Impact of RSV Infection in Transplant and Immunocompromised Population: Incidence and Co-Infections: Retrospective Analysis of a Single Centre
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Statistics
3. Results
3.1. Incidence of RSV Infection
3.2. Viral Coinfections
3.3. Bacterial Coinfections
3.4. Fungal Coinfections
3.5. Therapy Efficacy
4. Discussion
- The incidence of RSV in the immunocompromised patients was higher than in the control population (p = 0.01), especially in symptomatic lung transplant patients (p < 0.01) and in bone marrow transplant patients (p < 0.01)
- Viral coinfections: a high prevalence of influenza virus was found in patients with RSV compared to patients without RSV (p < 0.01). These data were also confirmed in transplant recipients (p < 0.01)
- Bacterial coinfections: a high prevalence of S. pneumoniae, M. pneumoniae, and Nocardia spp. was found in patients with RSV compared to patients without RSV (p < 0.01)
- Mycotic coinfections: a high prevalence of Aspergillus spp. was found in patients with RSV compared to patients without RSV (p < 0.01), which was also present in the transplant population (p = 0.048)
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
BAL | Bronchoalveolar lavage |
RSV | Respiratory syncytial virus |
CLAD | Chronic lung allograft dysfunction |
SOT | Solid organ transplant |
HCT | Hemopoietic cell transplant |
IFI | Invasive fungal infection |
RVI | Respiratory virus infection |
IAV | Influenza A virus |
HVP | Hybrid virus particle |
LRTI | Lower respiratory tract infection |
References
- Leard, L.E.; Holm, A.M.; Valapour, M.; Glanville, A.R.; Attawar, S.; Aversa, M.; Campos, S.V.; Christon, L.M.; Cypel, M.; Dellgren, G.; et al. Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation. J. Heart Lung Transplant. 2021, 40, 1349–1379. [Google Scholar] [CrossRef] [PubMed]
- Milstone, A.P.; Brumble, L.M.; Barnes, J.; Estes, W.; Loyd, J.E.; Pierson, R.N.; Dummer, S. A Single-Season Prospective Study of Respiratory Viral Infections in Lung Transplant Recipients. Eur. Respir. J. 2006, 28, 131–137. [Google Scholar] [CrossRef] [PubMed]
- de Zwart, A.; Riezebos-Brilman, A.; Lunter, G.; Vonk, J.; Glanville, A.R.; Gottlieb, J.; Permpalung, N.; Kerstjens, H.; Alffenaar, J.-W.; Verschuuren, E. Respiratory Syncytial Virus, Human Metapneumovirus, and Parainfluenza Virus Infections in Lung Transplant Recipients: A Systematic Review of Outcomes and Treatment Strategies. Clin. Infect. Dis. 2022, 74, 2252–2260. [Google Scholar] [CrossRef]
- Clausen, E.S.; Zaffiri, L. Infection prophylaxis and management of viral infection. Ann. Transl. Med. 2020, 8, 415. [Google Scholar] [CrossRef] [PubMed]
- Mahan, L.D.; Points, A.; Mohanka, M.R.; Bollineni, S.; Joerns, J.; Kaza, V.; La Hoz, R.M.; Gao, A.; Zhang, S.; Torres, F.; et al. Characteristics and Outcomes Among Lung Transplant Patients With Respiratory Syncytial Virus Infection. Transplant. Infect. Dis. 2021, 23, e13661. [Google Scholar] [CrossRef]
