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Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults

Cécile Tremblay, MD
Section Editor
Martin S Hirsch, MD
Deputy Editor
Anna R Thorner, MD


Human herpesvirus 6 (HHV-6) was first isolated and characterized from patients with lymphoproliferative disorders [1] and was originally named human B-lymphotropic virus. Its name was changed to human herpesvirus 6 as its tropism was further characterized [2].

There are two HHV-6 variants, HHV-6A and HHV-6B. Based on their distinctive biological properties and genome sequences, HHV-6A and HHV-6B have been classified as two distinct herpesvirus species [3]. The vast majority of documented primary infections and reactivation events are due to HHV-6B. HHV-6B infects most children within the first three years of life and, like other herpesviruses, it establishes latency after primary infection. HHV-6B may reactivate in immunocompromised hosts, especially following allogeneic hematopoietic cell transplantation (HCT). Little is known about the epidemiology or clinical implications of HHV-6A.

The clinical manifestations, diagnosis, and treatment of HHV-6 infection in adults will be presented here. The virology, pathogenesis, and epidemiology of HHV-6 infection, as well as clinical issues in children, are presented separately; HHV-6 infection in hematopoietic cell transplant recipients is also discussed elsewhere. (See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection" and "Human herpesvirus 6 infection in children: Clinical manifestations; diagnosis; and treatment" and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients".)


Immunocompetent hosts — HHV-6 infections usually occur during childhood and result in generally mild, self-limited illnesses. Possible disease associations with HHV-6 in immunocompetent adults are not proven other than a few cases of primary infection. (See "Human herpesvirus 6 infection in children: Clinical manifestations; diagnosis; and treatment", section on 'Clinical manifestations'.)

Primary infection — Primary infection in adults is rare. However, a mononucleosis-like syndrome of varying severity with prolonged lymphadenopathy has been described in association with HHV-6 seroconversion in adults [4-6]. Three adults with serologic evidence of HHV-6 infection had mild illnesses in association with bilateral, nontender, anterior, and posterior lymphadenopathy, which persisted for up to three months [5].


