Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Clinical manifestations and treatment of Epstein-Barr virus infection

John L Sullivan, MD
Section Editors
Martin S Hirsch, MD
Sheldon L Kaplan, MD
Deputy Editor
Jennifer Mitty, MD, MPH


Epstein-Barr virus (EBV) is a widely disseminated herpesvirus that is spread by intimate contact between susceptible persons and asymptomatic EBV shedders. EBV is the primary agent of infectious mononucleosis (IM), persists asymptomatically for life in nearly all adults, and is associated with the development of B cell lymphomas, T cell lymphomas, Hodgkin lymphoma and nasopharyngeal carcinomas in certain patients. Reactivation disease is not a prominent issue with EBV, in contrast to other common herpesviruses, but it has been associated with an aggressive lymphoproliferative disorder in transplant recipients [1]. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

The clinical manifestations and treatment of EBV infections will be reviewed here. The diagnosis of EBV as pertains to infectious mononucleosis is discussed separately. (See "Infectious mononucleosis in adults and adolescents".)


The majority of primary EBV infections throughout the world are subclinical and inapparent. Antibodies to EBV have been demonstrated in all population groups with a worldwide distribution; approximately 90 to 95 percent of adults are EBV-seropositive. The host range of EBV is restricted to humans and certain subhuman primates including squirrel monkeys and cotton top marmosets [2].


Like other members of the herpesvirus family, EBV has a latency phase. The host cells for the organism in humans are limited to B lymphocytes, T lymphocytes, epithelial cells and myocytes. Unlike herpes simplex (HSV) or cytomegalovirus (CMV), EBV is capable of transforming B cells but does not routinely display a cytopathic effect. A detailed discussion of the virology of EBV is found elsewhere. (See "Virology of Epstein-Barr virus".)


EBV can cause a number of primary infections, can lead to complications, and can induce a variety of malignancies.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Apr 04, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Odumade OA, Hogquist KA, Balfour HH Jr. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev 2011; 24:193.
  2. Miller G, Shope T, Lisco H, et al. Epstein-Barr virus: transformation, cytopathic changes, and viral antigens in squirrel monkey and marmoset leukocytes. Proc Natl Acad Sci U S A 1972; 69:383.
  3. Dunmire SK, Hogquist KA, Balfour HH. Infectious Mononucleosis. Curr Top Microbiol Immunol 2015; 390:211.
  4. Luzuriaga K, Sullivan JL. Infectious mononucleosis. N Engl J Med 2010; 362:1993.
  5. EVANS AS. Infectious mononucleosis in University of Wisconsin students. Report of a five-year investigation. Am J Hyg 1960; 71:342.
  6. Grose C. The many phases of infectious mononucleosis; the spectrum of Epstein-Barr virus infection in children. Pediatr Rev 1985; 7:35.
  7. Horwitz CA, Henle W, Henle G, et al. Clinical and laboratory evaluation of infants and children with Epstein-Barr virus-induced infectious mononucleosis: report of 32 patients (aged 10-48 months). Blood 1981; 57:933.
  8. Tamaki H, Beaulieu BL, Somasundaran M, Sullivan JL. Major histocompatibility complex class I-restricted cytotoxic T lymphocyte responses to Epstein-Barr virus in children. J Infect Dis 1995; 172:739.
  9. Fleisher G, Bologonese R. Epstein-Barr virus infections in pregnancy: a prospective study. J Pediatr 1984; 104:374.
  10. Goldberg GN, Fulginiti VA, Ray CG, et al. In utero Epstein-Barr virus (infectious mononucleosis) infection. JAMA 1981; 246:1579.
  11. Chang RS, Seto DS. Perinatal infection by Epstein-Barr virus. Lancet 1979; 2:201.
  12. Hudson LB, Perlman SE. Necrotizing genital ulcerations in a premenarcheal female with mononucleosis. Obstet Gynecol 1998; 92:642.
  13. Tselis A, Duman R, Storch GA, Lisak RP. Epstein-Barr virus encephalomyelitis diagnosed by polymerase chain reaction: detection of the genome in the CSF. Neurology 1997; 48:1351.
  14. Haverkos HW, Amsel Z, Drotman DP. Adverse virus-drug interactions. Rev Infect Dis 1991; 13:697.
  15. Triantos D, Porter SR, Scully C, Teo CG. Oral hairy leukoplakia: clinicopathologic features, pathogenesis, diagnosis, and clinical significance. Clin Infect Dis 1997; 25:1392.
  16. Epstein JB, Sherlock CH, Greenspan JS. Hairy leukoplakia-like lesions following bone-marrow transplantation. AIDS 1991; 5:101.
