Oral shedding of human herpesviruses and cytokine profiles in children and adolescents undergoing chemotherapy

Authors

DOI:

https://doi.org/10.5327/2525-5711.467

Keywords:

Cytokines, Saliva, Cancer survivors, Oral shedding, Human herpesviruses

Abstract

Objective: To characterize oral shedding of human herpesviruses (HHVs) and their association with salivary inflammatory cytokines in children and adolescents undergoing chemotherapy. Methods: This cross-sectional study included 65 participants: 39 in the study group (SG) and 26 in the control group (CG). Unstimulated saliva was analyzed by PCR for viral detection and quantification, and cytokines levels ((IL-4, IL-6, IL-8, IL-10, IFN-γ, and TNF-α) were measured using the Luminex® platform. Descriptive, comparative, and correlation analyses were performed (p<0.05). Results: In the SG, the most frequently detected viruses were HHV-7, HHV-6, EBV, and CMV. The HHV-7 viral load was significantly greater in the SG than in the CG (6.5 vs. 5.8 cp/mL; p = 0.0288). Only IL-4 differed significantly, with higher levels in the SG (8.4 vs. 7.2 pg/mL; p=0.0374). Weak correlations were found between CMV and IL-6 (r=0.34; p=0.0095) and between HHV-6 and TNF-α (r=–0.33; p=0.0125). Conclusion: Chemotherapy was associated with increased HHV-7 viral load and IL-4 levels, suggesting possible alterations in the oral immune environment, even in the absence of clinical manifestations. Overall, viral load had minimal influence on salivary inflammatory cytokines.

Author Biographies

Wallena Albuquerque da Cunha, Universidade de São Paulo, School of Dentistry, Department of Stomatology – São Paulo (SP), Brazil.

PhD, Department of Stomatology, School of Dentistry, University of São Paulo, SP, Brazil. https://orcid.org/0000-0002-3219-1273

Patricia Pinheiro Shibutani, Universidade de São Paulo, School of Dentistry, Department of Stomatology – São Paulo (SP), Brazil.

MSc student, Department of Stomatology, School of Dentistry, University of São Paulo, SP, Brazil. https://orcid.org/0000-0002-7115-7887



Fabiana Martins e Martins de Oliveira , Universidade de São Paulo, School of Dentistry, Department of Stomatology – São Paulo (SP), Brazil.

Full Professor, Department of Stomatology, School of Dentistry, University of São Paulo, SP, Brazil. https://orcid.org/0000-0002-4352-7959  



Luiz Alberto Valente Soares Júnior , Universidade de São Paulo, Department of Dentistry-Central Institute, Clinical Hospital of Medical School – São Paulo (SP), Brazil.

Department of Dentistry-Central Institute, Clinical Hospital of Medical School of the University of São Paulo, SP, Brazil. https://orcid.org/0000-0003-0717-7354



Paulo Henrique Braz-Silva, Universidade de São Paulo, Institute of Tropical Medicine of São Paulo, Laboratory of Virology – São Paulo (SP), Brazil.

 Full Professor, Department of Stomatology, School of Dentistry, University of São Paulo, SP, Brazil; Laboratory of Virology, Institute of Tropical Medicine of São Paulo, University of São Paulo, SP, Brazil. https://orcid.org/0000-0002-1842-9521

Marina Gallottini , Universidade de São Paulo, School of Dentistry, Department of Stomatology – São Paulo (SP), Brazil.

 Full Professor, Department of Stomatology, School of Dentistry, University of São Paulo, SP, Brazil. https://orcid.org/0000-0001-6071-5110

References

1. Miranda-Silva W, Knebel FH, Tozetto-Mendozo TR, Palmieri M, Fonseca FP, Camargo AA, et al. Herpesviruses in the oral cavity of patients subjected to allogeneic hematopoietic stem cell transplantation and its relationship with oral mucositis. Clin Oral Investig. 2020;24(10):3597-08. https://doi.org/10.1007/s00784-020-03234-3

2. Palmieri M, Martins VAO, Sumita LM, Tozetto-Mendoza TR, Romano BB, Machado CM, et al. Oral shedding of human herpesviruses in patients undergoing radiotherapy/chemotherapy treatment for head and neck squamous cell carcinoma. Clin Oral Investig. 2017;21(7):2291-301. https://doi.org/10.1007/s00784-016-2022-x

