Current Oral Health Reports

, Volume 5, Issue 4, pp 255–263 | Cite as

Herpesviral Infection in Periapical Periodontitis

  • Aleksandar JakovljevicEmail author
  • Miroslav Andric
  • Aleksandra Knezevic
  • Maja Miletic
  • Katarina Beljic-Ivanovic
  • Jelena Milasin
  • Mohammad Sabeti
Epidemiology (M Laine, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Epidemiology


Purpose of Review

This review describes the most recent findings on herpesviral infections and offers current concepts of herpesviral role in the pathogenesis of periapical periodontitis.

Recent Findings

Thirty articles reported data on herpesviral infection in periapical periodontitis. Epstein-Barr virus and human cytomegalovirus are the most frequently detected herpesviruses in periapical samples. The main hypothesis postulates a bidirectional herpesviral-bacterial relationship in the etiopathogenesis of periapical periodontitis. A high heterogeneity of herpesviruses incidence was registered within the studies, in part, due to various methodological approaches used in laboratory testing, different inclusion criteria, study design, seroprevalence of herpesviruses, and sociodemographic characteristics of investigated populations.


Herpesviruses have been shown to potentially impair local host defense in periapical tissue. Although it has been demonstrated that endodontic pathogenic bacteria are able to reactivate herpesviruses, further, in vitro studies should provide more data on herpesviruses as a factor in the pathogenesis of the periapical pathoses. It is, therefore, necessary to investigate potential benefits of antiviral therapy in well-designed controlled longitudinal studies.


Apical periodontitis Herpesviruses Epstein-Barr virus Human cytomegalovirus Bone resorption 



