Epstein-Barr virus

MICROBIOLOGY

• Member of the human gamma herpesvirus family.
• 90-95% in the U.S. infected by later adult years.
  • Most HIV+ individuals also harbor EBV.
• Establishes latent infection. Spread mostly by asymptomatic, intermittent shedding of virus into salivary secretions.
  • The virus also may be shed in semen and vaginal secretions.
• Primary infection: subclinical, especially in children or clinical (infectious mononucleosis, IM); peak incidence of IM in teens and early 20s.
• The presence of EBV may be considered as a tumor marker in the proper clinical context.
  • EBV can act as a cancer promoter in certain types of non-Hodgkin lymphoma (NHL, e.g., Burkitt’s lymphoma [mostly in Africa], diffuse large B-cell, extra-nodal natural killer/T-cell nasal type), Hodgkin’s lymphoma and nasopharyngeal carcinoma.
  • Tumors more common in settings of low CD4 counts.

CLINICAL

• EBV infection established in most individuals prior to HIV infection.
  • See module for details regarding infectious mononucleosis (primary EBV infection).
• EBV+ and HIV: >60x risk of lymphoma over the general population, though overall risk remains small.
  • In HIV, EBV most highly associated with primary CNS lymphoma (PCNSL).
    • EBV CSF PCR + in ~ specific 100%, especially if using high copy number (e.g., in thousands instead of low hundreds).
    • Studies suggest CSF PCR equivalent to brain Bx (sensitivity 83-100%, specificity 93-100%).
    • Now seen less frequently in the ART era.
  • Other lymphomas with EBV-association in HIV infection
    • Tend to affect young to middle-aged men > women.
    • Many are aggressive B-cell lymphomas, often with a predilection for the GI tract.
    • Diffuse Large B-cell lymphoma (DCBL) remains the main type of cancer in HIV-infected people.
      • Incidence of classic Hodgkin’s lymphoma (HL) has increased while other HIV-associated lymphomas such as Burkitt lymphoma, PEL, and PBL of the oral cavity type remain stable.
        • Plasmablastic lymphoma (PBL) + PCNSL + and primary effusion lymphoma (PEL) are a minor piece (about 7-8%) of DLBCL, which represent about 70% of the HIV-associated lymphomas.
      • PBL: uncommon but appears specific for middle-aged males. Often starts in the oral cavity. Has poor prognosis despite cART and chemotherapy.
      • PEL: rare, B-cell lymphoma that is primarily associated with KSHV, most cases also have EBV co-infection. This is a lymphoma of the serous membranes.
      • cHL: nearly all HIV-infected patients with classic HL are associated with EBV. Most patients have B symptoms and advanced disease at extra-nodal sites.
• Dx:
  • Primary CNS lymphoma: EBV PCR, if positive, in the proper clinical scenario and imaging.
  • Role of EBV PCR (quantitative) of blood uncertain: conflicting data regarding correlation with risk of HL and NHL.
  • The significance of EBV PCR in other tissues and fluids less certain, though described with smooth muscle tumors in HIV+ pts[15].
    • Clinical reliability depends on the assay used.
  • Low viral load in people with low CD4 counts not likely significant.
  • Infectious mononucleosis:
    • Monospot (heterophile antibodies, serum) used to dx IM (~90% positive).
    • 10% Monospot-negative and may require dx through EBV-specific serology, e.g., EBV capsid IgM, IgG, and EBNA antibodies.
  • False-positive Monospot may be caused by acute HIV infection, and symptoms can be similar.
    • If risk factors exist and suspected, test IM suspects with HIV viral load assay (acute retroviral syndrome).
  • Oral hairy leukoplakia:
    • Painless, white/gray patches on lateral margins of the tongue caused by intense lytic-phase replication of EBV [Fig]. Patches may spread to other parts of the tongue and oral cavity.
    • Ddx=thrush, squamous cell CA, leukoplakia, hyperplastic candidiasis, smoker’s keratosis, frictional keratosis, idiopathic leukoplakia, lichen planus and lichenoid mucosal reactions.
    • Dx by appearance and location, cannot scrape off, unlike Candida.
      • A lingual biopsy will show EBV in-situ hybridization that confirms but is usually unnecessary.
• Since EBV establishes latency within cells, eradication impossible.