  17. Greenspan D, Canchola AJ, MacPhail LA, et al. Effect of highly active antiretroviral therapy on frequency of oral warts. Lancet 2001; 357:1411.
  18. Birnbaum W, Hodgson TA, Reichart PA, et al. Prognostic significance of HIV-associated oral lesions and their relation to therapy. Oral Dis 2002; 8 Suppl 2:110.
  19. Walling DM, Etienne W, Ray AJ, et al. Persistence and transition of Epstein-Barr virus genotypes in the pathogenesis of oral hairy leukoplakia. J Infect Dis 2004; 190:387.
  20. Aldrete JS. Spontaneous rupture of the spleen in patients with infectious mononucleosis. Mayo Clin Proc 1992; 67:910.
  21. van Hal S, Senanayake S, Hardiman R. Splenic infarction due to transient antiphospholipid antibodies induced by acute Epstein-Barr virus infection. J Clin Virol 2005; 32:245.
  22. Asgari MM, Begos DG. Spontaneous splenic rupture in infectious mononucleosis: a review. Yale J Biol Med 1997; 70:175.
  23. Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 2004; 350:1328.
  24. Tangye SG, Palendira U, Edwards ES. Human immunity against EBV-lessons from the clinic. J Exp Med 2017; 214:269.
  25. Sullivan JL, Woda BA, Herrod HG, et al. Epstein-Barr virus-associated hemophagocytic syndrome: virological and immunopathological studies. Blood 1985; 65:1097.
  26. Guinee D Jr, Jaffe E, Kingma D, et al. Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 1994; 18:753.
  27. Myers JL, Kurtin PJ, Katzenstein AL, et al. Lymphomatoid granulomatosis. Evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol 1995; 19:1300.
  28. Haque AK, Myers JL, Hudnall SD, et al. Pulmonary lymphomatoid granulomatosis in acquired immunodeficiency syndrome: lesions with Epstein-Barr virus infection. Mod Pathol 1998; 11:347.
  29. Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer 1979; 43:360.
  30. Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid Granulomatosis. Prospective clinical and therapeutic experience over 10 years. N Engl J Med 1982; 306:68.
  31. Sordillo PP, Epremian B, Koziner B, et al. Lymphomatoid granulomatosis: an analysis of clinical and immunologic characteristics. Cancer 1982; 49:2070.
  32. Wilson WH, Kingma DW, Raffeld M, et al. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood 1996; 87:4531.
  33. Hanto DW. Classification of Epstein-Barr virus-associated posttransplant lymphoproliferative diseases: implications for understanding their pathogenesis and developing rational treatment strategies. Annu Rev Med 1995; 46:381.
  34. Capello D, Cerri M, Muti G, et al. Analysis of immunoglobulin heavy and light chain variable genes in post-transplant lymphoproliferative disorders. Hematol Oncol 2006; 24:212.
  35. BURKITT D. A sarcoma involving the jaws in African children. Br J Surg 1958; 46:218.
  36. Donati D, Espmark E, Kironde F, et al. Clearance of circulating Epstein-Barr virus DNA in children with acute malaria after antimalaria treatment. J Infect Dis 2006; 193:971.
  37. Miller G. Epstein-Barr virus: Biology, Pathogenesis, and Medical Aspects. In: Virology, Second Edition, Fields BN, Knipe DM (Eds), Raven Press, New York 1990. Vol 2, p.1921.
  38. Ziegler JL. Burkitt's lymphoma. N Engl J Med 1981; 305:735.
  39. Brown NA, Liu CR, Wang YF, Garcia CR. B-cell lymphoproliferation and lymphomagenesis are associated with clonotypic intracellular terminal regions of the Epstein-Barr virus. J Virol 1988; 62:962.
  40. Raab-Traub N, Flynn K. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell 1986; 47:883.
  41. Neri A, Barriga F, Inghirami G, et al. Epstein-Barr virus infection precedes clonal expansion in Burkitt's and acquired immunodeficiency syndrome-associated lymphoma. Blood 1991; 77:1092.
  42. Rooney CM, Gregory CD, Rowe M, et al. Endemic Burkitt's lymphoma: phenotypic analysis of tumor biopsy cells and of derived tumor cell lines. J Natl Cancer Inst 1986; 77:681.
  43. Gregory CD, Murray RJ, Edwards CF, Rickinson AB. Downregulation of cell adhesion molecules LFA-3 and ICAM-1 in Epstein-Barr virus-positive Burkitt's lymphoma underlies tumor cell escape from virus-specific T cell surveillance. J Exp Med 1988; 167:1811.
  44. Billaud M, Rousset F, Calender A, et al. Low expression of lymphocyte function-associated antigen (LFA)-1 and LFA-3 adhesion molecules is a common trait in Burkitt's lymphoma associated with and not associated with Epstein-Barr virus. Blood 1990; 75:1827.