The study was supported by grant no. 175075 from the Ministry of Education, Science and Technological Development of the Republic of Serbia.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki Declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Nair PN. Pathogenesis of apical periodontitis and the causes of endodontic failures. Crit Rev Oral Biol Med. 2004;15:348–81.CrossRefGoogle Scholar
  2. 2.
    Siqueira JF Jr, Alves FR, Rôças IN. Pyrosequencing analysis of the apical root canal microbiota. J Endod. 2011;37:1499–503. Scholar
  3. 3.
    Vianna ME, Conrads G, Gomes BP, Horz HP. Identification and quantification of archaea involved in primary endodontic infections. J Clin Microbiol. 2006;44:1274–82.CrossRefGoogle Scholar
  4. 4.
    Persoon IF, Crielaard W, Özok AR. Prevalence and nature of fungi in root canal infections: a systematic review and meta-analysis. Int Endod J. 2017;50:1055–66. Scholar
  5. 5.
    Stevens RH, Porras OD, Delisle AL. Bacteriophages induced from lysogenic root canal isolates of Enterococcus faecalis. Oral Microbiol Immunol. 2009;24:278–84. Scholar
  6. 6.
    •• Jakovljevic A, Andric M. Human cytomegalovirus and Epstein-Barr virus in etiopathogenesis of apical periodontitis: a systematic review. J Endod. 2014;40:6–15. This manuscript is the first systematic review on herpesviral infection in apical periodontitis. CrossRefPubMedGoogle Scholar
  7. 7.
    •• Jakovljevic A, Andric M, Knezevic A, Beljic-Ivanovic K, Miletic M, Jovanovic T, et al. Herpesviruses in periapical pathoses: un updated systematic review. In: Ongradi J, editor. Herpesviridae. Rijeka: InTech; 2016. This manuscript represents the updated first systematic review on herpesviral infection in periapical pathoses including periapical abscess. CrossRefGoogle Scholar
  8. 8.
    Persoon IF, Özok AR. Definitions and epidemiology of endodontic infections. Curr Oral Health Rep. 2017;4:278–85. Scholar
  9. 9.
    Slots J. Herpesviruses in periodontal diseases. Periodontol. 2005;38:33–62. Scholar
  10. 10.
    Slots J. Human viruses in periodontitis. Periodontol. 2010;53:89–110. Scholar
  11. 11.
    • Slots J. Periodontal herpesviruses: prevalence, pathogenicity, systemic risk. Periodontol. 2015;69:28–45. This manuscript is the narrative review on several aspects of herpesviral infection in periodontal disease. CrossRefGoogle Scholar
  12. 12.
    Pellet PE, Roizman B. The family: Herpesviridae a brief introduction. In: Knipe DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott Williams & Wilkins; 2007.Google Scholar
  13. 13.
    Slots J, Sabeti M, Simon JH. Herpesviruses in periapical pathosis: an etiopathogenic relationship? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96:327–31. Scholar
  14. 14.
    Smith MacDonald E, Nowzari H, Contreras A, Flynn J, Morrison J, Slots J. Clinical and microbiological evaluation of a bioabsorbable and a nonresorbable barrier membrane in the treatment of periodontal intraosseous lesions. J Periodontol. 1998;69:445–53. Scholar
  15. 15.
    Ongrádi J, Sallay K, Kulcsár G. The decreased antibacterial activity of oral polymorphonuclear leukocytes coincides with the occurrence of virus-carrying oral lymphocytes and epithelial cells. Folia Microbiol (Praha). 1987;32:438–47.CrossRefGoogle Scholar
  16. 16.
    Tortorella D, Gewurz BE, Furman MH, Schust DJ, Ploegh HL. Viral subversion of the immune system. Annu Rev Immunol. 2000;18:861–926. Scholar
  17. 17.
    Rossini G, Cerboni C, Santoni A, Landini MP, Landolfo S, Gatti D, et al. Interplay between human cytomegalovirus and intrinsic/innate host responses: a complex bidirectional relationship. Mediat Inflamm. 2012;2012:607276. Scholar
  18. 18.
    Mogensen TH, Paludan SR. Molecular pathways in virus-induced cytokine production. Microbiol Mol Biol Rev. 2001;65:131–50. Scholar
  19. 19.
    Alcami A, Koszinowski UH. Viral mechanisms of immune evasion. Trends Microbiol. 2000;8:410–8.CrossRefGoogle Scholar
  20. 20.