SITES OF INFECTION

• HIV-related lymphomas: various locations
  • B cell lymphoma (~100% CNS, ~50% peripheral lymphomas associated w/ EBV)
  • Plasmablastic B-cell lymphoma: often presents in the oral cavity.
  • T/NK cell lymphoma (10-100% depending on histological grade)
  • Sporadic Burkitt’s lymphoma (~25%),
  • Primary effusion lymphoma (70-80%, but 100% also contain HHV-8).
  • See Lymphoma, Non-Hodgkins (NHL), Lymphoma, Hodgkins, Lymphoma, Primary CNS (PCNSL).
• Nasopharyngeal carcinoma
• Leiomyosarcoma: mainly in children
• Oropharynx: oral hairy leukoplakia (OHL)
• Infectious mononucleosis: a cardinal triad of fever, lymphadenopathy and pharyngitis.
  • May be unclear if the presentation of primary EBV infection different in the setting of HIV.
    • More details about IM found in the Epstein-Barr virus ABX Guide module.

TREATMENT

Basis for recommendation

1. Patton LL, Ramirez-Amador V, Anaya-Saavedra G, et al. Urban legends series: oral manifestations of HIV infection. Oral Dis. 2013;19(6):533-50.  [PMID:23517181]

   Comment: The practical and heavily referenced review addresses questions regarding oral lesions in HIV-infected patients. The review includes topical therapies for OHL.
   

References

2. Mueller SM, Stoeckle M, Goldust M. Treatment options for oral hairy leucoplakia: A case report. Dermatol Ther. 2020;33(3):e13425.  [PMID:32301228]

   Comment: Seen less frequently nowadays, authors emphasize that OHL can occur in non-HIV settings and also that treatment approaches based on small studies from decades ago and best now handled in the HIV setting through ART.
   

3. Grewal R, Irimie A, Naidoo N, et al. Hodgkin's lymphoma and its association with EBV and HIV infection. Crit Rev Clin Lab Sci. 2018;55(2):102-114.  [PMID:29316828]

   Comment: HL (which is now the proper term for Hodgkin’s disease) appears to be a group of heterogeneous cancers that have EBV as a factor in at least some of the variants, especially in Africa and lower-resourced countries. HIV is the other virus implicated in the development of HL. EBV is seen more in HL but not in nodular lymphocyte-predominant HL. 60% of classic HL are negative for EBV.
   

4. Carbone A, Volpi CC, Gualeni AV, et al. Epstein-Barr virus associated lymphomas in people with HIV. Curr Opin HIV AIDS. 2017;12(1):39-46.  [PMID:27755151]

   Comment: EBV-related lymphomas in HIV-infected people are heterogeneous. Most are young or middle-aged, and men >> women. Lymphomas of EBV relationship appear to particularly favor the GI tract.
   

5. Grulich AE, Vajdic CM. The epidemiology of cancers in human immunodeficiency virus infection and after organ transplantation. Semin Oncol. 2015;42(2):247-57.  [PMID:25843729]

   Comment: EBV-related malignancies among the top causes of HIV, along with HHV8 and non-Hodgkin’s lymphoma (NHL). EBV may be the promoter in certain types of Burkitt’s lymphoma (mostly in Africa), NHL (including diffuse large B-cel, extra-nodal natural killer/T-cell nasal type) and nasopharyngeal carcinoma.
   

6. Yanagisawa K, Tanuma J, Hagiwara S, et al. Epstein-Barr viral load in cerebrospinal fluid as a diagnostic marker of central nervous system involvement of AIDS-related lymphoma. Intern Med. 2013;52(9):955-9.  [PMID:23648713]

   Comment: Authors using retrospective data suggest that a cut-off of EBV copies of 200/ml predicted CNS lesions (sensitivity 70-73%, specificity 85-93%) with both PCNSL and AIDS-related lymphoma, respectively. Best specificity was achieved using a cut-off of 2,000 copies.
   

