Archives of Virology

, Volume 164, Issue 5, pp 1249–1257 | Cite as

Evidence based on a meta-analysis of human cytomegalovirus infection in glioma

  • Karla P. R. A. Farias
  • Marcos L. MoreliEmail author
  • Vitor G. Floriano
  • Vivaldo G. da Costa


Malignant gliomas are the most common types of incurable primary brain tumours. Therefore, to better clarify the aetiology and pathogenesis of the disease and analyse the risk factors involved, several researchers have highlighted a possible link to human cytomegalovirus (HCMV). Regarding this potential link, the numbers of studies and controversies concerning the relationship between HCMV infections and malignant gliomas have significantly increased. Therefore, we conducted a meta-analysis of observational studies to summarize and pool the available results on the association of HCMV in patients with glioma. Our meta-analysis was based on the PRISMA algorithm, using fixed/random models through STATA IC 13.1 software. Thus, 32 studies were included with a total of 2,190 participants/specimens (glioma, n = 1,871; non-glioma, n = 319). The overall estimate of combined HCMV frequency in patients with glioma was 63% (95% confidence interval [CI]: 56-70). There was an association between HCMV infection and glioma (adjusted OR = 3, 95% CI: 1.7-5.3). The pooled subgroup analysis of viral markers also showed a positive association between the pp65 protein (OR = 3.1, 95% CI: 1.8-5), and gB nucleic acids (OR = 3.1, 95% CI: 1.1-8). For the viral marker IE1-72 protein, the pooled frequency and association results were higher. However, there was no correlation of higher viral association according to the histological subtypes and low/high grade of gliomas. In conclusion, the available evidence suggests an association between HCMV and glioma. Consequently, precautions should be taken, as discussed in this report.



This work was carried out as part of the master studies of K.P.R.A.F (Programa de Pós-graduação em Ciências Aplicadas à Saúde, UFG). VGC was the recipient of a FAPDF and CAPES fellowship at different times.

Author contributions

MLM and VGC designed the study. KPRAF, VGF and VGC performed data collection. VGC performed statistical analysis. All authors reviewed and approved the final version of the manuscript.


The study received financial support from FAPEG (010/2013) for English editing services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with research involving human participants and/or animals performed by any of the authors.

Informed consent


Supplementary material

705_2019_4206_MOESM1_ESM.doc (228 kb)
Supplementary material 1 (DOC 284 kb)