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Literature review current through: Sep 2016. | This topic last updated: Sep 22, 2015.
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  1. Salahuddin SZ, Ablashi DV, Markham PD, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986; 234:596.
  2. Ablashi DV, Salahuddin SZ, Josephs SF, et al. HBLV (or HHV-6) in human cell lines. Nature 1987; 329:207.
  3. International Committee on Taxonomy of Viruses. ICTV Master Species List 2011. http://talk.ictvonline.org/files/ictv_documents/m/msl/4090.aspx (Accessed on June 27, 2012).
  4. Akashi K, Eizuru Y, Sumiyoshi Y, et al. Brief report: severe infectious mononucleosis-like syndrome and primary human herpesvirus 6 infection in an adult. N Engl J Med 1993; 329:168.
  5. Niederman JC, Liu CR, Kaplan MH, Brown NA. Clinical and serological features of human herpesvirus-6 infection in three adults. Lancet 1988; 2:817.
  6. Maric I, Bryant R, Abu-Asab M, et al. Human herpesvirus-6-associated acute lymphadenitis in immunocompetent adults. Mod Pathol 2004; 17:1427.
  7. McCullers JA, Lakeman FD, Whitley RJ. Human herpesvirus 6 is associated with focal encephalitis. Clin Infect Dis 1995; 21:571.
  8. Birnbaum T, Padovan CS, Sporer B, et al. Severe meningoencephalitis caused by human herpesvirus 6 type B in an immunocompetent woman treated with ganciclovir. Clin Infect Dis 2005; 40:887.
  9. Isaacson E, Glaser CA, Forghani B, et al. Evidence of human herpesvirus 6 infection in 4 immunocompetent patients with encephalitis. Clin Infect Dis 2005; 40:890.
  10. Yao K, Honarmand S, Espinosa A, et al. Detection of human herpesvirus-6 in cerebrospinal fluid of patients with encephalitis. Ann Neurol 2009; 65:257.
  11. Hata A, Fujita M, Morishima T, et al. Acute cerebellar ataxia associated with primary human herpesvirus-6 infection: a report of two cases. J Paediatr Child Health 2008; 44:607.
  12. Troy SB, Blackburn BG, Yeom K, et al. Severe encephalomyelitis in an immunocompetent adult with chromosomally integrated human herpesvirus 6 and clinical response to treatment with foscarnet plus ganciclovir. Clin Infect Dis 2008; 47:e93.
  13. Whitley RJ, Lakeman FD. Human herpesvirus 6 infection of the central nervous system: is it just a case of mistaken association? Clin Infect Dis 2005; 40:894.
  14. Donati D, Akhyani N, Fogdell-Hahn A, et al. Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology 2003; 61:1405.
  15. Fotheringham J, Donati D, Akhyani N, et al. Association of human herpesvirus-6B with mesial temporal lobe epilepsy. PLoS Med 2007; 4:e180.
  16. Kawamura Y, Nakayama A, Kato T, et al. Pathogenic Role of Human Herpesvirus 6B Infection in Mesial Temporal Lobe Epilepsy. J Infect Dis 2015; 212:1014.
  17. Dockrell DH, Paya CV. Human herpesvirus-6 and -7 in transplantation. Rev Med Virol 2001; 11:23.
  18. Hentrich M, Oruzio D, Jäger G, et al. Impact of human herpesvirus-6 after haematopoietic stem cell transplantation. Br J Haematol 2005; 128:66.
  19. Yoshikawa T, Suga S, Asano Y, et al. A prospective study of human herpesvirus-6 infection in renal transplantation. Transplantation 1992; 54:879.
  20. Humar A, Malkan G, Moussa G, et al. Human herpesvirus-6 is associated with cytomegalovirus reactivation in liver transplant recipients. J Infect Dis 2000; 181:1450.
  21. Potenza L, Luppi M, Barozzi P, et al. HHV-6A in syncytial giant-cell hepatitis. N Engl J Med 2008; 359:593.
  22. Halme L, Arola J, Höckerstedt K, Lautenschlager I. Human herpesvirus 6 infection of the gastroduodenal mucosa. Clin Infect Dis 2008; 46:434.
  23. Nash PJ, Avery RK, Tang WH, et al. Encephalitis owing to human herpesvirus-6 after cardiac transplant. Am J Transplant 2004; 4:1200.
  24. Cone RW, Hackman RC, Huang ML, et al. Human herpesvirus 6 in lung tissue from patients with pneumonitis after bone marrow transplantation. N Engl J Med 1993; 329:156.
  25. Carrigan DR, Drobyski WR, Russler SK, et al. Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation. Lancet 1991; 338:147.
  26. Cone RW, Huang ML, Hackman RC. Human herpesvirus 6 and pneumonia. Leuk Lymphoma 1994; 15:235.
  27. Merlino C, Giacchino F, Segoloni GP, Ponzi AN. Human herpesvirus-6 infection and renal transplantation. Transplantation 1992; 53:1382.
  28. Volin L, Lautenschlager I, Juvonen E, et al. Human herpesvirus 6 antigenaemia in allogeneic stem cell transplant recipients: impact on clinical course and association with other beta-herpesviruses. Br J Haematol 2004; 126:690.
  29. Dietrich J, Blumberg BM, Roshal M, et al. Infection with an endemic human herpesvirus disrupts critical glial precursor cell properties. J Neurosci 2004; 24:4875.
  30. Challoner PB, Smith KT, Parker JD, et al. Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci U S A 1995; 92:7440.