7. Tsibris AM, Paredes R, Chadburn A, et al. Lymphoma diagnosis and plasma Epstein-Barr virus load during vicriviroc therapy: results of the AIDS Clinical Trials Group A5211. Clin Infect Dis. 2009;48(5):642-9.  [PMID:19191652]

   Comment: Because 4 lymphomas developed during a phase II trial of vicriviroc (a CCR5 antagonist), plasma EBV DNA was monitored in 116 pts who did not experience increases in detectable levels, suggesting that CCR5 antagonism by this drug did not lead to EBV reactivation.
   

8. Carbone A, Cesarman E, Spina M, et al. HIV-associated lymphomas and gamma-herpesviruses. Blood. 2009;113(6):1213-24.  [PMID:18955561]

   Comment: A thorough overview from an oncologic perspective points out that EBV-driven lymphomas often present with plasmablastic differentiation in HIV+ pts, and that ART appears to improve outcomes with combined chemotherapy protocols.
   Rating: Important
   

9. Corcoran C, Rebe K, van der Plas H, et al. The predictive value of cerebrospinal fluid Epstein-Barr viral load as a marker of primary central nervous system lymphoma in HIV-infected persons. J Clin Virol. 2008;42(4):433-6.  [PMID:18455472]

   Comment: Some have questioned the specificity of CSF EBV PCR in Dx of CNS lymphoma in HIV+ pts. This study suggests that the addition of quantitative aspect (namely >10,000 c/ml) improves specificity and positive predictive value compared to qualitative result for Dx of PCNSL (96% vs. 66% and 50% vs. 10%, respectively).
   Rating: Important
   

10. Orem J, Mbidde EK, Lambert B, et al. Burkitt's lymphoma in Africa, a review of the epidemiology and etiology. Afr Health Sci. 2007;7(3):166-75.  [PMID:18052871]

    Comment: The article discusses the controversy of whether HIV+ adults have a higher rate of Burkitt’s lymphoma.
    

11. Aboulafia DM, Ratner L, Miles SA, et al. Antiviral and immunomodulatory treatment for AIDS-related primary central nervous system lymphoma: AIDS Malignancies Consortium pilot study 019. Clin Lymphoma Myeloma. 2006;6(5):399-402.  [PMID:16640817]

    Comment: A small study suggests that treatment with ganciclovir, AZT, and IL-2 may have been helpful in 2/5 patients.
    

12. Kaaya EE, Castaños-Velez E, Ekman M, et al. AIDS and non AIDS-related malignant lymphoma in Tanzania. Afr Health Sci. 2006;6(2):69-75.  [PMID:16916294]

    Comment: The authors found high rates of EBV (72%) in tested tissues. HIV+ patients also had high rates of HHV-8 seropositivity, but this virus was not associated with tumor cell infection.
    

13. Bossolasco S, Falk KI, Ponzoni M, et al. Ganciclovir is associated with low or undetectable Epstein-Barr virus DNA load in cerebrospinal fluid of patients with HIV-related primary central nervous system lymphoma. Clin Infect Dis. 2006;42(4):e21-5.  [PMID:16421782]

    Comment: Along with Aboulafia ref, data suggesting that active replication of EBV may be playing role in PCNSL.
    

14. Bonnet F, Jouvencel AC, Parrens M, et al. A longitudinal and prospective study of Epstein-Barr virus load in AIDS-related non-Hodgkin lymphoma. J Clin Virol. 2006;36(4):258-63.  [PMID:16762591]

    Comment: EBV PCR was not helpful diagnostically, but higher EBV PCR viral load correlated with poorer outcomes in the HIV+ population with NHL.
    

15. Suankratay C, Shuangshoti S, Mutirangura A, et al. Epstein-Barr virus infection-associated smooth-muscle tumors in patients with AIDS. Clin Infect Dis. 2005;40(10):1521-8.  [PMID:15844077]

    Comment: Case series describing an association.
    Rating: Important
    

16. Ivers LC, Kim AY, Sax PE. Predictive value of polymerase chain reaction of cerebrospinal fluid for detection of Epstein-Barr virus to establish the diagnosis of HIV-related primary central nervous system lymphoma. Clin Infect Dis. 2004;38(11):1629-32.  [PMID:15156453]

    Comment: Small series refuting claimed high sensitivity/specificity of EBV CSF PCR. Here 26 pts studied with CNS processes, but PCR had only 29% positive predictive value, and specificity 79%. This study more likely reflects real-life statistics in evaluating a diffuse set of CNS conditions in HIV. Authors suggest tests useful for ruling out lymphoma, but Dx requires brain Bx.
    Rating: Important
    

