Beyond the Usual Suspects: RSV Infection in Patients With Hematological Malignancies Compared to Influenza and SARS‐COV‐2—A Report From the EPICOVIDEHA/EPIRESEHA Registry

Respiratory syncytial virus (RSV) is a major cause of acute respiratory infections and seasonal hospitalisations, particularly among immunocompromised adults [1]. In patients with hematological malignancies, RSV can cause severe complications, including pneumonia, respiratory failure, and death, especially in those with lymphopenia, recent HSCT, or comorbidities [2]. Although antivirals, monoclonal antibodies, and vaccines exist for other high-risk groups, their efficacy in this population remains uncertain [3]. Screening and diagnostic protocols are inconsistent, treatments are often empiric, and hematological patients are largely excluded from clinical trials. Moreover, comparative data versus influenza and SARS-CoV-2 are limited, impeding the development of targeted, evidence-based prevention and management strategies for this vulnerable group [4]. This study used the EPICOVIDEHA/EPIRESEHA registry [5] to describe RSV infection in adults with hematological malignancies (Jan 2023–Dec 2024), comparing it with influenza and SARS-CoV-2. Data were collected via the international registry (NCT04733729), with ethical approval from Fondazione Policlinico Gemelli (ID 3226); consent was waived due to anonymization. Eligible participants were adults (≥ 18 years) with laboratory-confirmed RSV and active hematological malignancy treatment within the past 5 years. Exclusions were benign hematologic conditions, solid tumors, age < 18, treatment-free > 5 years, or RSV diagnosis based only on imaging (Figure S1). Collected data included demographics, malignancy type/status, recent therapy, RSV diagnostics, clinical presentation, infection severity, antivirals, hospitalization, prior-year RSV vaccination, and survival. Malignancy was classified as controlled (partial/complete remission) or active (stable, refractory, newly diagnosed). Infection severity was categorized as asymptomatic, mild, severe, or critical. Asymptomatic cases were defined as patients without symptoms at onset who remained at home. Mild cases included those presenting with extra-pulmonary symptoms managed at home, or patients who were asymptomatic at onset but required hospitalization. Severe disease was defined by the presence of pulmonary symptoms (such as cough, dyspnea, or sputum production) regardless of setting, or by hospitalization with any non-respiratory symptom. Critical disease encompassed all cases requiring ICU admission, irrespective of symptoms at onset. Data were reviewed by hematology and infectious disease specialists; incomplete or inconsistent records were excluded. Two matching analyses were conducted—RSV versus influenza and RSV versus SARS-CoV-2—matching for age (±10 years), viral season, and malignancy type/status; sex was matched when feasible. Categorical variables are counts/percentages, continuous variables as medians with IQR and absolute ranges. Fisher's exact or chi-square tests compared categorical data; Mann–Whitney U tests for continuous variables. Survival was assessed via Kaplan–Meier estimates with log-rank tests. Univariable Cox regression identified mortality predictors, with variables p ≤ 0.1 entered into multivariable Cox regression using backward elimination. Hazard ratios (HR) with 95% confidence intervals (CI) were reported. Predictors included demographics, malignancy subtype/status, comorbidities, recent therapies (chemotherapy, immunotherapy, targeted therapy, HSCT, CAR-T, or none), co-infections, symptom burden, infection severity, antiviral use, secondary infections, and care setting. Analyses were performed in SPSS v25.0; significance set at p ≤ 0.05. Between January 2023 and December 2024, 243 patients with confirmed RSV infection were evaluated. Male predominance was observed (n = 140, 57.6%), with median age 64 years (IQR 52–73; range 18–93) (Table 1). Geographical distribution is in Table S1. Lymphoma (n = 63, 25.9%) and plasma cell disorders (n = 60, 24.7%) were most prevalent. Hematological malignancy was controlled in 48.1% (n = 117). Up to 30.0% (n = 73) had ≥ 2 comorbidities, most often chronic cardiopathy (n = 93, 38.3%) and diabetes mellitus (n = 33, 13.6%). Neutrophils ≥ 1000/μL and lymphocytes ≥ 500/μL were seen in 65.8% (n = 160) and 56.0% (n = 136) of patients. Immunochemotherapy (n = 74, 30.5%) and conventional chemotherapy (n = 45, 18.5%) were common recent treatments (Table 1). RSV was the sole pathogen in 88.5% (n = 215), with coinfections reported mainly with SARS-CoV-2 (n = 14, 5.9%). At RSV infection onset, 59.3% (n = 114) of patients had extra-pulmonary symptoms, 34.2% (n = 83) had pulmonary involvement, and 6.6% (n = 16) were asymptomatic. The most frequently reported symptoms were cough (n = 182; 75.2%) and fever (n = 137; 56.6%), followed by rhinorrhea (n = 54; 22.3%), respiratory distress (n = 49; 20.2%), and radiographic lung impairment (n = 46; 19.0%). Severe disease occurred in 63.8% (n = 155), and 27.2% (n = 66) were classified as mild. Hospital admission was required in 182 patients (74.9%), with a median stay of 14 days (IQR 7–26; range 1–119). ICU admission was necessary for 21 (8.6%), with a median ICU stay of 8 days (IQR 5–13; range 2–28). Specific antiviral therapy was administered in 17.7% (n = 43); most (n = 154, 63.4%) received supportive care. Secondary infections were mainly bacterial (n = 