ABSTRACT
Background
Respiratory viral infections (RVIs) significantly impact patients with hematologic malignancies (HMs). During the 2023–2024 respiratory viral (RV) season, we observed a decline in SARS‐CoV‐2‐related hospitalizations in our center compared to the two previous seasons. Given the changing epidemiology of RVIs in the post‐pandemic era, the low acceptance of SARS‐CoV‐2 and influenza vaccination, and the availability of new respiratory syncytial virus (RSV) vaccines in 2023, we aimed to compare outcomes of RSV, influenza, and SARS‐CoV‐2 infections in patients with HMs during the 2023–2024 RV season.
Methods
We retrospectively analyzed adults with HMs diagnosed with RSV, influenza, or SARS‐CoV‐2 between October 2023 and April 2024. The primary outcomes were lower respiratory tract infection (LRI), hospitalization, and 30‐day all‐cause mortality.
Results
We identified 503 patients with 536 consecutive RVIs: 50.0% with SARS‐CoV‐2, 26.1% with RSV, and 22.2% with influenza (1.7% co‐infections). Among RSV‐infected patients, 50.7% developed LRI, compared to 41.2% with influenza and 39.2% with SARS‐CoV‐2 (p = 0.076). The 30‐day all‐cause mortality was 9.3% for RSV, 7.6% for influenza, and 3.4% for SARS‐CoV‐2 (p = 0.037). In the multivariable analysis, RSV was associated with higher LRI rate compared to SARS‐CoV‐2, along with older age, refractory/relapsed cancer, nosocomial infections, and lymphopenia. Older age, allogeneic hematopoietic cell transplantation, nosocomial infections, and LRIs were associated with increased mortality.
Conclusions
During the 2023–2024 RV season, the clinical impact of these viruses on patients with HMs remains significant, with higher morbidity and mortality from RSV, highlighting the persistent unmet need for better management strategies for RVIs in the post‐pandemic era.
Keywords: hematologic malignancy, influenza, respiratory syncytial virus, respiratory viral infection, SARS‐CoV‐2
During the 2023‐2024 respiratory viral season, respiratory syncytial virus infection was associated with worse outcomes compared to infections caused by SARS‐CoV‐2 and influenza virus in patients with hematologic malignancies
1. Introduction
Respiratory viral infections (RVIs) pose a significant challenge to the health and survival of patients with hematologic malignancies (HMs) [1]. According to the US Centers for Disease Control and Prevention, SARS‐CoV‐2 remained the predominant pathogen leading to hospitalizations during the 2023–2024 respiratory viral (RV) season [2]. In the general population of hospitalized patients, COVID‐19 had a higher mortality rate than influenza infection during the 2023–2024 season, although this gap is narrowing [3]. However, we observed fewer SARS‐CoV‐2 hospitalizations at our institution in the 2023–2024 RV season compared to previous years during the pandemic (Figure S1). Similarly, the EPICOVIDEHA registry reported a notable decrease in COVID–19‐related critical infections and mortality rates among patients with HMs from 2020 to 2022 [4].
Respiratory syncytial virus (RSV) is increasingly recognized as a significant pathogen causing RVIs in adults [5, 6, 7, 8, 9]. Among patients with HMs, the morbidity and mortality attributed to RSV infections are high [10, 11]. While vaccination has improved the outcomes of influenza and SARS‐CoV‐2 RVIs in patients with HMs [12], the newly approved anti‐RSV vaccinations have not been studied yet in this population [13, 14]. As for treatment options, high‐quality clinical efficacy data are lacking for the use of ribavirin for RSV‐related RVIs [15, 16], unlike the effective treatments available for SARS‐CoV‐2 and influenza infections.
Given these evolving trends in the clinical impact of RVIs, this study aimed to compare the severity and outcomes of RSV, influenza, and SARS‐CoV‐2 infections in patients with HMs during the 2023–2024 post‐pandemic RV season.
2. Methods
2.1. Study Design
We conducted a retrospective cohort study involving consecutive adult patients with HMs who experienced symptomatic RVI caused by SARS‐CoV‐2, RSV, or influenza from October 1, 2023, to April 30, 2024. The presence of each viral pathogen was diagnosed using the BioFire Film Array Respiratory Panel 2.1 (BioFire Diagnostics, Salt Lake City, UT) obtained from either nasal swabs and/or bronchoalveolar fluid samples. RV co‐infection was defined as a positive PCR test for another respiratory virus detected within 2 weeks before or after the infection of interest. We included multiple episodes of viral infections for the same patient, provided that these episodes occurred at least 1 month apart and the patient had clinically recovered from the previous infection.
Patient data, including demographic and clinical characteristics, were collected from electronic medical records. Our primary outcomes of interest were lower respiratory tract infection (LRI; at presentation or progression during follow‐up), hospitalization, and 30‐day all‐cause mortality. Secondary outcomes were intensive care unit admission, oxygen requirement, mechanical ventilation, and mortality attributed to RVI within 30 days of diagnosis. Two infectious disease specialists (T.S. and F.K.) reviewed the data and verified the adjudication of outcomes. Of note, based on our institutional guidance, ribavirin is administered only to patients infected with RSV and are at high risk for progression to LRI or mortality (i.e., allogeneic HCT recipients with moderate‐to‐high Immunodeficiency Score Index [ISI]) [17].