  45. Rezk SA, Weiss LM. Epstein-Barr virus-associated lymphoproliferative disorders. Hum Pathol 2007; 38:1293.
  46. Levitskaya J, Coram M, Levitsky V, et al. Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 1995; 375:685.
  47. Masucci MG, Torsteindottir S, Colombani J, et al. Down-regulation of class I HLA antigens and of the Epstein-Barr virus-encoded latent membrane protein in Burkitt lymphoma lines. Proc Natl Acad Sci U S A 1987; 84:4567.
  48. Moormann AM, Bailey JA. Malaria - how this parasitic infection aids and abets EBV-associated Burkitt lymphomagenesis. Curr Opin Virol 2016; 20:78.
  49. Njie R, Bell AI, Jia H, et al. The effects of acute malaria on Epstein-Barr virus (EBV) load and EBV-specific T cell immunity in Gambian children. J Infect Dis 2009; 199:31.
  50. Levine AM. AIDS-related malignancies: the emerging epidemic. J Natl Cancer Inst 1993; 85:1382.
  51. Coté TR, Biggar RJ, Rosenberg PS, et al. Non-Hodgkin's lymphoma among people with AIDS: incidence, presentation and public health burden. AIDS/Cancer Study Group. Int J Cancer 1997; 73:645.
  52. Shibata D, Weiss LM, Hernandez AM, et al. Epstein-Barr virus-associated non-Hodgkin's lymphoma in patients infected with the human immunodeficiency virus. Blood 1993; 81:2102.
  53. Ometto L, Menin C, Masiero S, et al. Molecular profile of Epstein-Barr virus in human immunodeficiency virus type 1-related lymphadenopathies and lymphomas. Blood 1997; 90:313.
  54. Birx DL, Redfield RR, Tosato G. Defective regulation of Epstein-Barr virus infection in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related disorders. N Engl J Med 1986; 314:874.
  55. Kersten MJ, Klein MR, Holwerda AM, et al. Epstein-Barr virus-specific cytotoxic T cell responses in HIV-1 infection: different kinetics in patients progressing to opportunistic infection or non-Hodgkin's lymphoma. J Clin Invest 1997; 99:1525.
  56. Pluda JM, Yarchoan R, Jaffe ES, et al. Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med 1990; 113:276.
  57. Chadwick EG, Connor EJ, Hanson IC, et al. Tumors of smooth-muscle origin in HIV-infected children. JAMA 1990; 263:3182.
  58. McClain KL, Leach CT, Jenson HB, et al. Association of Epstein-Barr virus with leiomyosarcomas in young people with AIDS. N Engl J Med 1995; 332:12.
  59. Lee ES, Locker J, Nalesnik M, et al. The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation. N Engl J Med 1995; 332:19.
  60. Weiss LM, Strickler JG, Warnke RA, et al. Epstein-Barr viral DNA in tissues of Hodgkin's disease. Am J Pathol 1987; 129:86.
  61. Pallesen G, Hamilton-Dutoit SJ, Rowe M, Young LS. Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet 1991; 337:320.
  62. Ménard F, Besson C, Rincé P, et al. Hodgkin lymphoma-associated hemophagocytic syndrome: a disorder strongly correlated with Epstein-Barr virus. Clin Infect Dis 2008; 47:531.
  63. Chang KL, Albújar PF, Chen YY, et al. High prevalence of Epstein-Barr virus in the Reed-Sternberg cells of Hodgkin's disease occurring in Peru. Blood 1993; 81:496.
  64. Kusuda M, Toriyama K, Kamidigo NO, Itakura H. A comparison of epidemiologic, histologic, and virologic studies on Hodgkin's disease in western Kenya and Nagasaki, Japan. Am J Trop Med Hyg 1998; 59:801.
  65. Razzouk BI, Gan YJ, Mendonça C, et al. Epstein-Barr virus in pediatric Hodgkin disease: age and histiotype are more predictive than geographic region. Med Pediatr Oncol 1997; 28:248.
  66. Sixbey JW, Shirley P, Chesney PJ, et al. Detection of a second widespread strain of Epstein-Barr virus. Lancet 1989; 2:761.
  67. Gledhill S, Gallagher A, Jones DB, et al. Viral involvement in Hodgkin's disease: detection of clonal type A Epstein-Barr virus genomes in tumour samples. Br J Cancer 1991; 64:227.
  68. Boyle MJ, Sewell WA, Sculley TB, et al. Subtypes of Epstein-Barr virus in human immunodeficiency virus-associated non-Hodgkin lymphoma. Blood 1991; 78:3004.