  1. 1.
    Sanai N, Alvarez-Buylla A, Berger MS (2005) Neural stem cells and the origin of gliomas. N Engl J Med 353:811–822. CrossRefGoogle Scholar
  2. 2.
    Zong H, Verhaak RG, Canoll P (2012) The cellular origin for malignant glioma and prospects for clinical advancements. Expert Rev Mol Diagn 12:383–394. CrossRefGoogle Scholar
  3. 3.
    Polley MY, Lamborn KR, Chang SM, Butowski N, Clarke JL, Prados M (2011) Conditional probability of survival in patients with newly diagnosed glioblastoma. J Clin Oncol 29:4175e4180. CrossRefGoogle Scholar
  4. 4.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30. CrossRefGoogle Scholar
  5. 5.
    Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS (2017) CBTRUS statistical report: primary brain and other central nervous system tumours diagnosed in the United States in 2010–2014. Neuro-Oncol 19:1–88. CrossRefGoogle Scholar
  6. 6.
    Ohgaki H (2009) Epidemiology of brain tumours. Methods Mol Biol 472:323–342. CrossRefGoogle Scholar
  7. 7.
    Reuss D, von Deimling A (2009) Hereditary tumor syndromes and gliomas. Recent Results Cancer Res 171:83–102. CrossRefGoogle Scholar
  8. 8.
    Solomon IH, Ramkissoon SH, Milner DA, Folkerth RD (2014) Cytomegalovirus and glioblastoma: a review of evidence for their association and indications for testing and treatment. J Neuropathol Exp Neurol 73:994–998. CrossRefGoogle Scholar
  9. 9.
    Lawler SE (2015) Cytomegalovirus and glioblastoma; controversies and opportunities. J Neuro-Oncol 123:465–471. CrossRefGoogle Scholar
  10. 10.
    Sissons JG, Carmichael AJ (2002) Clinical aspects and management of cytomegalovirus infection. J Infect 44:78–83. CrossRefGoogle Scholar
  11. 11.
    Orlikowski D, Porcher R, Sivadon-Tardy V, Quincampoix JC, Raphael JC, Durand MC, Sharshar T, Roussi J, Caudie C, Annane D, Rozenberg F, Leruez-Ville M, Gaillard JL, Gault E (2011) Guillain-Barré syndrome following primary cytomegalovirus infection: a prospective cohort study. Clin Infect Dis 52:837–844. CrossRefGoogle Scholar
  12. 12.
    Cunha BA, Chawla K (2018) Fever of unknown origin (FUO): CMV infectious mononucleosis or lymphoma? Eur J Clin Microbiol Infect Dis 37:1373–1376. CrossRefGoogle Scholar
  13. 13.
    Cinatl J Jr, Vogel JU, Cinatl J, Weber B, Rabenau H, Novak M, Kornhuber B, Doerr HW (1996) Long-term productive human cytomegalovirus infection of a human neuroblastoma cell line. Int J Cancer 65:90–96.;2-M CrossRefGoogle Scholar
  14. 14.
    Michaelis M, Doerr HW, Cinatl J Jr (2009) The story of human cytomegalovirus and cancer: increasing evidence and open questions. Neoplasia 11:1–9. CrossRefGoogle Scholar
  15. 15.
    Soderberg-Naucler C (2006) Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer? J Intern Med 259:219–246. CrossRefGoogle Scholar
  16. 16.
    Michaelis M, Doerr HW, Cinatl J Jr (2009) Oncomodulation by human cytomegalovirus: evidence becomes stronger. Med Microbiol Immunol 198:79–81. CrossRefGoogle Scholar
  17. 17.
    Cobbs CS (2011) Evolving evidence implicates cytomegalovirus as a promoter of malignant glioma pathogenesis. Herpesviridae 2:10. CrossRefGoogle Scholar
  18. 18.
    Lehrer S, Green S, Ramanathan L, Rosenzweig K, Labombardi V (2012) No consistent relationship of glioblastoma incidence and cytomegalovirus seropositivity in whites, blacks, and Hispanics. Anticancer Res 32:1113–1116Google Scholar
  19. 19.
    Cobbs CS, Harkins L, Samanta M, Gillespie GY, Bharara S, King PH, Nabors LB, Cobbs CG, Britt WJ (2002) Human cytomegalovirus infection and expression in human malignant glioma. Cancer Research 62:3347–3350Google Scholar
  20. 20.
    Holdhoff M, Guner G, Rodriguez FJ, Hicks JL, Zheng Q, Forman MS, Ye X, Grossman SA, Meeker AK, Heaphy CM, Eberhart CG, De Marzo AM, Arav-Boger R (2017) Absence of cytomegalovirus in glioblastoma and other high-grade gliomas by real-time PCR, immunohistochemistry and in situ hybridization. Clin Cancer Res 23:3150–3157. CrossRefGoogle Scholar
  21. 21.
    Dziurzynski K, Chang SM, Heimberger AB, Kalejta RF, McGregor Dallas SR, Smit M, Soroceanu L, Cobbs CS (2012) Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol 14:246–255. CrossRefGoogle Scholar
  22. 22.
    Moher D, Liberati A, Tetzlaff J, Altman DG, The PG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097. CrossRefGoogle Scholar
  23. 23.
    Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P (2018) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Health Research Institute.
  24. 24.
    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558. CrossRefGoogle Scholar
  25. 25.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634. CrossRefGoogle Scholar
  26. 26.
    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101CrossRefGoogle Scholar
  27. 27.
    Louis DN, Perry A, Reifenberger G, Av Deimling, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization Classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. CrossRefGoogle Scholar
  28. 28.
    Baumgarten P, Michaeli M, Rothweiler F, Starzetz T, Rabenau HF, Berger A, Jennewein L, Braczynski AK, Franz K, Seifert V, Steinbach JP, Allwinn R, Mittelbronn M, Cinatl J Jr (2014) Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics. Neuro-Oncology 16:1469–1477. CrossRefGoogle Scholar
  29. 29.
    Libard S, Popova SN, Amini R-M, Kärjä V, Pietiläinen T, Hämäläinen KM, Sundström C, Hesselager G, Bergqvist M, Ekman S, Zetterling M, Smits A, Nilsson P, Pfeifer S, de Ståhl TD, Enblad G, Ponten F, Alafuzoff I (2014) Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade. PLoS One 9:e108861. CrossRefGoogle Scholar