Notably, episodes with co‐infection of two of the three viruses examined (RSV, influenza, and SARS‐CoV‐2) were excluded from several analyses, including the univariable analysis of the study population by viral pathogen and the multivariable analysis for LRI, to facilitate comparison among the three viruses. This study was approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center (PA15‐0002), and a waiver of patient informed consent was granted.
2.2. Definitions
Upper respiratory tract infection (URI) was diagnosed when the virus was detected in samples taken from the mucosal surfaces of the upper airways, accompanied by respiratory symptoms such as nasal congestion, cough, rhinorrhea, sinusitis, and pharyngitis, and the absence of clinical, radiologic, or other diagnostic evidence of LRI [16]. LRI was diagnosed when the virus was found in samples from the upper or lower airways, along with new or progressive pulmonary infiltrates suggestive of viral infection and at least one lower respiratory tract symptom (such as cough, sputum production, fever, hypoxia, shortness of breath, or pleuritic chest pain). Probable LRI was defined in cases where the virus was detected only in nasopharyngeal samples, while laboratory‐confirmed LRI required the detection of the virus in bronchoalveolar lavage fluid [16]. Nosocomial RVI was defined as a new‐onset infection that occurred at least 48 h after hospital admission for influenza, at least 5 days after admission for RSV, and at least 14 days after admission for SARS‐CoV‐2 [18, 19, 20].
2.3. Statistical Analysis
Categorical data were compared using the Chi‐square test or Fisher's exact test. For continuous data, the one‐way analysis of variance (ANOVA), the Student's t‐test, the Kruskal–Wallis test, or the Mann–Whitney U test was employed, depending on the number of groups being compared and whether the data were normally distributed. Logistic regression analysis was conducted to identify the independent predictors of primary outcomes. Initially, a univariable logistic regression analysis was performed. Variables with p values ≤ 0.25 from the univariable analyses were selected to create an initial multivariable logistic regression model. The complete model was then refined to a final model through the backward elimination procedure, ensuring that all remaining variables had p values less than 0.05. Kaplan–Meier curves were used to illustrate the 30‐day all‐cause mortality rates, and a log‐rank test was conducted to compare these curves. All tests were two‐sided, with p values less than 0.05 considered significant. Statistical analyses were performed using SPSS Statistics software (version 25; IBM, Armonk, NY, USA) and SAS software (version 9.4; SAS Institute Inc., Cary, NC, USA).
3. Results
We included 503 patients with 536 consecutive episodes of RVI. SARS‐CoV‐2 was the most prevalent virus detected, accounting for 268 episodes (50.0%), followed by RSV (140 episodes, 26.1%), and influenza (119 episodes, 22.2%). Nine episodes (1.7%) involved co‐infections of the viruses, comprising six cases of influenza and SARS‐CoV‐2, two cases of RSV and influenza, and one case of RSV and SARS‐CoV‐2. At presentation, 329 (61.4%) episodes were classified as URIs, and 7.3% progressed to LRIs within 30 days of follow‐up.
3.1. Comparison of RSV, Influenza, and SARS‐CoV‐2 RVIs
The characteristics and outcomes of patients infected with the three viruses are shown in Table 1. Briefly, the RSV group had more high‐risk patients, such as those with an underlying malignancy of acute myeloid leukemia (30.0%), a history of allogeneic HCT (44.3%), and having nosocomial infections (10.7%). In contrast, the SARS‐CoV‐2 group had a higher proportion of patients with non‐Hodgkin lymphoma (25.4%) and fewer nosocomial infections (3.4%).
TABLE 1.