- Palmer, S.M.; Henshaw, N.G.; Howell, D.N.; Miller, S.E.; Davis, R.D.; Tapson, V.F. Community Respiratory Viral Infection in Adult Lung Transplant Recipients. Chest 1998, 113, 944–950. [Google Scholar] [CrossRef]
- Tejada, S.; Martinez-Reviejo, R.; Karakoc, H.N.; Peña-López, Y.; Manuel, O.; Rello, J. Ribavirin for Treatment of Subjects with Respiratory Syncytial Virus-Related Infection: A Systematic Review and Meta-Analysis. Adv. Ther. 2022, 39, 4037–4051. [Google Scholar] [CrossRef]
- Ison, M.G.; Hirsch, H.H. Community-Acquired Respiratory Viruses in Transplant Patients: Diversity, Impact, Unmet Clinical Needs. Clin. Microbiol. Rev. 2019, 32, e00042-19. [Google Scholar] [CrossRef]
- Papi, A.; Ison, M.G.; Langley, J.M.; Lee, D.-G.; Leroux-Roels, I.; Martinon-Torres, F.; Schwarz, T.F.; van Zyl-Smit, R.N.; Campora, L.; Dezutter, N.; et al. Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults. N. Engl. J. Med. 2023, 388, 595–608. [Google Scholar] [CrossRef]
- Walsh, E.E.; Marc, G.P.; Zareba, A.M.; Falsey, A.R.; Jiang, Q.; Patton, M.; Polack, F.P.; Llapur, C.; Doreski, P.A.; Ilangovan, K.; et al. Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults. N. Engl. J. Med. 2023, 388, 1465. [Google Scholar] [CrossRef]
- Wilson, E.; Goswami, J.; Baqui, A.H.; Doreski, P.A.; Perez-Marc, G.; Zaman, K.; Monroy, J.; Duncan, C.J.; Ujiie, M.; Rämet, M.; et al. Efficacy and Safety of an mRNA-Based RSV PreF Vaccine in Older Adults. N. Engl. J. Med. 2023, 389, 2233. [Google Scholar] [CrossRef] [PubMed]
- Cantral, D.E.; Tape, T.G.; Reed, E.C.; Spurzem, J.R.; Rennard, S.I.; Thompson, A.B. Quantitative culture of bronchoalveolar lavage fluid for the diagnosis of bacterial pneumonia. Am. J. Med. 1993, 95, 601–607. [Google Scholar] [CrossRef] [PubMed]
- Bailey, E.S.; Zemke, J.N.; Choi, J.Y.; Gray, G.C. A Mini-Review of Adverse Lung Transplant Outcomes Associated with Respiratory Viruses. Front. Immunol. 2019, 10, 2861. [Google Scholar] [CrossRef] [PubMed]
- Manuel, O.; Estabrook, M.; American Society of Transplantation Infectious Diseases Community of Practice. RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin. Transplant. 2019, 33, e13511. [Google Scholar] [CrossRef]
- Solidoro, P.; Curtoni, A.; Costa, C.; De Rosa, F.G.; Bondi, A.; Sidoti, F.; Shbaklo, N.; Patrucco, F.; Favre, D.; Zanotto, E.; et al. The Epidemiology of Respiratory Syncytial Virus and the Impact of the COVID-19 Pandemic in a Retrospective Evaluation. Pathogens 2025, 4, 375. [Google Scholar] [CrossRef]
- Branche, A.R.; Saiman, L.; E Walsh, E.; Falsey, A.R.; Sieling, W.D.; Greendyke, W.; Peterson, D.R.; Vargas, C.Y.; Phillips, M.; Finelli, L. Incidence of Respiratory Syncytial Virus Infection Among Hospitalized Adults, 2017–2020. Clin. Infect. Dis. 2022, 74, 1004–1011. [Google Scholar] [CrossRef]
- Testaert, H.; Bouet, M.; Valour, F.; Gigandon, A.; Lafon, M.-E.; Philit, F.; Sénéchal, A.; Casalegno, J.-S.; Blanchard, E.; Le Pavec, J.; et al. Incidence, management and outcome of respiratory syncytial virus infection in adult lung transplant recipients: A 9-year retrospective multicenter study. Clin. Microbiol. Infect. 2021, 27, 897–903. [Google Scholar] [CrossRef]