    Sabeti M, Kermani V, Sabeti S, Simon JH. Significance of human cytomegalovirus and Epstein-Barr virus in inducing cytokine expression in periapical lesions. J Endod. 2012;38:47–50. Scholar
  21. 21.
    Hernádi K, Gyöngyösi E, Mészáros B, Szakács L, Szalmás A, Csoma E, et al. Elevated tumor necrosis factor-alpha expression in periapical lesions infected by Epstein-Barr virus. J Endod. 2013;39:456–60. Scholar
  22. 22.
    Teughels W, Sliepen I, Quirynen M, Haake SK, Van Eldere J, Fives-Taylor P, et al. Human cytomegalovirus enhances a. actinomycetemcomitans adherence to cells. J Dent Res. 2007;86:175–80. Scholar
  23. 23.
    Dai L, DeFee MR, Cao Y, Wen J, Wen X, Noverr MC, et al. Lipoteichoic acid (LTA) and lipopolysaccharides (LPS) from periodontal pathogenic bacteria facilitate oncogenic herpesvirus infection within primary oral cells. PLoS One. 2014;9:e101326. Scholar
  24. 24.
    Sabeti M, Slots J. Herpesviral-bacterial coinfection in periapical pathosis. J Endod. 2004;30:69–72. Scholar
  25. 25.
    Verdugo F, Castillo A, Simonian K, Castillo F, Farez-Vidal E, D'Addona A. Periodontopathogen and Epstein-Barr virus-associated periapical periodontitis may be the source of retrograde infectious peri-implantitis. Clin Implant Dent Relat Res. 2015;17:199–207. Scholar
  26. 26.
    Stern J, Shai E, Zaks B, Halabi A, Houri-Haddad Y, Shapira L, et al. Reduced expression of gamma interferon in serum and marked lymphoid depletion induced by porphyromonas gingivalis increase murine morbidity and mortality due to cytomegalovirus infection. Infect Immun. 2004;72:5791–8. Scholar
  27. 27.
    Ferreira DC, Rôças IN, Paiva SS, Carmo FL, Cavalcante FS, Rosado AS, et al. Viral-bacterial associations in acute apical abscesses. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011a;112:264–71. Scholar
  28. 28.
    Ferreira DC, Paiva SSM, Carmo FL Rôças IN, Rosado AS, Santos KR, et al. Identification of herpesviruses types 1 to 8 and human papillomavirus in acute apical abscesses. J Endod. 2011b;37:10–6. Scholar
  29. 29.
    Rauch B. Attempts to isolate a virus from infected root canals and periapical tissue using monkey kidney cells cultures. J Can Dent Assoc. 1958;24:404–10.Google Scholar
  30. 30.
    Shindell E. Studies on the possible presence of a virus in subacute and chronic periapical granulomas. Oral Surg Oral Med Oral Pathol. 1962;15:1382–4. Scholar
  31. 31.
    Parra B, Slots J. Detection of human viruses in periodontal pockets using polymerase chain reaction. Oral Microbiol Immunol. 1996;11:289–93. Scholar
  32. 32.
    Contreras A, Slots J. Mammalian viruses in human periodontitis. Oral Microbiol Immunol. 1996;11:381–6. Scholar
  33. 33.
    Sabeti M, Valles Y, Nowzari H, Simon JH, Kermani-Arab V, Slots J. Cytomegalovirus and Epstein-Barr virus DNA transcription in endodontic symptomatic lesions. Oral Microbiol Immunol. 2003;18:104–8. Scholar
  34. 34.
    Sabeti M, Simon JH, Slots J. Cytomegalovirus and Epstein-Barr virus are associated with symptomatic periapical pathosis. Oral Microbiol Immunol. 2003;18:327–8. Scholar
  35. 35.
    Sabeti M, Simon JH, Nowzari H, Slots J. Cytomegalovirus and Epstein-Barr virus active infection in periapical lesions of teeth with intact crowns. J Endod. 2003;29:321–3. Scholar
  36. 36.
    Sabeti M, Slots J. Herpesviral-bacterial coinfection in periapical pathosis. J Endod. 2004;30:69–72. Scholar
  37. 37.
    Slots J, Nowzari H, Sabeti M. Cytomegalovirus infection in symptomatic periapical pathosis. Int Endod J. 2004;37:519–24. Scholar
  38. 38.
    Kabak SL, Kabak YS, Anischenko SL. Light microscopic study of periapical lesions associated with asymptomatic apical periodontitis. Ann Anat. 2005;187:185–94. Scholar
  39. 39.
    Yildirim S, Yapar M, Kubar A, Slots J. Human cytomegalovirus, Epstein-Barr virus and bone resorption-inducing cytokines in periapical lesions of deciduous teeth. Oral Microbiol Immunol. 2006;21:107–11. Scholar
  40. 40.
    Saboia-Dantas CJ, Coutrin de Toledo LF, Sampaio-Filho HR, Siqueira JF Jr. Herpesviruses in asymptomatic apical periodontitis lesions: an immunohistochemical approach. Oral Microbiol Immunol. 2007;22:320–5. Scholar