Baseline characteristics and clinical outcomes of patients with hematologic malignancies and respiratory viral infections by pathogen (excluding nine cases with co‐infections).
| N (%) | |||||
|---|---|---|---|---|---|
| Variable |
Total (N = 527) |
RSV (N = 140) |
Influenza (N = 119) |
SARS‐CoV‐2 (N = 268) |
p value a |
| Demographics | |||||
| Mean (± SD) age at RVI diagnosis, years | 60.1 ± 15.9 | 58.4 ± 17.0 | 59.8 ± 15.4 | 61.2 ± 15.6 | 0.235 |
| Sex | |||||
| Female | 199 (37.8) | 49 (35.0) | 45 (37.8) | 105 (39.2) | 0.710 |
| Male | 328 (62.2) | 91 (65.0) | 74 (62.2) | 163 (60.8) | |
| Race/ethnicity | |||||
| Non‐Hispanic White | 301 (57.1) | 86 (61.4) | 57 (47.9) | 158 (59.0) | 0.062 |
| Black | 70 (13.3) | 14 (10.0) | 22 (18.5) | 34 (12.7) | 0.123 |
| Hispanic | 116 (22.0) | 32 (22.9) | 32 (26.9) | 52 (19.4) | 0.250 |
| Asian | 29 (5.5) | 6 (4.3) | 5 (4.2) | 18 (6.7) | 0.462 |
| Other | 11 (2.1) | 2 (1.4) | 3 (2.5) | 6 (2.2) | 0.804 |
| Smoking status | |||||
| Never | 329 (62.5) | 88 (62.9) | 68 (57.1) | 173 (64.6) | 0.378 |
| Former | 181 (34.3) | 45 (32.1) | 44 (37.0) | 92 (34.3) | 0.717 |
| Current | 17 (3.2) | 7 (5.0) | 7 (5.9) | 3 (1.1) | 0.019 |
| Influenza vaccination (current season) | 131 (24.9) | 36 (25.7) | 25 (21.0) | 70 (26.1) | 0.541 |
| SARS‐CoV‐2 vaccination status | |||||
| Median SARS‐CoV‐2 vaccine dose (range) | 2 (0–8) | 2 (0–8) | 2 (0–6) | 2 (0–8) | 0.278 |
| 0–2 doses | 299 (56.7) | 86 (61.4) | 70 (58.8) | 143 (53.4) | 0.258 |
| At least 3 doses | 228 (43.3) | 54 (38.6) | 49 (41.2) | 125 (46.6) | |
| HM characteristics | |||||
| HM diagnosis | |||||
| AML | 116 (22.0) | 42 (30.0) | 22 (18.6) | 52 (19.4) | 0.028 |
| ALL | 55 (10.4) | 13 (9.3) | 13 (10.9) | 29 (10.8) | 0.873 |
| CML/CMML | 20 (3.8) | 4 (2.9) | 8 (6.7) | 8 (3.0) | 0.164 |
| CLL/SLL | 29 (5.5) | 4 (2.9) | 8 (6.7) | 17 (6.3) | 0.274 |
| Non‐Hodgkin lymphoma | 110 (20.9) | 22 (15.7) | 20 (16.8) | 68 (25.4) | 0.035 |
| Hodgkin lymphoma | 10 (1.9) | 3 (2.1) | 1 (0.8) | 6 (2.2) | 0.629 |
| MDS/MPN | 45 (8.5) | 13 (9.3) | 6 (5.0) | 26 (9.7) | 0.297 |
| Multiple myeloma | 138 (26.2) | 37 (26.4) | 40 (33.7) | 61 (22.8) | 0.081 |
| Other | 4 (0.8) | 2 (1.4) | 1 (0.8) | 1 (0.4) | 0.503 |
| HM status at RVI diagnosis | |||||
| Remission | 315 (59.8) | 88 (62.9) | 73 (61.3) | 154 (57.5) | 0.530 |
| Relapsed/refractory | 148 (28.1) | 29 (20.7) | 37 (31.1) | 82 (30.6) | 0.077 |
| Active on first‐line therapy | 64 (12.1) | 23 (16.4) | 9 (7.6) | 32 (11.9) | 0.093 |
| Active antineoplastic treatment within 30 days of RVI diagnosis | 290 (55.0) | 69 (49.3) | 67 (56.3) | 154 (57.5) | 0.275 |
| Steroid use within 30 days of RVI diagnosis (prednisone equivalent) | |||||
| Any dose | 221 (41.9) | 66 (47.1) | 40 (33.6) | 115 (42.9) | 0.080 |
| Peak dose of ≤1 mg/kg/day b | 116 (52.5) | 38 (57.6) | 14 (35.0) | 64 (55.7) | 0.049 |
| Peak dose of >1 mg/kg/day b | 105 (47.5) | 28 (42.4) | 26 (65.0) | 51 (44.3) | |
| History of HCT c | |||||
| Autologous | 83 (15.7) | 28 (20.0) | 26 (21.8) | 29 (10.8) | 0.006 |
| Allogeneic | 151 (28.7) | 62 (44.3) | 30 (25.2) | 59 (22.0) | <0.001 |
| History of cellular therapy c | |||||
| CAR T‐cell therapy | 48 (9.1) | 9 (6.4) | 11 (9.2) | 28 (10.4) | 0.407 |
| BiTE therapy | 8 (1.5) | 1 (0.7) | 2 (1.7) | 5 (1.9) | 0.656 |
| RVI clinical course and outcomes | |||||
| Site of infection at presentation | |||||
| URI | 325 (61.7) | 78 (55.7) | 74 (62.2) | 173 (64.6) | 0.217 |
| LRI | 202 (38.3) | 62 (44.3) | 45 (37.8) | 95 (35.4) | |
| Progression from URI to LRI d | 23 (7.1) | 9 (11.5) | 4 (5.4) | 10 (5.8) | 0.210 |
| Median time to progression from URI to LRI, days (range) | 7 (3–29) | 8 (3–15) | 5 (5–6) | 13 (5–29) | 0.047 |
| Total LRI (presentation and progression) | 225 (42.7) | 71 (50.7) | 49 (41.2) | 105 (39.2) | 0.076 |
| LRI type e | |||||
| Probable | 178 (79.1) | 57 (80.3) | 43 (87.8) | 78 (74.3) | 0.153 |