- Permpalung, N.; Thaniyavarn, T.; Saullo, J.L.; Arif, S.; Miller, R.A.; Reynolds, J.M.; Alexander, B.D. Oral and Inhaled Ribavirin Treatment for Respiratory Syncytial Virus Infection in Lung Transplant Recipients. Transplantation 2020, 104, 1280–1286. [Google Scholar] [CrossRef]
- Peghin, M.; Hirsch, H.H.; Len, Ó.; Codina, G.; Berastegui, C.; Sáez, B.; Solé, J.; Cabral, E.; Solé, A.; Zurbano, F.; et al. Epidemiology and Immediate Indirect Effects of Respiratory Viruses in Lung Transplant Recipients: A 5-Year Prospective Study. Am. J. Transplant. 2016, 17, 1304–1312. [Google Scholar] [CrossRef]
- Fisher, C.E.; Preiksaitis, C.M.; Lease, E.D.; Edelman, J.; Kirby, K.A.; Leisenring, W.M.; Raghu, G.; Boeckh, M.; Limaye, A.P. Symptomatic Respiratory Virus Infection and Chronic Lung Allograft Dysfunction. Clin. Infect. Dis. 2016, 62, 313–319. [Google Scholar] [CrossRef]
- Kramer, S.C.; Pirikahu, S.; Casalegno, J.-S.; de Cellès, M.D. Characterizing the interactions between influenza and respiratory syncytial viruses and their implications for epidemic control. Nat. Commun. 2024, 15, 10066. [Google Scholar] [CrossRef] [PubMed]
- Haney, J.; Vijayakrishnan, S.; Streetley, J.; Dee, K.; Goldfarb, D.M.; Clarke, M.; Mullin, M.; Carter, S.D.; Bhella, D.; Murcia, P.R. Coinfection by influenza A virus and respiratory syncytial virus produces hybrid virus particles. Nat. Microbiol. 2022, 7, 1879–1890. [Google Scholar] [CrossRef] [PubMed]
- Waterlow, N.R.; Kleynhans, J.; Wolter, N.; Tempia, S.; Eggo, R.M.; Hellferscee, O.; Lebina, L.; Martinson, N.; Wagner, R.G.; Moyes, J.; et al. Transient Increased Risk of Influenza Infection Following RSV Infection in South Africa: Findings From the PHIRST Study, South Africa, 2016–2018. BMC Med. 2023, 21, 441. [Google Scholar] [CrossRef] [PubMed]
- Pott, H.; LeBlanc, J.J.; ElSherif, M.S.; Hatchette, T.F.; McNeil, S.A.; Andrew, M.K.; on behalf of the Serious Outcomes Surveillance (SOS) Network of the Canadian Immunization Research Network (CIRN). Clinical features and outcomes of influenza and RSV coinfections: A report from Canadian immunization research network serious outcomes surveillance network. BMC Infect. Dis. 2024, 24, 147. [Google Scholar] [CrossRef]
- Walzl, G.; Tafuro, S.; Moss, P.; Openshaw, P.J.; Hussell, T. Influenza virus lung infection protects from respiratory syncytial virus-induced immunopathology. J. Exp. Med. 2000, 192, 1317–1326. [Google Scholar] [CrossRef]
- Drori, Y.; Jacob-Hirsch, J.; Pando, R.; Glatman-Freedman, A.; Friedman, N.; Mendelson, E.; Mandelboim, M. Influenza A Virus Inhibits RSV Infection via a Two-Wave Expression of IFIT Proteins. Viruses 2020, 12, 1171. [Google Scholar] [CrossRef]
- Czerkies, M.; Kochańczyk, M.; Korwek, Z.; Prus, W.; Lipniacki, T.; Williams, B.R.G. Respiratory Syncytial Virus Protects Bystander Cells Against Influenza a Virus Infection by Triggering Secretion of Type I and Type III Interferons. Nat. Commun. 2024, 15, 10066. [Google Scholar] [CrossRef]