  31. Rotola A, Merlotti I, Caniatti L, et al. Human herpesvirus 6 infects the central nervous system of multiple sclerosis patients in the early stages of the disease. Mult Scler 2004; 10:348.
  32. Soldan SS, Leist TP, Juhng KN, et al. Increased lymphoproliferative response to human herpesvirus type 6A variant in multiple sclerosis patients. Ann Neurol 2000; 47:306.
  33. Alvarez-Lafuente R, De las Heras V, Bartolomé M, et al. Relapsing-remitting multiple sclerosis and human herpesvirus 6 active infection. Arch Neurol 2004; 61:1523.
  34. Alvarez-Lafuente R, De Las Heras V, Bartolomé M, et al. Beta-interferon treatment reduces human herpesvirus-6 viral load in multiple sclerosis relapses but not in remission. Eur Neurol 2004; 52:87.
  35. Alvarez-Lafuente R, de las Heras V, García-Montojo M, et al. Human herpesvirus-6 and multiple sclerosis: relapsing-remitting versus secondary progressive. Mult Scler 2007; 13:578.
  36. Tuke PW, Hawke S, Griffiths PD, Clark DA. Distribution and quantification of human herpesvirus 6 in multiple sclerosis and control brains. Mult Scler 2004; 10:355.
  37. Rotola A, Cassai E, Tola MR, et al. Human herpesvirus 6 is latent in peripheral blood of patients with relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 1999; 67:529.
  38. Hay KA, Tenser RB. Leukotropic herpesviruses in multiple sclerosis. Mult Scler 2000; 6:66.
  39. Härmä M, Höckerstedt K, Lautenschlager I. Human herpesvirus-6 and acute liver failure. Transplantation 2003; 76:536.
  40. Chevret L, Boutolleau D, Halimi-Idri N, et al. Human herpesvirus-6 infection: a prospective study evaluating HHV-6 DNA levels in liver from children with acute liver failure. J Med Virol 2008; 80:1051.
  41. Sairenji T, Yamanishi K, Tachibana Y, et al. Antibody responses to Epstein-Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome. Intervirology 1995; 38:269.
  42. Ablashi DV, Eastman HB, Owen CB, et al. Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. J Clin Virol 2000; 16:179.
  43. Gold D, Bowden R, Sixbey J, et al. Chronic fatigue. A prospective clinical and virologic study. JAMA 1990; 264:48.
  44. Levine PH, Jacobson S, Pocinki AG, et al. Clinical, epidemiologic, and virologic studies in four clusters of the chronic fatigue syndrome. Arch Intern Med 1992; 152:1611.
  45. Di Luca D, Dolcetti R, Mirandola P, et al. Human herpesvirus 6: a survey of presence and variant distribution in normal peripheral lymphocytes and lymphoproliferative disorders. J Infect Dis 1994; 170:211.
  46. Yadav M, Chandrashekran A, Vasudevan DM, Ablashi DV. Frequent detection of human herpesvirus 6 in oral carcinoma. J Natl Cancer Inst 1994; 86:1792.
  47. Chi J, Gu B, Zhang C, et al. Human herpesvirus 6 latent infection in patients with glioma. J Infect Dis 2012; 206:1394.
  48. Comar M, D'Agaro P, Campello C, et al. Human herpes virus 6 in archival cardiac tissues from children with idiopathic dilated cardiomyopathy or congenital heart disease. J Clin Pathol 2009; 62:80.
  49. Picard D, Janela B, Descamps V, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response. Sci Transl Med 2010; 2:46ra62.
  50. Ozcan D, Seçkin D, Bilezikçi B, Arslan H. The role of human herpesvirus-6, Epstein–Barr virus and cytomegalovirus infections in the etiopathogenesis of different types of cutaneous drug reactions. Int J Dermatol 2010; 49:1250.
  51. Goto M, Shimizu F, Takeo N, et al. Drug-induced hypersensitivity syndrome due to carbapenem antibiotics. J Dermatol 2010; 37:374.
  52. Gentile I, Talamo M, Borgia G. Is the drug-induced hypersensitivity syndrome (DIHS) due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review. BMC Infect Dis 2010; 10:49.
  53. Saida S, Yoshida A, Tanaka R, et al. A case of drug-induced hypersensitivity syndrome-like symptoms following HHV-6 encephalopathy. Allergol Int 2010; 59:83.
  54. Descamps V, Ranger-Rogez S. DRESS syndrome. Joint Bone Spine 2014; 81:15.
  55. Spira TJ, Bozeman LH, Sanderlin KC, et al. Lack of correlation between human herpesvirus-6 infection and the course of human immunodeficiency virus infection. J Infect Dis 1990; 161:567.
  56. Fairfax MR, Schacker T, Cone RW, et al. Human herpesvirus 6 DNA in blood cells of human immunodeficiency virus-infected men: correlation of high levels with high CD4 cell counts. J Infect Dis 1994; 169:1342.
  57. Bossolasco S, Marenzi R, Dahl H, et al. Human herpesvirus 6 in cerebrospinal fluid of patients infected with HIV: frequency and clinical significance. J Neurol Neurosurg Psychiatry 1999; 67:789.
  58. Dolcetti R, Di Luca D, Carbone A, et al. Human herpesvirus 6 in human immunodeficiency virus-infected individuals: association with early histologic phases of lymphadenopathy syndrome but not with malignant lymphoproliferative disorders. J Med Virol 1996; 48:344.