| Laboratory‐confirmed | 47 (20.9) | 14 (19.7) | 6 (12.2) | 27 (25.7) | |
| Respiratory viral co‐infection (during ±2 weeks) | |||||
|
Any Rhinovirus |
54 (10.2) | 17 (12.1) | 19 (16.0) | 18 (6.7) | 0.015 |
| 30 (5.7) | 9 (6.4) | 9 (7.6) | 12 (4.5) | 0.437 | |
| Coronavirus (non‐SARS‐CoV‐2) | 10 (1.9) | 4 (2.9) | 3 (2.5) | 3 (1.1) | 0.404 |
| Parainfluenza | 7 (1.3) | 3 (2.1) | 4 (3.4) | 0 (0.0) | 0.018 |
| Human metapneumovirus | 3 (0.6) | 0 (0.0) | 1 (0.8) | 2 (0.7) | 0.576 |
| Adenovirus | 4 (0.8) | 1 (0.7) | 2 (1.7) | 1 (0.4) | 0.392 |
| Nosocomial infection | 34 (6.5) | 15 (10.7) | 10 (8.4) | 9 (3.4) | 0.010 |
| Lymphopenia ( < 200 cells/µL) | 105 (19.9) | 31 (22.1) | 16 (13.4) | 58 (21.6) | 0.131 |
| Neutropenia ( < 500 cells/µL) | 73 (13.9) | 23 (16.4) | 12 (10.1) | 38 (14.2) | 0.330 |
| Lymphopenia and neutropenia | 47 (8.9) | 17 (12.1) | 6 (5.0) | 24 (9.0) | 0.136 |
| Elevated creatinine level ( ≥ 1.2 mg/dL) | 157 (29.8) | 43 (30.7) | 36 (30.3) | 78 (29.1) | 0.937 |
| Hospital admission | |||||
| Any | 340 (64.5) | 84 (60.0) | 80 (67.2) | 176 (65.7) | 0.410 |
| Secondary to RVI | 254 (48.2) | 63 (45.0) | 64 (53.8) | 127 (47.4) | 0.345 |
| ICU admission f | 39 (11.5) | 13 (15.5) | 10 (12.5) | 16 (9.1) | 0.302 |
| Oxygen requirement (maximal) | |||||
| None | 379 (71.9) | 94 (67.2) | 83 (69.8) | 202 (75.4) | 0.179 |
| Nasal cannula | 92 (17.5) | 23 (16.4) | 25 (21.0) | 44 (16.4) | 0.510 |
| Face mask | 5 (0.9) | 1 (0.7) | 1 (0.8) | 3 (1.1) | 0.914 |
| HFNC | 19 (3.6) | 7 (5.0) | 3 (2.5) | 9 (3.4) | 0.540 |
| BiPAP | 12 (2.3) | 6 (4.3) | 3 (2.5) | 3 (1.1) | 0.123 |
| Mechanical ventilation | 20 (3.8) | 9 (6.4) | 4 (3.4) | 7 (2.6) | 0.153 |
| HFNC/BiPAP/mechanical ventilation | 51 (9.7) | 22 (15.7) | 10 (8.4) | 19 (7.1) | 0.017 |
| Antiviral therapy (may overlap) | |||||
| Any therapy | 434 (81.8) | 100 (71.4) | 106 (91.6) | 225 (84.0) | < 0.001 |
| Oral Ribavirin | — | 97 (69.3) | — | — | — |
| Oseltamivir | — | — | 108 (90.8) | — | — |
| Baloxavir | — | — | 9 (7.6) | — | — |
| Peramivir | — | — | 2 (1.7) | — | — |
| Remdesivir | — | — | — | 171 (63.8) | — |
| Nirmatrelvir/ritonavir | — | — | — | 60 (22.4) | — |
| Molnupiravir | — | — | — | 10 (3.7) | — |
| IVIG | 79 (15.0) | 31 (22.1) | 7 (5.9) | 41 (15.3) | 0.001 |
| Antiviral timing from symptom onset g | |||||
| Within 48 h | 139 (32.0) | 27 (27.0) | 30 (27.5) | 82 (36.4) | 0.205 |
| After 48 h | 257 (59.2) | 66 (66.0) | 66 (60.6) | 125 (55.6) | |
| Unknown | 38 (8.8) | 7 (7.0) | 13 (11.9) | 18 (8.0) | |
| 30‐day all‐cause mortality | 31 (5.9) | 13 (9.3) | 9 (7.6) | 9 (3.4) | 0.037 |
| 30‐day RVI‐related mortality | 24 (4.6) | 12 (8.6) | 5 (4.2) | 7 (2.6) | 0.023 |
Note: Data are for 527 viral episodes in 498 patients, with nine episodes excluded due to co‐infection with any two of the three viruses studied.
Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; BiPAP, bilevel positive airway pressure; BiTE, bispecific T‐cell engager; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; HCT, hematopoietic stem cell transplantation; HFNC, high‐flow nasal cannula; HM, hematologic malignancy; ICU, intensive care unit; IVIG, intravenous immunoglobulin; LRI, lower respiratory tract infection; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; RSV, respiratory syncytial virus; RVI, respiratory virus infection; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; SD, standard deviation; SLL, small lymphocytic lymphoma; URI, upper respiratory tract infection.
The one‐way analysis of variance (ANOVA) was used for normally distributed continuous variables, the Kruskal–Wallis test was used for non‐parametric continuous variables, and the Chi‐square test or Fisher's exact test was used for categorical variables.
N = 221.
Only the most recent procedure (allogeneic/autologous HCT, CAR T‐cell therapy, or BiTE therapy) was considered.
N = 325.
N = 225.
N = 340.
N = 434.