- Tian, J.; Liu, C.; Wang, X.; Zhang, L.; Zhong, G.; Huang, G.; Wang, H.; Hu, H.; Gong, L.; Liu, D. Comparative analysis of clinical features of lower respiratory tract infection with respiratory syncytial virus and influenza virus in adults: A retrospective study. BMC Pulm. Med. 2023, 23, 350. [Google Scholar] [CrossRef]
- Besteman, S.B.; Bogaert, D.; Bont, L.; Mejias, A.; Ramilo, O.; Weinberger, D.M.; Dagan, R. Interactions between respiratory syncytial virus and Streptococcus pneumoniae in the pathogenesis of childhood respiratory infections: A systematic review. Lancet Respir. Med. 2024, 12, 915–932. [Google Scholar] [CrossRef]
- Wiseman, D.J.; Thwaites, R.S.; Ritchie, A.I.; Finney, L.; Macleod, M.; Kamal, F.; Shahbakhti, H.; van Smoorenburg, L.H.; Kerstjens, H.A.; Wildenbeest, J.; et al. Respiratory Syncytial Virus-related Community Chronic Obstructive Pulmonary Disease Exacerbations and Novel Diagnostics: A Binational Prospective Cohort Study. Am. J. Respir. Crit. Care Med. 2024, 210, 994–1001. [Google Scholar] [CrossRef]
- Permpalung, N.; Liang, T.; Gopinath, S.; Bazemore, K.; Mathew, J.; Ostrander, D.; Durand, C.M.; Shoham, S.; Zhang, S.X.; Marr, K.A.; et al. Invasive fungal infections after respiratory viral infections in lung transplant recipients are associated with lung allograft failure and chronic lung allograft dysfunction within 1 year. J. Heart Lung Transplant. 2023, 42, 953–963. [Google Scholar] [CrossRef] [PubMed]
- de Zwart, A.E.; Riezebos-Brilman, A.; Alffenaar, J.W.; van den Heuvel, E.R.; Gan, C.T.; van der Bij, W.; Kerstjens, H.A.; Verschuuren, E.A. Evaluation of 10 years of parainfluenza virus, human metapneumovirus, and respiratory syncytial virus infections in lung transplant recipients. Am. J. Transplant. 2020, 20, 3529–3537. [Google Scholar] [CrossRef] [PubMed]
- Martín-Cerezuela, M.; Cuéllar-Monreal, M.J.; Monte-Boquet, E.; Solé-Jover, A.; Poveda-Andrés, J.L. Oral Ribavirin for Treatment of Respiratory Syncytial Virus in Lung Transplantation Recipients. Transplant. Proc. 2021, 53, 2702–2705. [Google Scholar] [CrossRef] [PubMed]
Total | RSV+ | p vs. Control | |
---|---|---|---|
Control population | 460 | 7 1.5% | |
Immunocompromised | 802 | 33 4.1% | 0.01 |
Transplant recipients | 466 | 24 5.1% | <0.01 |
Lung transplant recipients | 305 | 11 3.6% | ns |
Symptomatic lung transplant recipients | 219 | 11 5% | <0.01 |
Surveillance lung transplant recipients | 86 | / / | / |
Other solid organs transplant recipients | 80 | 2 2.5% | ns |
Hematopoietic cells transplant recipients | 81 | 11 13.6% | <0.01 |
Oncology | 350 | 9 2.6% | ns |
Solid organ malignancy | 80 | 1 1.2% | ns |
Hematologic malignancy | 270 | 8 3% | ns |
Test for Other Viruses | Test for CMV | Test for Influenza | |||||||
---|---|---|---|---|---|---|---|---|---|
Neg | POS | p | Neg | Pos | p | Neg | Pos | p | |
Total population, n | 835 | 441 | ns | 1146 | 130 | ns | 1232 | 44 | 0.001 |
Positive test for RSV, n (%) | 22 (2.6) | 17 (3.8) | 33 (2.9) | 6 (4.6) | 33 (2.7) | 6 (13.6) | |||
Immunocompromised, n | 512 | 276 | ns | 690 | 98 | ns | 759 | 29 | 0.001 |
Positive test for RSV, n (%) | 18 (3.6) | 14 (5.1) | 27 (3.9) | 5 (5.1) | 27 (3.5) | 5 (17.2) | |||