  59. Couillard M, Joly JR, Deschênes L, Richer G. Evaluation of variables in immunofluorescence procedures for the detection of antibodies against human herpesvirus 6 (HHV-6). Diagn Microbiol Infect Dis 1992; 15:313.
  60. Robert C, Agut H, Aubin JT, et al. Detection of antibodies to human herpesvirus-6 using immunofluorescence assay. Res Virol 1990; 141:545.
  61. Chou SW, Scott KM. Rises in antibody to human herpesvirus 6 detected by enzyme immunoassay in transplant recipients with primary cytomegalovirus infection. J Clin Microbiol 1990; 28:851.
  62. Nielsen L, Vestergaard BF. A mu-capture immunoassay for detection of human herpes virus-6 (HHV-6) IgM antibodies in human serum. J Clin Virol 2002; 25:145.
  63. Nishimura N, Yoshikawa T, Ozaki T, et al. In vitro and in vivo analysis of human herpesvirus-6 U90 protein expression. J Med Virol 2005; 75:86.
  64. Norton RA, Caserta MT, Hall CB, et al. Detection of human herpesvirus 6 by reverse transcription-PCR. J Clin Microbiol 1999; 37:3672.
  65. Fujiwara N, Namba H, Ohuchi R, et al. Monitoring of human herpesvirus-6 and -7 genomes in saliva samples of healthy adults by competitive quantitative PCR. J Med Virol 2000; 61:208.
  66. Blumberg BM, Mock DJ, Powers JM, et al. The HHV6 paradox: ubiquitous commensal or insidious pathogen? A two-step in situ PCR approach. J Clin Virol 2000; 16:159.
  67. Ihira M, Ohta A, Sugata K, et al. Loop-mediated isothermal amplification for discriminating between human herpesvirus 6 A and B. J Virol Methods 2008; 154:223.
  68. Fotheringham J, Akhyani N, Vortmeyer A, et al. Detection of active human herpesvirus-6 infection in the brain: correlation with polymerase chain reaction detection in cerebrospinal fluid. J Infect Dis 2007; 195:450.
  69. Canto CL, Sumita LM, Machado AF, et al. Optimization of the Sybr Green real time PCR for the detection of Human Herpes Virus type 6 (HHV-6). Rev Inst Med Trop Sao Paulo 2008; 50:61.
  70. Deback C, Agbalika F, Scieux C, et al. Detection of human herpesviruses HHV-6, HHV-7 and HHV-8 in whole blood by real-time PCR using the new CMV, HHV-6, 7, 8 R-gene kit. J Virol Methods 2008; 149:285.
  71. Engelmann I, Petzold DR, Kosinska A, et al. Rapid quantitative PCR assays for the simultaneous detection of herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6 DNA in blood and other clinical specimens. J Med Virol 2008; 80:467.
  72. Flamand L, Gravel A, Boutolleau D, et al. Multicenter comparison of PCR assays for detection of human herpesvirus 6 DNA in serum. J Clin Microbiol 2008; 46:2700.
  73. Caserta MT, Hall CB, Schnabel K, et al. Diagnostic assays for active infection with human herpesvirus 6 (HHV-6). J Clin Virol 2010; 48:55.
  74. Crawford JR, Kadom N, Santi MR, et al. Human herpesvirus 6 rhombencephalitis in immunocompetent children. J Child Neurol 2007; 22:1260.
  75. Williams MV. HHV-6: response to antiviral agents. In: Human herpesvirus-6: epidemiology, molecular biology, and clinical pathology, Ablashi DV, Krueger RF, Salahuddin SZ (Eds), Elsevier Biomedical Press, Amsterdam p.317.
  76. Manichanh C, Olivier-Aubron C, Lagarde JP, et al. Selection of the same mutation in the U69 protein kinase gene of human herpesvirus-6 after prolonged exposure to ganciclovir in vitro and in vivo. J Gen Virol 2001; 82:2767.
  77. De Bolle L, Manichanh C, Agut H, et al. Human herpesvirus 6 DNA polymerase: enzymatic parameters, sensitivity to ganciclovir and determination of the role of the A961V mutation in HHV-6 ganciclovir resistance. Antiviral Res 2004; 64:17.
  78. Isegawa Y, Hara J, Amo K, et al. Human herpesvirus 6 ganciclovir-resistant strain with amino acid substitutions associated with the death of an allogeneic stem cell transplant recipient. J Clin Virol 2009; 44:15.
  79. Bonnafous P, Boutolleau D, Naesens L, et al. Characterization of a cidofovir-resistant HHV-6 mutant obtained by in vitro selection. Antiviral Res 2008; 77:237.
  80. Ljungman P, Dahl H, Xu YH, et al. Effectiveness of ganciclovir against human herpesvirus-6 excreted in saliva in stem cell transplant recipients. Bone Marrow Transplant 2007; 39:497.
  81. Ogata M, Kikuchi H, Satou T, et al. Human herpesvirus 6 DNA in plasma after allogeneic stem cell transplantation: incidence and clinical significance. J Infect Dis 2006; 193:68.
  82. Tiacci E, Luppi M, Barozzi P, et al. Fatal herpesvirus-6 encephalitis in a recipient of a T-cell-depleted peripheral blood stem cell transplant from a 3-loci mismatched related donor. Haematologica 2000; 85:94.
  83. Seeley WW, Marty FM, Holmes TM, et al. Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology 2007; 69:156.
  84. Bethge W, Beck R, Jahn G, et al. Successful treatment of human herpesvirus-6 encephalitis after bone marrow transplantation. Bone Marrow Transplant 1999; 24:1245.
  85. Olli-Lähdesmäki T, Haataja L, Parkkola R, et al. High-dose ganciclovir in HHV-6 encephalitis of an immunocompetent child. Pediatr Neurol 2010; 43:53.