Antiviral treatment was administered for 81.8% of viral episodes. Among the 325 patients presented with URI, 251 received antiviral treatment, while 74 did not. A higher proportion of untreated patients were in outpatient settings (82.4% vs. 43.4%, p < 0.001), had an underlying lymphoma diagnosis (29.7% vs. 17.9%, p = 0.027), and were less likely to be lymphopenic at diagnosis (5.4% vs. 20.3%, p = 0.003). In the RSV group, oral ribavirin was administered in 97 of the 140 episodes (69.3%), and in one case, the patient was also treated with an aerosolized formulation of ribavirin. Among the 78 RSV‐infected patients presenting with URIs, 8 of 45 ribavirin‐treated patients (17.8%) experienced progression to LRIs, compared with 1 of 33 (3.0%) in the untreated group. In the influenza group, oseltamivir was administered in 108 (90.8%) patients, including 9 (7.6%) in combination with Baloxavir. Among the 74 influenza‐infected patients presenting with URIs, 4 of 63 oseltamivir‐treated cases (6.3%) progressed to LRIs, with no progression in the untreated group (0/11). In the SARS‐CoV‐2 group, 225 patients (84.0%) received antiviral treatment, comprising 171 (63.8%) who received remdesivir, 60 (22.4%) who received nirmatrelvir and ritonavir, and 10 (3.7%) who received molnupiravir. In addition, 15 patients received more than one type of antiviral treatment during follow‐up. Among the 173 patients infected with SARS–CoV–2 and presenting with URIs, 140 (80.9%) were treated with antivirals. Among patients presenting with URI and receiving antiviral treatment, 10 (7.1%) progressed to LRIs, compared with none of the untreated patients (0/33).
In the subgroup of patients presenting with URI and treated with antivirals, no significant association was observed between the timing of treatment initiation (within 48 h or beyond of symptom onset) and the rate of progression to LRI, except for patients infected with SARS‐CoV‐2 (p = 0.062).
3.2. Risk Factors for LRI
In the RSV group, 44.3% of patients presented with LRIs, and 11.5% of patients with URIs progressed to LRIs within 30 days. When compared to RSV, the rates of LRI at presentation and LRI progression were lower in the influenza (37.8% and 5.4%, respectively) and SARS‐CoV‐2 groups (35.4% and 5.8%, respectively), although the differences were not statistically significant (Table 1). Moreover, in the RSV group, 15.7% of patients required a high‐flow nasal cannula, bilevel positive airway pressure, or mechanical ventilation, compared with 8.4% in the influenza group and 7.1% in the SARS‐CoV‐2 group (p = 0.017). A comparison of the study population based on the site of infection (lower or upper respiratory tract) is presented in Table S1.
In the multivariable analysis for LRI at presentation or progression (Table 2), RSV was associated with a higher LRI risk than SARS‐CoV‐2 (adjusted odds ratio, 1.77 [95% CI, 1.14–2.76]; p = 0.012), as were older age, relapsed or refractory HM (compared with remission), nosocomial infection, and lymphopenia ( < 200 cells/µL).
TABLE 2.
Multivariable analysis (logistic regression model) of risk factors for lower respiratory tract infections.
| Independent predictors | aOR | 95% CI | p value |
|---|---|---|---|
| Age (every 5‐year increase) | 1.13 | 1.07–1.20 | < 0.0001 |
| HM status at RVI diagnosis | < 0.001 | ||
| Remission | Reference | ||
| Relapse/refractory | 2.26 | 1.49–3.43 | < 0.001 |
| Active on first‐line therapy | 1.15 | 0.64–2.05 | 0.6410 |
| Pathogen a | 0.038 | ||
| RSV | 1.77 | 1.14–2.76 | 0.012 |
| Influenza | 1.12 | 0.70–1.78 | 0.720 |
| SARS‐CoV‐2 | Reference | ||
| Nosocomial infection | 3.05 | 1.32–7.03 | 0.009 |
| Lymphopenia ( < 200 cells/µL) | 1.69 | 1.04–2.73 | 0.033 |
Abbreviations: 95% CI, 95% confidence interval; aOR, adjusted odds ratio; HM, hematologic malignancy; RSV, respiratory syncytial virus; RVI, respiratory tract infection; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.
Patients infected with more than one pathogen were excluded from the analysis (N = 9).
3.3. Risk Factors for Hospitalization
Hospitalization rates, either related to RVI or not, were comparable across the three virus groups. Specifically, the hospitalization rates were 60.0% for RSV, 45.0% related to RVI, 67.2% for influenza, 53.8% related to RVI, 65.7% for SARS‐CoV‐2, and 47.4% related to RVI. The differences in these rates were not statistically significant (Table 1).
Several factors were associated with increased hospitalization rates, including older age, male sex, LRI at presentation or progression to LRI, lack of influenza vaccination during the relevant season, HM that is not in remission, lymphopenia, and neutropenia (Table S2).
3.4. Risk Factors for 30‐Day Mortality
In the univariable analysis, RSV infections were associated with a higher 30‐day all‐cause mortality compared to SARS‐CoV‐2 infections (9.3% vs. 3.4%; p = 0.037) (Table 1, Table S3). The Kaplan–Meier curve depicted higher mortality rates for RSV and influenza infections than for SARS‐CoV‐2 (Figure 1).
FIGURE 1.
All‐cause mortality rate within 30 days by pathogen. RSV, respiratory syncytial virus; RVI, respiratory viral infection; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2. Created in BioRender. Shafat, T. (2025) https://BioRender.com/p5rsvvq.