Transplant, n | 277 | 179 | ns | 377 | 79 | ns | 444 | 12 | 0.001 |
Positive test for RSV, n (%) | 12 (4.5) | 11 (6.5) | 18 (4.8) | 5 (6.3) | 19 (4.3) | 4 (33.3) | |||
Lung transplant, n | 183 | 116 | ns | 239 | 60 | ns | / | / | / |
Positive test for RSV, n (%) | 5 (2.7) | 5 (4.3) | 7 (2.9) | 3 (5) | |||||
Symptomatic lung tx, n | 138 | 76 | ns | 177 | 37 | ns | / | / | / |
Positive test for RSV, n (%) | 5 (3.6) | 5 (6.6) | 7 (3.9) | 3 (8.1) | |||||
Surveillance lung tx, n | / | / | / | / | / | / | / | / | / |
Positive test for RSV, n (%) | |||||||||
Other solid organs tx, n | / | / | / | / | / | / | / | / | / |
Positive test for RSV, n (%) | |||||||||
Hematopoietic cells tx, n | 47 | 32 | ns | 69 | 10 | ns | 73 | 6 | 0.001 |
Positive test for RSV, n (%) | 5 (10.6) | 6 (18.7) | 9 (13.0) | 2 (20.0) | 7 (9.6) | 4 (66.6) | |||
Oncologic, n | 238 | 107 | ns | / | / | / | 327 | 18 | ns |
Positive test for RSV, n (%) | 6 (2.5) | 3 (2.9) | 8 (4.4) | 1 (5.5) | |||||
Solid organ malign, n | / | / | / | / | / | / | / | / | / |
Positive test for RSV, n (%) | |||||||||
Hematologic malign, n | 189 | 78 | ns | / | / | / | 251 | 16 | ns |
Positive test for RSV, n (%) | 5 (2.6) | 3 (3.8) | 7 (2.8) | 1 (6.2) |
Test for Bacteria | Test for S. pneumoniae | |||||
---|---|---|---|---|---|---|
Neg | Pos | p | Neg | Pos | p | |
Total population | 656 | 363 | ns | 1010 | 9 | 0.001 |
Positive test for RSV, n (%) | 16 (2.4) | 17 (4.7) | 31 (3.1) | 2 (22.2) | ||
Immunocompromised | 444 | 231 | ns | 671 | 4 | 0.041 |
Positive test for RSV, n (%) | 15 (3.4) | 14 (6.1) | 28 (4.2) | 1 (25) | ||
Transplant | 239 | 156 | ns | 392 | 3 | 0.030 |
Positive test for RSV, n (%) | 12 (5.0) | 9 (5.8) | 20 (5.1) | 1 (33.3) | ||
Lung transplant | 152 | 110 | ns | / | / | / |
Positive test for RSV, n (%) | 5 (3.3) | 4 (3.6) | ||||
Symptomatic lung tx | 95 | 83 | ns | / | / | / |
Positive test for RSV, n (%) | 5 (5.3) | 4 (4.8) | ||||
Surveillance lung tx | / | / | / | / | / | / |
Positive test for RSV, n (%) | ||||||
Other solid organs tx | / | / | / | / | / | / |
Positive test for RSV, n (%) | ||||||
Hematopoietic cells tx | 55 | 19 | ns | / | / | / |
Positive test for RSV, n (%) | 6 (10.9) | 5 (26.3) | ||||
Oncologic | 214 | 77 | 0.02 | / | / | / |
Positive test for RSV, n (%) | 3 (1.4) | 5 (6.5) | ||||
Solid organ malign. | / | / | / | / | / | / |
Positive test for RSV, n (%) | ||||||
Hematologic malign. | 179 | 54 | 0.03 | / | / | / |
Positive test for RSV, n (%) | 3 (1.7) | 4 (7.4) |
Test for Nocardia | Test for M. pneumoniae | |||||
---|---|---|---|---|---|---|
Neg | Pos | p | Neg | Pos | p | |
Total population | 1016 | 3 | 0.003 | 1015 | 4 | 0.006 |
Positive test for RSV, n (%) | 31 (3.0) | 2 (66.7) | 31 (3.0) | 2 (50.0) | ||
Immunocompromised | 672 | 3 | 0.005 | / | / | / |
Positive test for RSV, n (%) | 27 (4.0) | 2 (66.6) | ||||
Transplant | 392 | 3 | 0.01 | / | / | / |
Positive test for RSV, n (%) | 19 (4.8) | 2 (66.6) | ||||
Lung transplant | 260 | 2 | ns | / | / | / |
Positive test for RSV, n (%) | 8 (3.1) | 1 (50.0) | ||||
Symptomatic lung tx | / | / | / | / | / | / |