  41. 41.
    Andric M, Milasin J, Jovanovic T, Todorovic LJ. Human cytomegalovirus is present in odontogenic cysts. Oral Microbiol Immunol. 2007;22:347–51. Scholar
  42. 42.
    Yazdi KA, Sabeti M, Jabalameli F, Eman eini M, Kolahdouzan SA, Slots J. Relationship between human cytomegalovirus transcription and symptomatic apical periodontitis in Iran. Oral Microbiol Immunol. 2008;23:510–4. Scholar
  43. 43.
    Sunde PT, Olsen I, Enersen M, Beiske K, Grinde B. Human cytomegalovirus and Epstein-Barr virus in apical and marginal periodontitis: a role in pathology? J Med Virol. 2008;80:1007–11. Scholar
  44. 44.
    Sabeti M, Daneshmand A, Simon JH, Slots J. Cytomegalovirus-infected inflammatory cells in dental periapical lesions. Oral Microbiol Immunol. 2009;24:434–6. Scholar
  45. 45.
    Li H, Chen V, Chen Y, Baumgartner JC, Machida CA. Herpesviruses in endodontic pathoses: association of Epstein-Barr virus with irreversible pulpitis and apical periodontitis. J Endod. 2009;35:23–9. Scholar
  46. 46.
    Chen V, Chen Y, Li H, Kent K, Baumgartner JC, Machida CA. Herpesviruses in abscesses and cellulitis of endodontic origin. J Endod. 2009;35:182–8. Scholar
  47. 47.
    Hernádi K, Szalmás A, Mogyorósi R, Czompa L, Veress G, Csoma E, et al. Prevalence and activity of Epstein-Barr virus and human cytomegalovirus in symptomatic and asymptomatic apical periodontitis lesions. J Endod. 2010;36:1485–9. Scholar
  48. 48.
    Hernádi K, Csoma E, Adám B, Szalmás A, Gyöngyösi E, Veress G, et al. Association of human herpesvirus 6 subtypes with symptomatic apical periodontitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112:401–6. Scholar
  49. 49.
    Ozbek SM, Ozbek A, Yavuz MS. Detection of human cytomegalovirus and Epstein-Barr virus in symptomatic and asymptomatic apical periodontitis lesions by real-time PCR. Med Oral Patol Oral Cir Bucal. 2013;18:811–6. Scholar
  50. 50.
    Ozbek A, Ozbek SM. Detection of herpesviruses and human papillomavirus in acute apical abscesses by real-time PCR. Clin Oral Investig. 2015;19:343–7. Scholar
  51. 51.
    Makino K, Takeichi O, Hatori K, Imai K, Ochiai K, Ogiso B. Epstein-Barr virus infection in chronically inflamed periapical granulomas. PLoS One. 2015;10:e0121548. Scholar
  52. 52.
    Ozbek SM, Ozbek A, Demiray T. Prevalence of several herpesviruses and human papillomavirus in acute apical abscesses. Int Endod J. 2016;49:519–25. Scholar
  53. 53.
    Popovic J, Gasic J, Zivkovic S, Kesic L, Mitic A, Nikolic M, et al. Prevalence of human cytomegalovirus and Epstein-Barr virus in chronic periapical lesions. Intervirology. 2015;58:271–7. Scholar
  54. 54.
    Jakovljevic A, Andric M, Knezevic A, Soldatovic I, Nikolic N, Karalic D, et al. Human cytomegalovirus and Epstein-Barr virus genotypes in apical periodontitis lesions. J Endod. 2015;41:1847–51. Scholar
  55. 55.
    •• Jakovljevic A, Andric M, Nikolic N, Coric V, Krezovic S, Carkic J, et al. Levels of oxidative stress biomarkers and bone resorption regulators in apical periodontitis lesions infected by Epstein-Barr virus. Int Endod J. 2018;51:593–604. This manuscript is an original research on human apical periodontitis samples investigating the exact mechanisms of Epstein-Barr virus in alveolar bone resorption. CrossRefPubMedGoogle Scholar
  56. 56.
    Jakovljevic A, Knezevic A, Nikolic N, Soldatovic I, Jovanovic T, Milasin J, et al. Herpesviruses viral loads and levels of proinflammatory cytokines in apical periodontitis. Oral Dis. 2018;24:840–6. Scholar
  57. 57.
    •• Makino K, Takeichi O, Imai K, Inoue H, Hatori K, Himi K, et al. Porphyromonas endodontalis reactivates latent Epstein-Barr virus. Int Endod J. 2018. This manuscript is an original in vitro research related to direct influence of Porphyromonas endodontalis to reactivation of Epstein-Barr virus.CrossRefGoogle Scholar
  58. 58.
