence of RSV was 7% (95% CI, 5–10), and 10% (95% CI, 7–14) at 3 years (Figure S1). Median follow-up was 9 months (IQR, 3–20). RSV infection occurred more frequently among patients treated for myeloma with BCMA CAR-T (14/105, 13%) than among those treated for lymphoma with CD19 CAR-T (24/562, 4%; p = 0.002).

A total of 38 patients developed RSV infection. Median age was 62 years (range, 23–78), and 60% were male. Among RSV cases, 28% experienced ≥ grade 2 CRS, and 89% had received bridging therapy. Median time from CAR-T infusion to RSV diagnosis was 8 months (IQR, 3–23), with 74% (28/38) of infections occurring beyond day +100. During the study period, 563 CAR-T recipients were treated at MSKCC (37 RSV cases) and 104 at the Israeli center (1 RSV case, severe LRTI), reflecting marked differences in case numbers across centers.

Overall, 27 patients of diagnosed patients (71%) had URTI and 11 (29%) presented with or progressed to LRTI. Eight LRTIs were severe (grade 3–4). Eight patients (all with LRTI) required hospitalization for RSV, all requiring supplemental oxygen. One patient was admitted to the ICU, but none required invasive ventilation. Key comparisons are summarized in Table S1. No RSV attributable deaths occurred. One patient died of bilateral pneumonia 7 weeks after RSV diagnosis; bronchoscopy and autopsy were not performed, and the etiology could not be confirmed. This death was therefore not classified as RSV attributable.

In comparative analyses for LRTI vs. URTI, older age (median 68 vs. 61 respectively; p=0.03) and profound lymphopenia at RSV diagnosis (median ALC, 0.30 vs. 0.80 ×10⁹/L respectively; p = 0.006) were associated with worse outcomes (Figure 1, Table S2). Notably, CD4⁺ counts tended to be lower among severe cases (67 vs 160 cells/μL; p=0.076; available in 17 patients). Similarly, patients with URTI only were more likely to have received IGRT in the preceding 3 months although this finding did not reach statistical significance (LRTI, 1/11[9%] vs. URTI 6/27 [22%]; p=0.6). A higher proportion of myeloma patients had received IGRT prior to infection compared with lymphoma patients (4/14 [29%] vs. 3/27 [11%]), likely reflecting different practice patterns; however, this difference was not significant (p = 0.2). Infections clustered in winter (Figure S2), with few cases during the COVID-19 pandemic, likely reflecting the impact of masking and social distancing (Figure S3).

Figure 1. Absolute lymphocyte count (ALC) by RSV infection severity.

Boxplot comparing ALC (×10⁹/L) in patients with mild or moderate vs. severe RSV infection following CAR-T therapy, in patients where lab data was available. ALC values were computationally extracted within ±30 days of RSV diagnosis. Severe infection was defined as CTCAE grade ≥3. Median ALC was significantly lower in patients with severe infection (0.30 vs. 0.80 ×10⁹/L; p = 0.006).

No other clinical, disease-related, or treatment-related variables were associated with RSV severity (Table S1).

Eight patients (21%) received ribavirin (all oral), almost exclusively among those with severe LRTI; one patient received ribavirin preemptively for URTI. Treatment selection and small numbers preclude assessment of efficacy. Only two patients (5%) had received an adult RSV vaccine before infection; both experienced mild infections.

Discussion

This multicenter analysis provides a focused description of RSV epidemiology, severe disease predictors, and outcomes after CAR-T. We observed a 2-year cumulative incidence of 7%, with nearly one-third of diagnosed cases progressing to LRTI, paralleling the burden described after HCT (5, 6). Myeloma patients were more frequently diagnosed with RSV but did not experience more severe infections. The strongest predictors of severity were host related, older age and lymphopenia, which are also well-established risk factors of severe disease in the post-transplant setting (5, 10). Importantly, with the profound and prolonged B-cell aplasia after CAR-T, we found a numerically lower likelihood of LRTI in patients receiving IGRT. In contrast, other humoral parameters did not predict severity, and this observation differs from IVIG impact in the HCT settings where impaired cell-mediated immunity seems to correlate with RSV progression and severity (5, 11). While IGRT may help mitigate bacterial infections in CAR-T survivors (1, 12) its usefulness for reducing RVI severity remains to be established (1, 8). Real world therapeutic practice for RSV in our cohort reflected approaches extrapolated from other immunocompromised patients. The use of ribavirin, often combined with IVIG, was reserved for severe LRTI. IVIG was administered in selected cases based on clinical judgment highlighting the need for more robust evaluation of RSV treatment effectiveness in CAR-T recipients. The observation that most infections occurred beyond day +100 supports extended clinical vigilance during survivorship, especially in winter RSV seasons and also highlights window in which RSV vaccination strategies should be explored. Vaccination in our cohort was rare but associated with mild disease in both vaccinated individuals.

The single death from bilateral pneumonia 7 weeks post RSV underscores the challenge of causal adjudication in profoundly immunocompromised hosts. Lack of bronchoscopy or postmortem evaluation precluded attribution to RSV, including virus triggered late complications and highlights the need for standardized diagnostic work ups in future studies.

The strengths of our study are the large and multi-center experience that provides insights into risks and outcomes of RSV disease progression to guide prevention and early intervention. Specifically, we share the real-world experience that receipt of IVIG within the 12 weeks prior to RSV infection was associated with a numerically lower risk of LRTI. These findings raise the hypothesis that preemptive IVIG may have a role in mitigating RSV-related morbidity. A systematic evaluation of IVIG as a preventative strategy is currently being explored in a multicenter trial (NCT05952804).

The limitations of our study include the retrospective design, modest sample size that included only a small number of infections in the first 100 days, and incomplete ascertainment of some variables across centers, precluding multivariable modeling. Additionally, only clinically attended cases were captured, so mild or late infections may have been missed due to less frequent follow-up. Furthermore, testing practices differed across centers, with unequal detection of RSV cases. Immunologic data were captured within ±30 days of RSV onset and were not uniformly available, particularly CD4⁺ and CD19⁺ subsets, that were often missing especially at later timepoints. Co-pathogen testing and bronchoscopy were not standardized. Therapeutic practices, such as timing of ribavirin and IVIG, varied by center.

Conclusions

RSV is an important infectious complication post CAR-T, with most infections occurring beyond day 100 and progression to LRTI in nearly one third of diagnosed cases. Older age and lymphopenia at diagnosis were associated with RSV severity. IGRT receiving patients were less likely to experience severe disease although this was not statistically significant on univariate analysis and able to be rigorously evaluated due to practice heterogeneity. Our finding support prompt testing of respiratory symptoms, and consideration of early antiviral therapy in high-risk CAR-T survivors, and exploring the role of vaccination, IVIG or passive monoprophylaxis in reducing RSV severity after CAR-T.

Data Availability:

The data supporting the findings of this study are available from the corresponding author upon reasonable request.