  30. 30.
    Bianchi E, Roncarati P, Hougrand O, Guérin-EI Khourouj V, Boreux R, Kroonen J, Martin D, Robe P, Rogister B, Delvenne P, Deprez M (2015) Human cytomegalovirus and primary intracranial tumours: frequency of tumour infection and lack of correlation with systemic immune anti-viral responses. Neuropathol Appl Neurobiol 41:e29–e40. CrossRefGoogle Scholar
  31. 31.
    Mocarski ES, Shenk T, Griffiths PD, Pass RF (2013) Cytomegalovirus and their replication. In: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE (eds) Fields virology, 4th edn. Lippincott Williams & Wilkins, Philadelphia, pp 1960–2014Google Scholar
  32. 32.
    Sinclair J, Sissons P (2006) Latency and reactivation of human cytomegalovirus. J Gen Virol 87:1763–1779. CrossRefGoogle Scholar
  33. 33.
    Lee CH, Lee GC, Chan YJ, Chiou CJ, Ahn JH, Hayward GS (1999) Factors affecting human cytomegalovirus gene expression in human monocyte cell lines. Mol Cells 9:37–44Google Scholar
  34. 34.
    Keyes LR, Bego MG, Soland M, St Jeor S (2012) Cyclophilin A is required for efficient human cytomegalovirus DNA replication and reactivation. J Gen Virol 93:722–732. CrossRefGoogle Scholar
  35. 35.
    Priel E, Wohl A, Teperberg M, Nass D, Cohen Z (2015) Human cytomegalovirus viral load in tumor and peripheral blood samples of patients with malignant gliomas. J Clin Neurosci 22:326–330. CrossRefGoogle Scholar
  36. 36.
    Mitchell DA, Xie W, Schmittling R, Learn C, Friedman A, McLendon RE, Sampson JH (2007) Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro-Oncology 10:10–18. CrossRefGoogle Scholar
  37. 37.
    Lau SK, Chen YY, Chen WG, Diamond DJ, Mamelak AN, Zaia JA, Weiss LM (2005) Lack of association of cytomegalovirus with human brain tumors. Mod Pathol 18:838–843. CrossRefGoogle Scholar
  38. 38.
    Sabatier J, Uro-Coste E, Pommepuy I, Labrousse F, Allart S, Trémoulet M, Delisle MB, Brousset P (2005) Detection of human cytomegalovirus genome and gene products in central nervous system tumours. Br J Cancer 92:747–750. CrossRefGoogle Scholar
  39. 39.
    Poltermann S, Schlehofer B, Steindorf K, Schnitzler P, Geletneky K, Schlehofer JR (2006) Lack of association of herpesviruses with brain tumors. J Neurovirol 12:90–99. CrossRefGoogle Scholar
  40. 40.
    Fonseca RF, Kawamura MT, Oliveira JA, Teixeira A, Alves G, Carvalho MGC (2012) The prevalence of human cytomegalovirus DNA in gliomas of Brazilian patients. Mem Inst Oswaldo Cruz 107:953–954. CrossRefGoogle Scholar
  41. 41.
    Yamashita Y, Ito Y, Isomura H, Takemura N, Okamoto A, Motomura K, Tsujiuchi T, Natsume A, Wakabayashi T, Toyokuni S, Tsurumi T (2014) Lack of presence of the human cytomegalovirus in human glioblastoma. Mod Pathol 27:922–929. CrossRefGoogle Scholar
  42. 42.
    Hashida Y, Taniguchi A, Yawata T, Hosokawa S, Murakami M, Hiroi M, Ueba T, Daibata M (2015) Prevalence of human cytomegalovirus, polyomaviruses, and oncogenic viruses in glioblastoma among Japanese subjects. Infect Agent Cancer 10:3. CrossRefGoogle Scholar
  43. 43.
    Taha MS, Abdalhamid BA, El-Badawy SA, Sorour YM, Almsned FM, Al-Abbadi MA (2015) Expression of cytomegalovirus in glioblastoma multiforme: myth or reality? Br J Neurosurg. Google Scholar
  44. 44.
    Garcia-Martinez A, Alenda C, Irles E, Ochoa E, Quintanar T, Rodriguez-Lescure A, Soto JL, Barbera VM (2017) Lack of cytomegalovirus detection in human glioma. Virol J 14:216. CrossRefGoogle Scholar
  45. 45.
    Strojnik T, Duh D, Lah TT (2017) Prevalence of neurotropic viruses in malignant glioma and their onco-modulatory potential. Vivo 31:221–229. CrossRefGoogle Scholar
  46. 46.
    Yang CF, Ho HL, Lin SC, Hsu CY, Ho DMT (2017) Detection of human cytomegalovirus in glioblastoma among Taiwanese subjects. PLoS One 12:e0179366. CrossRefGoogle Scholar
  47. 47.
    Scheurer ME, Bondy ML, Aldape KD, El-Zein R (2008) Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol 116:79. CrossRefGoogle Scholar
  48. 48.
    Cobbs CS (2014) Response to “Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics”. Neuro-Oncology 16:1435–1436. CrossRefGoogle Scholar
  49. 49.
    Han S, Deng J, Wang S, Liu H, Cheng W, Wu A (2017) Decreased human leukocyte antigen A*02:01 frequency is associated with risk of glioma and existence of human cytomegalovirus: a case–control study in Northern China. Cancer Immunol Immunother 66:1265–1273. CrossRefGoogle Scholar
  50. 50.
    Tarragó D, Quereda C, Tenorio A (2003) Different cytomegalovirus glycoprotein B genotype distribution in serum and cerebrospinal fluid specimens determined by a novel multiplex nested PCR. J Clin Microbiol 41:2872–2877. CrossRefGoogle Scholar
  51. 51.
    dos Santos CJ, Stangherlin LM, Figueiredo EG, Corrêa C, Teixeira MJ, da Silva MCC (2014) High prevalence of HCMV and viral load in tumor tissues and peripheral blood of glioblastoma multiforme patients. J Med Virol 86:1953–1961. CrossRefGoogle Scholar
  52. 52.
    Hammer GP, du Prel JB, Blettner M (2009) Avoiding bias in observational studies. Dtsch Arztebl Int 106:664–668. Google Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of Health ScienceFederal University of GoiásJataiBrazil
  2. 2.Department of Biochemistry and ImmunologyUniversity of São PauloRibeirão PretoBrazil
  3. 3.Department of Cellular BiologyUniversity of BrasíliaBrasíliaBrazil

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