  69. Young LS, Yao QY, Rooney CM, et al. New type B isolates of Epstein-Barr virus from Burkitt's lymphoma and from normal individuals in endemic areas. J Gen Virol 1987; 68 ( Pt 11):2853.
  70. Deacon EM, Pallesen G, Niedobitek G, et al. Epstein-Barr virus and Hodgkin's disease: transcriptional analysis of virus latency in the malignant cells. J Exp Med 1993; 177:339.
  71. Glaser SL, Lin RJ, Stewart SL, et al. Epstein-Barr virus-associated Hodgkin's disease: epidemiologic characteristics in international data. Int J Cancer 1997; 70:375.
  72. Ho JH. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1978; 4:182.
  73. Andersson-Anvret M, Forsby N, Klein G, Henle W. Relationship between the Epstein-Barr virus and undifferentiated nasopharyngeal carcinoma: correlated nucleic acid hybridization and histopathological examination. Int J Cancer 1977; 20:486.
  74. Lo S, Ho WK, Wei WI. Outcome of patients with positive Epstein-Barr virus serologic status in the absence of nasopharyngeal carcinoma in Hong Kong. Arch Otolaryngol Head Neck Surg 2004; 130:770.
  75. Pathmanathan R, Prasad U, Sadler R, et al. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med 1995; 333:693.
  76. Brooks L, Yao QY, Rickinson AB, Young LS. Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J Virol 1992; 66:2689.
  77. Busson P, McCoy R, Sadler R, et al. Consistent transcription of the Epstein-Barr virus LMP2 gene in nasopharyngeal carcinoma. J Virol 1992; 66:3257.
  78. Mosialos G, Birkenbach M, Yalamanchili R, et al. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 1995; 80:389.
  79. Anagnostopoulos I, Hummel M, Kreschel C, Stein H. Morphology, immunophenotype, and distribution of latently and/or productively Epstein-Barr virus-infected cells in acute infectious mononucleosis: implications for the interindividual infection route of Epstein-Barr virus. Blood 1995; 85:744.
  80. Jones JF, Shurin S, Abramowsky C, et al. T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections. N Engl J Med 1988; 318:733.
  81. Chen CL, Sadler RH, Walling DM, et al. Epstein-Barr virus (EBV) gene expression in EBV-positive peripheral T-cell lymphomas. J Virol 1993; 67:6303.
  82. Quintanilla-Martinez L, Kumar S, Fend F, et al. Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Blood 2000; 96:443.
  83. Jaffe ES. Classification of natural killer (NK) cell and NK-like T-cell malignancies. Blood 1996; 87:1207.
  84. Jaffe ES, Chan JK, Su IJ, et al. Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas. Definitions, differential diagnosis, and epidemiology. Am J Surg Pathol 1996; 20:103.
  85. Cheung MM, Chan JK, Lau WH, et al. Primary non-Hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol 1998; 16:70.
  86. Emile JF, Boulland ML, Haioun C, et al. CD5-CD56+ T-cell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas. Blood 1996; 87:1466.
  87. Tynell E, Aurelius E, Brandell A, et al. Acyclovir and prednisolone treatment of acute infectious mononucleosis: a multicenter, double-blind, placebo-controlled study. J Infect Dis 1996; 174:324.
  88. Brandfonbrener A, Epstein A, Wu S, Phair J. Corticosteroid therapy in Epstein-Barr virus infection. Effect on lymphocyte class, subset, and response to early antigen. Arch Intern Med 1986; 146:337.
  89. van der Horst C, Joncas J, Ahronheim G, et al. Lack of effect of peroral acyclovir for the treatment of acute infectious mononucleosis. J Infect Dis 1991; 164:788.
  90. Torre D, Tambini R. Acyclovir for treatment of infectious mononucleosis: a meta-analysis. Scand J Infect Dis 1999; 31:543.
  91. Bollard CM, Gottschalk S, Torrano V, et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol 2014; 32:798.
  92. www.clinicaltrials.gov/ct2/show/NCT01498484 (Accessed on May 01, 2015).
  93. Thorley-Lawson DA, Poodry CA. Identification and isolation of the main component (gp350-gp220) of Epstein-Barr virus responsible for generating neutralizing antibodies in vivo. J Virol 1982; 43:730.
  94. North JR, Morgan AJ, Thompson JL, Epstein MA. Purified Epstein-Barr virus Mr 340,000 glycoprotein induces potent virus-neutralizing antibodies when incorporated in liposomes. Proc Natl Acad Sci U S A 1982; 79:7504.
  95. Epstein MA, Morgan AJ, Finerty S, et al. Protection of cottontop tamarins against Epstein-Barr virus-induced malignant lymphoma by a prototype subunit vaccine. Nature 1985; 318:287.