3. van der Beek MT, Laheij AM, Raber-Durlacher JE, von dem Borne PA, Wolterbeek R, van der Blij-de Brouwer CS, et al. Viral loads and antiviral resistance of herpesviruses and oral ulcerations in hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2012;47(9):1222-8. https://doi.org/10.1038/bmt.2012.2

4. Costa ALF, Santos BA, Torregrossa VR, Miranda ECM, Vigorito AC, Palmieri M, et al. Oral shedding of CMV and HSV-1 in hematopoietic stem cell transplantation patients. Oral Dis. 2021;27(6):1572-79. https://doi.org/10.1111/odi.13690

5. Nicolatou-Galitis O, Athanassiadou P, Kouloulias V, Sotiropoulou-Lontou A, Dardoufas K, Polychronopoulou A, et al. Herpes simplex virus-1 (HSV-1) infection in radiation-induced oral mucositis. Support Care Cancer. 2006;14(7):753-62. https://doi.org/10.1007/s00520-005-0006-5

6. Chen Y-K, Hou H-A, Chow J-M, Chen Y-C, Hsueh P-R, Tien H-F. The impact of oral herpes simplex virus infection and candidiasis on chemotherapy-induced oral mucositis among patients with hematological malignancies. Eur J Clin Microbiol Infect Dis. 2011;30(6):753-9. https://doi.org/10.1007/s10096-010-1148-z

7. Grinde B. Herpesviruses: latency and reactivation - viral strategies and host response. J Oral Microbiol. 2013;5(1):22766. https://doi.org/10.3402/jom.v5i0.22766

8. Agut H, Bonnafous P, Gautheret-Dejean A. Human Herpesviruses 6A, 6B, and 7. Microbiol Spectr. 2016;4(3). https://doi.org/10.1128/microbiolspec.dmih2-0007-2015

9. Raposo JV, Sarmento DJS, Pinto RBDS, Lopes AO, Gallottini M, Tozetto-Mendoza TR, et al. Longitudinal study on oral shedding of human betaherpesviruses 6 and 7 in renal transplant recipients reveals active replication. J Oral Microbiol. 2020;12(1):1785801. https://doi.org/10.1080/20002297.2020.1785801

10. Diesch T, Filippi C, Fritschi N, Filippi A, Ritz N. Cytokines in saliva as biomarkers of oral and systemic oncological or infectious diseases: A systematic review. Cytokine. 2021;143:155506. https://doi.org/10.1016/j.cyto.2021.155506

11. Sahibzada HA, Khurshid Z, Khan RS, Naseem M, Siddique KM, Mali M, et al. Salivary IL-8, IL-6 and TNF-α as Potential Diagnostic Biomarkers for Oral Cancer. Diagnostics (Basel). 2017;7(2):21. https://doi.org/10.3390/diagnostics7020021

12. Rinderknecht C, Filippi C, Ritz N, Fritschi N, Simmen U, Filippi A, et al. Associations between salivary cytokines and oral health, age, and sex in healthy children. Sci Rep. 2022;12(1):15991. https://doi.org/10.1038/s41598-022-20475-2

13. Lima LR, Silva AP, Schmidt-Chanasit J, Paula VS. Diagnosis of human herpes virus 1 and 2 (HHV-1 and HHV-2): use of a synthetic standard curve for absolute quantification by real time polymerase chain reaction. Mem Inst Oswaldo Cruz. 2017;112(3):220-3. https://doi.org/10.1590/0074-02760160354

14. Raposo JV, Alves ADR, Dos Santos da Silva A, Dos Santos DC, Melgaço JG, Moreira OC, et al. Multiplex qPCR facilitates identification of betaherpesviruses in patients with acute liver failure of unknown etiology. BMC Infect Dis. 2019;19(1):773. https://doi.org/10.1186/s12879-019-4309-4

15. Tozetto-Mendoza TR, Ibrahim KY, Tateno AF, de Oliveira CM, Sumita LM, Sanchez MCA, et al. Genotypic distribution of HHV-8 in AIDS individuals without and with Kaposi sarcoma: Is genotype B associated with better prognosis of AIDS-KS? Medicine (Baltimore). 2016;95(48):e5291. https://doi.org/10.1097/MD.0000000000005291

16. Pels E. Comparison of saliva interleukin-2 concentration to the condition of gums in children with acute lymphoblastic leukaemia during anti-tumour treatment. Cancer Chemother Pharmacol. 2015;76(1):205-10. https://doi.org/10.1007/s00280-015-2750-7