In the multivariable analysis, independent predictors of 30‐day all‐cause mortality (Table 3) included age ≥ 60 years, history of allogeneic HCT, nosocomial infection, and LRI. Importantly, receiving at least three doses of the SARS‐CoV‐2 vaccines was associated with lower rates of 30‐day all‐cause mortality for any of the three viruses than receiving 0–2 doses. Specifically, patients with RSV or influenza infections who received at least three doses of the SARS‐CoV‐2 vaccine had a mortality rate of 4.9% compared to 10.9% in those who received fewer than three doses (p = 0.088). Interestingly, patients who received at least three SARS‐CoV‐2 vaccine doses were more frequently vaccinated against influenza during this season (37.0% vs. 15.7% of patients receiving 0–2 doses; p < 0.001).
TABLE 3.
Multivariable analysis (logistic regression model) of risk factors for 30‐day all‐cause mortality.
| Independent predictors | aOR | 95% CI | p value |
|---|---|---|---|
| Age ≥ 60 years | 3.47 | 1.36–8.81 | 0.009 |
| History of allogeneic HCT | 2.42 | 1.06–5.53 | 0.035 |
| SARS‐CoV‐2 vaccination status | |||
| 0–2 doses | Reference | ||
| ≥ 3 doses | 0.25 | 0.10–0.65 | 0.004 |
| Nosocomial infection | 6.73 | 2.62–17.29 | < 0.0001 |
| Site of infection | |||
| URI | Reference | < 0.0001 | |
| LRI | 14.03 | 3.86–50.97 |
Abbreviations: 95% CI, 95% confidence interval; aOR, adjusted odds ratio; HCT, hematopoietic stem cell transplantation; LRI, lower respiratory tract infection; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; URI, upper respiratory tract infection.
3.5. Subgroup Analysis of HCT and Cellular Therapy Recipients
We performed a subgroup analysis of 297 viral episodes in 275 HCT and cellular therapy recipients. Tables S4 and S5 depict the baseline and clinical characteristics and outcomes, stratified by pathogen or site of infection. Notably, the LRI rate was lower in patients with SARS‐CoV‐2 infection (32.2%) than in those with RSV (48.0%) or influenza (46.4%) infection (p = 0.035), with no significant differences in the 30‐day all‐cause mortality rates.
For allogeneic HCT recipients (n = 157), the median ISI was 3 (range: 0–10) with no significant differences between the three virus groups (Table S4). Higher ISI was associated with an increased incidence of LRI; 22.7% of patients with low‐risk scores (ISI 0–2) experienced LRI, compared to 45.5% with moderate‐risk scores (ISI 3–6), and 68.0% of patients with high‐risk scores (ISI 7–10, p = 0.001). In addition, higher ISI was associated with 30‐day mortality; no patients with low‐risk scores died within 30 days, whereas 6.8% of patients with moderate‐risk and 32.0% of those with high‐risk did ( < 0.001). In the multivariate analysis for LRI (Table 4), RSV (adjusted odds ratio, 2.33 [95% CI, 1.31–4.15]; p = 0.004) and influenza (adjusted odds ratio, 2.25 [95% CI, 1.18–4.28]; p = 0.013) infections were independently associated with greater LRI risk than SARS‐CoV‐2 infections, as were older age, steroid exposure within 30 days of RVI diagnosis, and lymphopenia ( < 200 cells/µL). In the multivariate analysis for 30‐day all‐cause mortality (Table 5), nosocomial infection and LRI were independently associated with an increased risk for mortality.
TABLE 4.
Multivariable analysis (logistic regression model) of risk factors for lower respiratory tract infection among hematopoietic cell transplant or cellular therapy recipients.
| Independent predictors | aOR | 95% CI | p value |
|---|---|---|---|
| Age (every 5‐year increase) | 1.09 | 1.01–1.18 | 0.037 |
| Steroid use within 30 days of RVI diagnosis | 1.66 | 1.01–2.73 | 0.045 |
| Pathogen a | 0.007 | ||
| RSV | 2.33 | 1.31–4.15 | 0.004 |
| Influenza | 2.25 | 1.18–4.28 | 0.013 |
| SARS‐CoV‐2 | Reference | ||
| Lymphopenia ( < 200 cells/µL) | 2.45 | 1.33–4.50 | 0.004 |
Abbreviations: 95% CI, 95% confidence interval; aOR, adjusted odds ratio; HCT, hematopoietic stem cell transplantation; RSV, respiratory syncytial virus; RVI, respiratory tract infection; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.
Patients infected with more than one pathogen were excluded from the analysis (N = 7).
TABLE 5.
Multivariable analysis (logistic regression model) of risk factors for 30‐day all‐cause mortality among hematopoietic cell transplant or cellular therapy recipients.
| Independent predictors | aOR | 95% CI | p value |
|---|---|---|---|
| Nosocomial infection | 5.87 | 1.80–19.11 | 0.003 |
| Site of infection | |||
| URI | Reference | 0.007 | |
| LRI | 48.20 | 2.93–793.33 |
Note: The estimates of the effect sizes of infection site (URI vs. LRI) in the model were inflated because no patients with URIs died within 30 days of infection.
Abbreviations: 95% CI, 95% confidence interval; aOR, adjusted odds ratio; HCT, hematopoietic stem cell transplantation; LRI, lower respiratory tract infection; URI, upper respiratory tract infection.