Positive test for RSV, n (%) | ||||||
Surveillance lung tx | / | / | / | / | / | / |
Positive test for RSV, n (%) | ||||||
Other solid organ tx | / | / | / | / | / | / |
Positive test for RSV, n (%) | ||||||
Hematopoietic cells tx | / | / | / | / | / | / |
Positive test for RSV, n (%) | ||||||
Oncologic | / | / | / | / | / | / |
Positive test for RSV, n (%) | ||||||
Solid organs malign. | / | / | / | / | / | / |
Positive test for RSV, n (%) | ||||||
Hematologic malign. | / | / | / | / | / | / |
Positive test for RSV, n (%) |
Test for Aspergillus | |||
---|---|---|---|
Neg | Pos | p | |
Total population | 976 | 43 | 0.001 |
Positive test for RSV, n (%) | 28 (2.9) | 5 (11.6) | |
Immunocompromised | 639 | 36 | 0.038 |
Positive test for RSV, n (%) | 25 (3.9) | 4 (11.1) | |
Transplant | 375 | 20 | 0.048 |
Positive test for RSV, n (%) | 18 (4.8) | 3 (15.0) | |
Lung transplant | / | / | / |
Positive test for RSV, n (%) | |||
Symptomatic lung tx | / | / | / |
Positive test for RSV, n (%) | |||
Surveillance lung tx | / | / | / |
Positive test for RSV, n (%) | |||
Other solid organ tx | / | / | / |
Positive test for RSV, n (%) | |||
Hematopoietic cells tx | 68 | 6 | ns |
Positive test for RSV, n (%) | 9 (13.2) | 2 (33.3) | |
Oncologic | 274 | 17 | ns |
Positive test for RSV, n (%) | 7 (2.5) | 1 (5.9) | |
Solid organs malign. | / | / | / |
Positive test for RSV, n (%) | |||
Hematologic malign. | 219 | 14 | ns |
Positive test for RSV, n (%) | 6 (2.7) | 1 (7.1) |
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Solidoro, P.; Curtoni, A.; Minuto, S.; Shbaklo, N.; De Rosa, F.G.; Bondi, A.; Sidoti, F.; Patrucco, F.; Zanotto, E.; Corcione, S.; et al. Impact of RSV Infection in Transplant and Immunocompromised Population: Incidence and Co-Infections: Retrospective Analysis of a Single Centre. J. Clin. Med. 2025, 14, 4803. https://doi.org/10.3390/jcm14134803
Solidoro P, Curtoni A, Minuto S, Shbaklo N, De Rosa FG, Bondi A, Sidoti F, Patrucco F, Zanotto E, Corcione S, et al. Impact of RSV Infection in Transplant and Immunocompromised Population: Incidence and Co-Infections: Retrospective Analysis of a Single Centre. Journal of Clinical Medicine. 2025; 14(13):4803. https://doi.org/10.3390/jcm14134803
Chicago/Turabian StyleSolidoro, Paolo, Antonio Curtoni, Sara Minuto, Nour Shbaklo, Francesco Giuseppe De Rosa, Alessandro Bondi, Francesca Sidoti, Filippo Patrucco, Elisa Zanotto, Silvia Corcione, and et al. 2025. "Impact of RSV Infection in Transplant and Immunocompromised Population: Incidence and Co-Infections: Retrospective Analysis of a Single Centre" Journal of Clinical Medicine 14, no. 13: 4803. https://doi.org/10.3390/jcm14134803
APA StyleSolidoro, P., Curtoni, A., Minuto, S., Shbaklo, N., De Rosa, F. G., Bondi, A., Sidoti, F., Patrucco, F., Zanotto, E., Corcione, S., Boffini, M., Marro, M., Costa, C., & Rinaldo, R. F. (2025). Impact of RSV Infection in Transplant and Immunocompromised Population: Incidence and Co-Infections: Retrospective Analysis of a Single Centre. Journal of Clinical Medicine, 14(13), 4803. https://doi.org/10.3390/jcm14134803