17. Walling DM, Flaitz CM, Nichols CM. Epstein-Barr virus replication in oral hairy leukoplakia: response, persistence, and resistance to treatment with valacyclovir. J Infect Dis. 2003;188(6):883-90.  [PMID:12964120]

    Comment: Small RCT of 19 HIV+ pts. examining the use of valacyclovir (with better bioavailability than acyclovir) in the treatment of OHL. Most cases resolved, though in some cases productive EBV replication recurred after discontinuation of treatment. In a few treated cases, treatment failed, which authors attributed to drug-resistant EBV.
    Rating: Important
    

18. Crawford DH, Swerdlow AJ, Higgins C, et al. Sexual history and Epstein-Barr virus infection. J Infect Dis. 2002;186(6):731-6.  [PMID:12198605]

    Comment: A study of university students in Scotland suggests EBV acquired more frequently in those sexually active. However, since kissing and intercourse are closely related behaviors, it is still unclear whether EBV is commonly acquired by other than salivary shedding.
    

19. Vidrih JA, Walensky RP, Sax PE, et al. Positive Epstein-Barr virus heterophile antibody tests in patients with primary human immunodeficiency virus infection. Am J Med. 2001;111(3):192-4.  [PMID:11530029]

    Comment: The report describes 3 pts suspected of IM with positive heterophile (Monospot) testing who instead had acute HIV infection, with EBV-specific serologies not suggesting acute EBV infection. These cases add to other reports showing that the Monospot can be falsely positive in pts with primary HIV infection.
    

20. Rosenberg ES, Caliendo AM, Walker BD. Acute HIV infection among patients tested for mononucleosis. N Engl J Med. 1999;340(12):969.  [PMID:10094651]

    Comment: A retrospective study examined unselected pts with suspected IM who had negative heterophile antibody tests. 2% had HIV disease by plasma HIV RNA testing. Of those, half had primary HIV infection, and half had chronic HIV disease.
    Rating: Important
    

21. Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology. 1997;48(3):687-94.  [PMID:9065549]

    Comment: One of the better papers suggesting the diagnostic utility of CSF EBV DNA PCR in patients with PCNSL. In 136 HIV+ pts with brain lesions, examining both EBV DNA or T. gondii-DNA tests, the positive predictive value for PCNSL increased to >0.96. Regardless, the authors suggested that brain Bx still necessary to establish Dx of PCNSL. However, brain Bx mortality may be ~2%, so this needs to be weighed against risks of inappropriately receiving brain irradiation.
    

22. Beral V, Peterman T, Berkelman R, et al. AIDS-associated non-Hodgkin lymphoma. Lancet. 1991;337(8745):805-9.  [PMID:1672911]

    Comment: Report from pre-HAART era suggesting a 60-fold increased risk of NHL in HIV+ pts and linking risks to EBV. From CDC-gathered information, 1686 cases were immunoblastic lymphoma, 548 primary CNS lymphoma, and 590 Burkitt’s lymphoma, a condition not normally associated with immunosuppression.
    

23. Kakoma I, Mwendapole RM, Bulsara M, et al. Profiles of heterophile antibody to various mammalian erythrocytes in rural populations of Zambia. Comp Immunol Microbiol Infect Dis. 1987;10(1):51-7.  [PMID:3107888]

    Comment: An older study from Zambia backs up the perception of the low incidence of infectious mononucleosis in this country, as this serosurvey found minimal evidence of heterophile antibodies.
    

24. Dias EP, Israel MS, Silva Junior A, et al. Prevalence of oral hairy leukoplakia in 120 pediatric patients infected with HIV-1. Braz Oral Res. 2006;20(2):103-7.  [PMID:16878201]

    Comment: OHL described in a subclinical (histopathological) basis in ~17% of HIV+ pediatric patients, which is higher than prior reports in adult populations.
    

Media

Oral hairy leukoplakia

Advanced OHL afflicting lateral tongue margins. This EBV driven process occurs only under immunosuppressive conditions, but can be seen in HIV with CD4 < 500 cells.

Source: CDC/J. S. Greenspan DDS & S. Silverman, Jr. DDS