4. Discussion
In our cohort of patients with HMs infected with RSV, influenza, or SARS‐CoV‐2 during the 2023–2024 RV season, we observed high rates of morbidity, such as LRI (43%) and hospitalization (65%, with 12% having subsequent intensive care unit admission), as well as a 6% overall 30‐day all‐cause mortality. RSV infection was associated with a higher risk for LRI compared to SARS‐CoV‐2, while for recipients of HCT and cellular therapy, both RSV and influenza infections had a greater risk for LRI than SARS‐CoV‐2. In addition, patients with RSV or influenza infections experienced higher 30‐day mortality than those infected with SARS‐CoV‐2.
The significant impact of RSV infection, compared to other respiratory viruses, in patients with HMs was previously reported [10, 21, 22, 23]. The results of a large population‐based, retrospective, multicenter US study presented at the 2024 American Society of Clinical Oncology meeting [11] reported worse outcomes for RSV than for influenza or SARS‐CoV‐2 infections in terms of progression to LRI, hospitalization, and respiratory failure in more than 6000 patients with HMs during the 2022–2023 period. On the other hand, the decline in mortality since the beginning of the pandemic among patients with HMs infected by SARS‐CoV‐2 has been previously described [24, 25]. Better outcomes, including survival, are attributed to the widespread use of SARS‐CoV‐2 vaccines, effective antiviral therapies, and the emergence of less virulent circulating subvariants of SARS‐CoV‐2. In contrast, preventive and treatment options for RSV in patients with HMs are limited. Unfortunately, recent advancements in anti‐RSV prevention, including the approval of anti‐RSV vaccines for adults, have not been well studied in immunocompromised patients [13, 14]. With the limited data and the questionable efficacy of ribavirin for management of RSV infections in immunocompromised patients underscore the unmet need for different therapeutic options to be properly investigated in this patient population. For influenza infections, antiviral agents, such as oseltamivir, are effective and accessible, and may prevent progression to LRI and mortality in HCT recipients [26] and patients with leukemia [27]. On the other hand, the overall effectiveness of the influenza vaccine is only 30%–50% in the adult population [28] and is further reduced in patients with HMs [29]. In addition, patients with HMs have low vaccination uptake [23], as reflected in our cohort (25%); however, it is possible that some of these patients were not eligible for vaccination due to recent HCT or concurrent chemotherapy. Effective and accessible preventive and therapeutic strategies for RSV, as well as improving influenza vaccine efficacy and uptake in this patient population, constitute a significant unmet need and should be underscored.
Other identified risk factors for LRI in our cohort were previously reported, including older age [30], recent systemic steroid exposure [23, 31], malignancy status, nosocomial infection [32], and lymphopenia [22, 23, 30].
In addition, LRI emerged as the most significant risk factor for 30‐day all‐cause mortality in both the overall cohort of patients with HMs and the subgroup of recipients of HCT and cellular therapy, with the caveat that the mortality models showed inflated estimates of the effect size related to the site of infection (LRI vs. URI), along with wide confidence intervals. This could be partly explained by the limited number of deaths in the URI group, while no deaths were reported among the subgroup of recipients of HCT and cellular therapy with URI. The association between LRI and mortality is well described [10, 23, 33], highlighting the importance of early, prompt diagnosis and treatment at the URI stage to prevent progression to LRIs.
We found that administering three or more doses of the SARS‐CoV‐2 vaccines reduced the 30‐day all‐cause mortality rate. Several published studies of patients with HMs reported that SARS–CoV‐2 vaccines were protective against COVID‐19‐related hospitalization and death [34, 35]. In addition, in the general population, an association between SARS–CoV–2 vaccination and a reduced mortality risk from non‐COVID‐19 causes has also been reported [36]. As mentioned above, those who were appropriately vaccinated against SARS‐CoV‐2 were more frequently vaccinated against influenza in our cohort, although the overall rate of anti‐influenza vaccination was low. Therefore, we hypothesize that the vaccination status for SARS‐CoV‐2 may indicate a higher overall acceptance of vaccines in general and possibly greater awareness of infection prevention measures, prompt medical evaluation, and diagnosis.
Antiviral treatment was administered in most patients in our cohort for the three viruses. While oseltamivir is recommended for all patients with HMs and influenza infections [37], the treatment of COVID‐19 with antivirals in this patient population is mainly based on the severity of the infection, with an emphasis on early treatment initiation in these patients [38, 39]. Similarly, for RSV infection, ribavirin is recommended for patients with HMs or in HCT and cellular therapy recipients who are at risk for progression and mortality [15, 16]. In our cohort, we postulate that patients who were not treated with antivirals at the URI stage and recovered uneventfully were at low risk for progression to LRI based on our institutional practices.
Our study has some limitations. First, most patients presented primarily with LRI, and thus, we could not analyze the risk factors for progression from URI in these patients. Second, our study included patients tested at our institution in outpatient and inpatient settings, potentially missing infected individuals diagnosed at other locations or mildly symptomatic patients who were not tested. Third, because our study was based on a single‐center experience, the findings may not be generalizable to broader populations or patients with cancer with different underlying malignancies. Fourth, the retrospective nature of our study limited our ability to account for all potential confounding factors, although we applied analyses to adjust for known potential confounders.
In summary, we described our experience during the 2023–2024 RV season at our institution, focusing on the outcomes of patients with HMs diagnosed with RVIs, such as RSV, influenza, and SARS‐CoV‐2. Among these viruses, SARS‐CoV‐2 was the most commonly diagnosed, and it was associated with better outcomes in terms of LRI and 30‐day mortality rates. In contrast, RSV was associated with the worst outcomes. These findings highlight the urgent need to develop improved prevention and treatment strategies for all RVIs, and underscore current ones, such as already available vaccines for RSV and Influenza, as poor outcomes related to most respiratory viruses continue to be a major concern.