    Jakovljevic A, Kuzmanovic Pficer J, Dragan IF, Knezevic A, Miletic M, Beljic-Ivanovic K, et al. The role of varicella zoster virus in the development of periapical pathoses and root resorption: a systematic review. J Endod. 2017;43:1230–6. This manuscript systematically reviews and assesses the level of the evidence on the role of Varicella Zoster Virus in the development of periapical pathoses and root resorption. CrossRefPubMedGoogle Scholar
  59. 59.
    •• Sabeti M, Vahdati SA. Endodontic herpesviruses: prevalence, pathogenicity and systemic risk. J Dent Forecast. 2018;1:1005 This manuscript is the narrative review on several aspects of herpesviral infection in periapical disease.Google Scholar
  60. 60.
    •• Sabeti M. Viruses in endodontic pathosis. In: Fouad AF, editor. Endodontic microbiology. Hoboken: Wiley; 2017. This manuscript is the narrative review on several aspects of herpesviral infection in periapical disease.CrossRefGoogle Scholar
  61. 61.
    European Society of Endodontics. Quality guidelines for endodontic treatment: consensus report of the European Society of Endodontics. Int Endod J. 2006;39:921–30. Scholar
  62. 62.
    American Association of Endodontist. Guide to Clinical Endodontics. Sixth Edition. Available at:
  63. 63.
    Stowe RP, Peek MK, Perez NA, Yetman DL, Cutchin MP, Goodwin JS. Herpesvirus reactivation and socioeconomic position: a community-based study. J Epidemiol Community Health. 2010;64:666–71. Scholar
  64. 64.
    Maeda A, Sato T, Wakiguchi H. Epidemiology of Epstein-Barr virus (EBV) infection and EBV-associated diseases. Nihon Rinsho. 2006;64:609–12.PubMedGoogle Scholar
  65. 65.
    Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010;20:202–13. Scholar
  66. 66.
    Siqueira JF Jr, Rôças IN. Microbiology and treatment of acute apical abscesses. Clin Microbiol Rev. 2013;26:255–73. Scholar
  67. 67.
    Jakovljevic A, Andric M, Miletic M, Beljic-Ivanovic K, Knezevic A, Mojsilovic S, et al. Epstein-Barr virus infection induces bone resorption in apical periodontitis via increased production of reactive oxygen species. Med Hypotheses. 2016;94:40–2. Scholar
  68. 68.
    Lassoued S, Ben Ameur R, Ayadi W, Gargouri B, Ben Mansour R, Attia H. Epstein-Barr virus induces an oxidative stress during the early stages of infection in B lymphocytes, epithelial, and lymphoblastoid cell lines. Mol Cell Biochem. 2008;313:179–86. Scholar
  69. 69.
    Lee NK, Choi YG, Baik JY, Han SY, Jeong DW, Bae YS, et al. A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood. 2005;106:852–9. Scholar
  70. 70.
    Wright WE, Davis ML, Geffen DB, Martin SE, Nelson MJ, Straus SE. Alveolar bone necrosis and tooth loss. A rare complication associated with herpes zoster infection of the fifth cranial nerve. Oral Surg Oral Med Oral Pathol. 1983;56:39–46.CrossRefGoogle Scholar
  71. 71.
    Arvin AM, Gilden D. Varicella-zoster virus. In: Knipe DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott Williams & Wilkins; 2013.Google Scholar
  72. 72.
    Haque T, Crawford DH. PCR amplification is more sensitive than tissue culture methods for Epstein-Barr virus detection in clinical material. J Gen Virol. 1997;78:3357–60. Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Aleksandar Jakovljevic
    • 1
    Email author
  • Miroslav Andric
    • 2
  • Aleksandra Knezevic
    • 3
  • Maja Miletic
    • 1
  • Katarina Beljic-Ivanovic
    • 4
  • Jelena Milasin
    • 5
  • Mohammad Sabeti
    • 6
  1. 1.Department of Pathophysiology, School of Dental MedicineUniversity of BelgradeBelgradeSerbia
  2. 2.Department of Oral Surgery, School of Dental MedicineUniversity of BelgradeBeogradSerbia
  3. 3.Department of Virology, Institute of Microbiology and Immunology, Faculty of MedicineUniversity of BelgradeBeogradSerbia
  4. 4.Department of Restorative Odontology and Endodontics, School of Dental MedicineUniversity of BelgradeBeogradSerbia
  5. 5.Department of Biology and Human Genetics, School of Dental MedicineUniversity of BelgradeBeogradSerbia
  6. 6.Department of Endodontics, School of DentistryUniversity of CaliforniaSan FranciscoUSA

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