44, 18.1%) (Table 1). The 30-day mortality rate was 6.2% (n = 15), with causes including hematological malignancy alone (n = 4, 1.6%), combined with RSV (n = 6, 2.5%), or RSV alone (n = 3, 1.2%). Mortality was significantly associated with fungal infections (aHR 5.059; 95% CI: 1.583–16.166; p = 0.006) and bacterial infections (aHR 3.264; 95% CI: 1.089–9.784; p = 0.035) (Tables 1 and S2). RSV vs. influenza comparison (n = 178 each) showed key differences: influenza patients were more often vaccinated (11.2% vs. 0.6%; p < 0.001), had more chronic cardiopathy (52.2% vs. 38.2%; p = 0.010), and fever (57.9% vs. 73.0%; p = 0.004) and received more antivirals (82.0% vs. 15.2%; p < 0.001). RSV patients more frequently received immunoglobulins/corticosteroids (16.9%) and had more bacterial (21.3% vs. 12.4%; p = 0.033) and viral (5.6% vs. 1.1%; p = 0.035) secondary infections. RSV cases spent fewer days in intermediate care (median 5 vs. 12; p = 0.010) (Table 1). RSV vs. SARS-CoV-2 comparison (n = 203 each): SARS-CoV-2 patients were more often vaccinated (9.4% vs. 0.5%; p < 0.001). RSV patients had fewer asymptomatic infections (7.4% vs. 18.2%) but presented more often with pulmonary involvement (33.0% vs. 19.2%; p < 0.001). Compared with SARS-CoV-2, RSV cases demonstrated significantly higher frequencies of cough (74.9% vs. 41.4%; p < 0.001), lung impairment (17.7% vs. 7.9%; p = 0.007), and respiratory distress (20.7% vs. 9.4%; p = 0.003), as well as higher rates of severe disease (62.1% vs. 40.4%; p < 0.001) and hospitalization (74.4% vs. 54.2%; p < 0.001). Treatment differed: SARS-CoV-2 patients received more antivirals/corticosteroids (68.5% vs. 14.3%), while most RSV patients received none (69.0% vs. 27.1%; p < 0.001) (Table 1). No significant differences in 30-day survival were observed among RSV, influenza, and SARS-CoV-2 patients (Figure 1). Our multicenter observational study of 243 patients with hematological malignancies and RSV infection offers new insights into the clinical presentation and therapeutic challenges of RSV in this population. By comparing RSV with influenza and SARS-CoV-2, we identified distinct clinical patterns and highlighted several unmet needs that are critical for improving care. Lymphoid neoplasms—especially lymphoma and plasma cell disorders—were most common, reflecting known susceptibility of lymphoproliferative disorders to respiratory viruses due to impaired immunity and frequent use of B-cell–depleting therapies like rituximab and daratumumab [6], which hinder humoral responses and prolong infection vulnerability. Over half of patients had active hematological malignancies at RSV diagnosis, likely contributing to the observed severity and high hospitalization rate. Active disease increases inflammatory burden, cumulative immunosuppression, and reduces functional status [7]. In line with existing literature [8], cardiovascular disease and diabetes—common comorbidities in this cohort—are independently linked to worse outcomes in respiratory viral infections, further amplifying RSV severity. Neutropenia or lymphopenia at diagnosis occurred in only ~10% of patients, lower than in high-risk populations like acute leukemia or HSCT recipients [2]. This likely reflects the predominance of indolent lymphoid malignancies, where immune impairment is driven more by treatment and chronic immunosuppression than cytopenias. About half of the cohort had recent chemotherapy or immunochemotherapy, supporting the link between recent therapy and RSV severity, consistent with prior reports [2, 3]. RSV vaccination coverage was minimal, much lower than influenza and SARS-CoV-2, likely due to the recent availability of RSV vaccines and their exclusion from national or disease-specific guidelines. By contrast, established recommendations and routine use of influenza and SARS-CoV-2 vaccines likely explain their higher uptake. Coinfections were rare, with SARS-CoV-2 most common, reflecting their co-circulation in hematological patients [2]. Asymptomatic RSV was uncommon; most initially had extrapulmonary symptoms, progressing to pulmonary involvement in approximately two-thirds, underscoring the need for close monitoring. In contrast, SARS-CoV-2 was often asymptomatic, likely due to broader testing, whereas RSV diagnosis remains largely symptom-driven and hospital-based, potentially delaying care. Hospitalization occurred in 75% of cases, though ICU admission was rare, indicating that RSV often requires inpatient care but less frequently leads to critical illness. Despite generally milder symptoms than influenza, RSV caused more secondary infections—mainly bacterial—affecting ~20% of patients and significantly contributing to mortality, likely due to RSV-induced epithelial injury. Antiviral treatment, primarily ribavirin, was administered in fewer than 20% of cases. This limited use reflects the lack of randomized trial data supporting its efficacy and the absence of treatment guidelines for non-transplant patients with hematological malignancies. In contrast, influenza was more frequently treated with oseltamivir, which has a stronger evidence base. While COVID-19 benefits from multiple validated antiviral options, treatment of RSV remains empirical and inconsistently applied. All-cause mortality was ~6%, with RSV as a primary or contributing factor in most deaths. Fatal cases were largely linked to secondary infections, supporting the role of RSV-induced epithelial damage in facilitating bacterial and