17. Szabo YZ, Slavish DC. Measuring salivary markers of inflammation in health research: A review of methodological considerations and best practices. Psychoneuroendocrinology. 2021;124:105069. https://doi.org/10.1016/j.psyneuen.2020.105069

18. Paganini A, Fritschi N, Filippi C, Ritz N, Simmen U, Scheinemann K, et al. Comparative analysis of salivary cytokine profiles in newly diagnosed pediatric patients with cancer and healthy children. Sci Rep. 2025;15(1):3544. https://doi.org/10.1038/s41598-025-87608-1

19. Velten DB, Zandonade E, Miotto MHMB. Prevalence of oral manifestations in children and adolescents with cancer submitted to chemotherapy. BMC Oral Health. 2017;17:49. https://doi.org/10.1186/s12903-016-0331-8

20. Ramphal R, Grant RM, Dzolganovski B, Constantin J, Tellier R, Allen U, et al. Herpes simplex virus in febrile neutropenic children undergoing chemotherapy for cancer: a prospective cohort study. Pediatr Infect Dis J. 2007;26(8):700-4. https://doi.org/10.1097/inf.0b013e31805cdc11

21. Mendonça RMH, Araújo M, Levy CE, Morari J, Silva RA, Yunes JA, et al. Prospective evaluation of HSV, Candida spp, and oral bacteria on the severity of oral mucositis in pediatric acute lymphoblastic leukemia. Support Care Cancer. 2012;20(5):1101-7. https://doi.org/10.1007/s00520-011-1190-0

22. Gantt S, Casper C. Human herpesvirus 8-associated neoplasms: the roles of viral replication and antiviral treatment. Curr Opin Infect Dis. 2011;24(4):295-301. https://doi.org/10.1097/qco.0b013e3283486d04

23. van Velzen M, Ouwendijk WJD, Selke S, Pas SD, van Loenen FB, Osterhaus ADME, et al. Longitudinal study on oral shedding of herpes simplex virus 1 and varicella-zoster virus in individuals infected with HIV. J Med Virol. 2013;85(9):1669-77. https://doi.org/10.1002/jmv.23634

24. Rechenchoski DZ, Faccin-Galhardi LC, Linhares REC, Nozawa C. Herpesvirus: an underestimated virus. Folia Microbiol (Praha). 2017;62(2):151-6. https://doi.org/10.1007/s12223-016-0482-7

25. Kerr JR. Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors. J Clin Pathol. 2019;72(10):651-8. https://doi.org/10.1136/jclinpath-2019-205822

26. Houen G, Trier NH. Epstein-Barr Virus and Systemic Autoimmune Diseases. Front Immunol. 2021;11:587380. https://doi.org/10.3389/fimmu.2020.587380

27. Silva-Filho JL, Caruso-Neves C, Pinheiro AAS. IL-4: an important cytokine in determining the fate of T cells. Biophys Rev. 2014;6(1):111-8. https://doi.org/10.1007/s12551-013-0133-z

28. Yamanishi K. Human herpesvirus 6. Microbiol Immunol. 1992;36(6):551-61. https://doi.org/10.1111/j.1348-0421.1992.tb02055.x

29. Dagna L, Pritchett JC, Lusso P. Immunomodulation and immunosuppression by human herpesvirus 6A and 6B. Future Virol. 2013;8(3):273-87. https://doi.org/10.2217/fvl.13.7

30. Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R, et al. A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea. Support Care Cancer. 2010;18(8):993-1006. https://doi.org/10.1007/s00520-010-0900-3

Downloads

Published

2026-08-12

How to Cite

1.
Cunha WA da, Shibutani PP, Oliveira FM e M de, Soares Júnior LAV, Braz-Silva PH, Gallottini M. Oral shedding of human herpesviruses and cytokine profiles in children and adolescents undergoing chemotherapy. J Oral Diagn [Internet]. 2026 Aug. 12 [cited 2026 Nov. 7];11. Available from: https://www.jordi.com.br/revista/article/view/467

Issue

Vol. 11 (2026)

Section

Original Article

License

Copyright (c) 2026 Wallena Albuquerque da Cunha, Patricia Shibutani , Fabiana Martins e Martins de Oliveira , Luiz Alberto Valente Soares Júnior , Paulo Henrique Braz-Silva, Marina Gallottini

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.