Author Contributions
Study conceptualization and design: Amy Spallone, Tali Shafat, and Roy F. Chemaly. Data extraction, collection, and validation: Tali Shafat and Jennifer Jackson. Analysis: Ying Jiang and Tali Shafat. Data interpretation: Tali Shafat, Amy Spallone, and Roy F. Chemaly. Writing the original draft: Tali Shafat. Reviewing and editing the manuscript: Amy Spallone, Lior Nesher, and Roy F. Chemaly. Supervision of the work: Roy F. Chemaly. Reviewing the manuscript and approving the final version: All authors.
Conflicts of Interest
Fareed Khawaja received research funding from Eurofins Viracor and SymBio Pharmaceuticals, which was paid to the institution. Lior Nesher received research funding from Pfizer and F2G; honoraria for educational lectures from Pfizer, GSK, MSD, Moderna, AstraZeneca, and Takeda; and participation in advisory boards for GSK, MSD, Medison, and AstraZeneca. Roy F. Chemaly is a consultant and advisor for ADMA Biologics, Merck/MSD, Takeda, Shionogi, Gilead, AiCuris, Astellas, Tether, Oxford Immunotec, Karius, Moderna, InflaRX, Pfizer, Invivyd, Biotest, Assembly Bio, IntegerBio, Eurofins Viracor, Symbio, and Ansun Biopharma. He also received research grants paid to his institution from Merck, Karius, AiCuris, Ansun Biopharma, Takeda, Genentech, and Eurofins Viracor. The other authors declare no conflicts of interest.
Supporting information
Supplementary Figure 1: Weekly overall hospital admissions (%) by respiratory virus (2021‐2024) COVID‐19, coronavirus disease 2019; RSV, respiratory syncytial virus. The black arrow indicates the 2023‐2024 respiratory viral season. Created in BioRender. Shafat, T. (2025) https://BioRender.com/b93oa80. Supplementary Table 1: Baseline Characteristics and Clinical Outcomes of Patients with Hematologic Malignancies and Respiratory Viral Infection by Site of Infection. Supplementary Table 2: Baseline Characteristics and Clinical Outcomes of Patients with Hematologic Malignancies and Respiratory Viral Infections by Hospital Admission. Supplementary Table 3: Baseline Characteristics and Clinical Outcomes of Patients with Hematologic Malignancies and Respiratory Viral Infections by 30‐Day Survival. Supplementary Table 4: Baseline Characteristics and Clinical Outcomes Among Hematopoietic Cell Transplant or Cellular Therapy Recipients with Respiratory Viral Infections Stratified by Pathogen. Supplementary Table 5: Baseline Characteristics and Clinical Outcomes of Patients with Hematologic Malignancies and Respiratory Viral Infections by Site of Infection Among Hematopoietic Cell Transplant or Cellular Therapy Recipients.
Visual Abstract
Acknowledgments
We thank Don Norwood, Scientific Editor in the Research Medical Library at the University of Texas MD Anderson Cancer Center, for editing this article. An abstract based on these results was presented at the fifth Symposium on Infectious Diseases in the Immunocompromised Host, held in May 2025, in Seattle, WA, USA. Furthermore, an abstract based on the subgroup analysis of HCT and cellular therapy recipients was presented as a poster at the 2025 Tandem Meetings in Honolulu, Hawaii, in February 2025.
Shafat T., Spallone A., Khawaja F., et al. “Respiratory Syncytial Virus Exceeded SARS‐CoV‐2 and Influenza in Lower Respiratory Infection and Mortality Rates Among Patients With Hematologic Malignancies During the 2023–2024 Respiratory Virus Season.” Transplant Infectious Disease 27, no. 6 (2025): e70113. 10.1111/tid.70113
Funding: The authors received no specific funding for this work.
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Associated Data
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Supplementary Materials
Supplementary Figure 1: Weekly overall hospital admissions (%) by respiratory virus (2021‐2024) COVID‐19, coronavirus disease 2019; RSV, respiratory syncytial virus. The black arrow indicates the 2023‐2024 respiratory viral season. Created in BioRender. Shafat, T. (2025) https://BioRender.com/b93oa80. Supplementary Table 1: Baseline Characteristics and Clinical Outcomes of Patients with Hematologic Malignancies and Respiratory Viral Infection by Site of Infection. Supplementary Table 2: Baseline Characteristics and Clinical Outcomes of Patients with Hematologic Malignancies and Respiratory Viral Infections by Hospital Admission. Supplementary Table 3: Baseline Characteristics and Clinical Outcomes of Patients with Hematologic Malignancies and Respiratory Viral Infections by 30‐Day Survival. Supplementary Table 4: Baseline Characteristics and Clinical Outcomes Among Hematopoietic Cell Transplant or Cellular Therapy Recipients with Respiratory Viral Infections Stratified by Pathogen. Supplementary Table 5: Baseline Characteristics and Clinical Outcomes of Patients with Hematologic Malignancies and Respiratory Viral Infections by Site of Infection Among Hematopoietic Cell Transplant or Cellular Therapy Recipients.
Visual Abstract