fungal superinfections [9]. The higher rate of bacterial co-infection observed in RSV compared with influenza may reflect several interrelated mechanisms. RSV is known to cause pronounced epithelial damage and impair mucociliary clearance, facilitating bacterial adherence and colonization of the lower respiratory tract. In addition, delayed diagnosis and the limited availability of specific antiviral or immunomodulatory therapies for RSV likely contribute to prolonged viral replication and immune dysregulation, further predisposing patients to secondary bacterial infection. In contrast, influenza is more routinely diagnosed and promptly treated with established antivirals, which may mitigate the risk of bacterial superinfection. This finding underscores the importance of improving timely RSV diagnostics, expanding vaccine coverage, and developing effective antivirals to prevent secondary infections and improve outcomes in this high-risk population. Although invasive fungal disease occurred in only 5%–6% of cases, it carried very high mortality, underscoring the need to consider and manage superinfections in RSV-infected patients with hematological malignancies. The recent approval of RSV vaccines for older and immunocompromised adults is a major advance. Future studies should evaluate vaccine immunogenicity, safety, and effectiveness in patients with hematological malignancies, especially those on B-cell–depleting therapy [10]. Greater access to rapid and multiplex diagnostics could enable earlier detection, while clinical trials of new antivirals or combination therapies, as well as studies on prophylactic or pre-emptive strategies, are needed to guide future practice. This study has several limitations, including its retrospective design, potential selection and reporting biases, incomplete or inconsistent RSV testing, lack of data on viral load, genotyping, and subtype, partial treatment information, and absence of immunological parameters, limiting assessment of host vulnerability. RSV is a clinically significant respiratory infection in patients with hematological malignancies—especially those with active lymphoid neoplasms, recent chemotherapy, or coinfections—causing high hospitalization, secondary infection, and mortality rates. Compared with influenza and SARS-CoV-2, RSV remains underdiagnosed, undertreated, and under-vaccinated, highlighting the urgent need to improve vaccines, diagnostics, and therapies. J.S.-G., F.M., O.A.C., and L.P. contributed to study design and study supervision. J.S.-G. did the statistical plan and analysis. J.S.-G., F.M., O.A.C., and L.P. interpreted the data and wrote the paper. All the authors recruited and documented participants, critically read, reviewed, and agreed to publish the manuscript. This study was funded by AstraZeneca GmbH (AstraZeneca Germany), which had no role in the design, data collection, analysis, interpretation, or writing of the manuscript. We would like to express our deepest gratitude to everyone who contributed to the development of this manuscript. In particular, we wish to pay special tribute to Dr. Alberto López-García. His dedication, knowledge, and unwavering support have been instrumental in advancing the EPICOVIDEHA/EPIRESEHA research since its inception. His legacy will endure through this work, and he will always be remembered with great appreciation and respect. Ethical approval was granted by the institutional review board of Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome (Study ID 3226), as well as by local ethics committees where applicable. Given the complete anonymization of patient data, the need for informed consent was waived in accordance with the specific requirements of participating institutions. J.S.-G. has received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Gilead, Menarini, and Pfizer; and has participated on a Data Safety Monitoring Board or Advisory Board for Pfizer, outside of the submitted work. O.A.C. has received grants or contracts from BMBF, Cidara, EU-DG RTD (101037867), F2G, Gilead, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; consulting fees from Abbvie, AiCuris, Biocon, Cidara, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Moderna, Molecular Partners, MSG-ERC, Noxxon, Octapharm, Pfizer, PSI, Scynexis, Seres; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Abbott, Abbvie, Al-Jazeera Pharmaceuticals/Hikma, Gilead, Grupo Biotoscana/United Medical/Knight, MedScape, MedUpdate, Merck/MSD, Noscendo, Pfizer, Shionogi, streamedup!; payment for expert testimony from Cidara; a German patent (“Geschlossene Inkubationssysteme mit verbessertem Atemwegszugang für Untersuchungsvorrichtungen,” DE 10 2021 113 007.7), filed by the University of Cologne and listing Oliver A. Cornely as one of three inventors; participation on a Data Safety Monitoring Board or Advisory Board from Boston Strategic Partners, Cidara, IQVIA, Janssen, MedPace, PSI, Pulmocide, Shionogi, The Prime Meridian Group; stock or stock options from CoRe Consulting, EasyRadiology; and other financial or non-financial interests from Wiley, outside of the submitted work. Other authors declare no competing interests related to the submitted work. All authors had full access to the data and had final responsibility for the decision to submit for publication. The corresponding author can provide the data supporting the findings of this study upon a reasonable request. Data S1: Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.