Human Herpesvirus 6 Infection Clinical Presentation
- Author: Michelle R Salvaggio, MD, FACP; Chief Editor: Burke A Cunha, MD more...
Human herpesvirus 6 (HHV-6) infection is often asymptomatic. Symptomatic manifestations occur predominately after primary infection in infants and after either primary or reactivation disease in immunocompromised adults.
HHV-6 is the single most common cause of hospital visits in infants with fever. Approximately 20% of HHV-6 infections manifest as roseola, which is characterized by the abrupt onset of an initial febrile phase of 3-5 days, with temperatures reaching 40°C. With the fever, some children exhibit bilateral periorbital edema in the prodrome.
This initial phase may be followed by an erythematous maculopapular rash that appears when the temperature normalizes. The rash starts at the trunk and spreads centrifugally to the face and limbs. More commonly, the infection presents as an acute nonspecific febrile illness in a child younger than 2 years. HHV-6 infection may also manifest as a rash and no fever.
Symptoms reported in children may include the following:
Ear symptoms, otitis
Upper respiratory tract symptoms
Gastrointestinal (GI) symptoms, including liver dysfunction and hepatitis
Fever-induced seizures 
Symptoms of meningoencephalitis 
Symptoms reported in adults may include the following:
Fever with lymphadenopathy, a mononucleosislike disease with negative test results for acute cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection
Symptoms consistent with hepatitis
Symptoms consistent with encephalitis
It is possible that HHV-6 may play a role in multiple sclerosis (MS). HHV-6 antigen has been demonstrated in the oligodendrocytes of patients with MS. In addition, HHV-6 DNA and high rates of immunoglobulin M (IgM) antibody to HHV-6 have been detected in patients with relapsing-remitting type MS, but not in those with chronic progressive MS disease or in control subjects.
Symptoms reported in immunocompromised hosts and transplant recipients may include the following:
Fever, usually very high
Symptoms of graft versus host disease (GVHD)
Symptoms of graft rejection
Symptoms of interstitial pneumonitis
Symptoms of meningoencephalitis or myelitis 
Symptoms reported in patients with HIV infection may include the following:
Symptoms of interstitial pneumonitis
Symptoms of meningoencephalitis
Physical findings of HHV-6 infection are those expected with the symptoms described (see History). Most cases of HHV-6 infection are asymptomatic. Very few physical examination findings exist in children who are infected with HHV-6 until skin findings become apparent.
Findings in infants that may suggest HHV-6 infection include the following (see the images below):
High-grade fever (>39.5°C [103°F]), typically persisting for 3-5 days and then resolving abruptly; undifferentiated febrile illness without rash or localizing signs is possible
Erythematous macular or maculopapular rash on the trunk, arms, neck, and face, and later on the lower extremities – The rash commonly appears during or within a few hours after defervescence; it is nonpruritic and mildly elevated, consists of rose-pink papules, and blanches on pressure; it usually fades in 1-2 days
Inflamed tympanic membranes
Signs of upper and, occasionally, lower respiratory tract involvement
Hepatomegaly (a common GI sign)
Central nervous system (CNS) manifestations – Most children are playful despite high-grade fever; however, anorexia, irritability, and listlessness may be presenting signs; febrile seizures occur in 10-15% of primary infections; HHV-6 is a major precipitant of seizures in infants, not merely because of the high fever but also because HHV-6 replicates in the CNS9-month-old infant boy presented with 1-day history of high-grade fever and irritability. In emergency department, patient underwent septic workup, including lumbar puncture (adhesive bandage), with normal cerebrospinal fluid analysis results. He was admitted to hospital9-month-old infant boy presented with 1-day history of high-grade fever and irritability. In emergency department, patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to hospital. High-grade fever abruptly resolved on day 3 of hospitalization. Within a few hours, erythematous, pink papular (roseola) nonpruritic rash appeared, mainly on trunk.9-month-old infant boy presented with 1-day history of high-grade fever and irritability. In emergency department, patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to hospital. High-grade fever abruptly resolved on day 3 of hospitalization. Within a few hours, erythematous, pink papular (roseola) nonpruritic rash appeared, mainly on trunk. Patient was playful after supportive therapy. Antibiotics were discontinued after 2 days of negative culture.
HHV-6 infection in adults can have a wide variety of manifestations, which may range from mild to severe. Findings in healthy adults may include the following:
CNS manifestations (eg, meningismus and mental status changes)
Reports of encephalitis as a complication of exanthema subitum and the appreciation that HHV-6 is highly neurotropic predicted that the virus might be associated with encephalitis in other settings as well. Current controversy exists regarding reports of HHV-6 in the brains of patients with MS. Active HHV-6 infection in the CNS has been postulated to promote inflammatory injury and demyelination, but this is far from proven.
Findings in immunocompromised individuals may include the following:
Signs of pneumonitis
Mental status changes or meningismus
Immunocompromised individuals with HHV-6 infection may experience organ failure and death. Patients who have undergone transplantation may experience accelerated rejection of the transplant.
Pellett PE, Ablashi DV, Ambros PF, Agut H, Caserta MT, et al. Chromosomally integrated human herpesvirus 6: questions and answers. Rev Med Virol. 2012 May. 22(3):144-55. [Medline].
Agut H. Deciphering the clinical impact of acute human herpesvirus 6 (HHV-6) infections. J Clin Virol. 2011 Nov. 52(3):164-71. [Medline].
Strong MJ, O'Grady T, Lin Z, Xu G, Baddoo M, Parsons C, et al. Epstein-Barr Virus and Human Herpesvirus 6 Detection in a non-Hodgkin's Diffuse Large B-Cell Lymphoma Cohort using RNA-Seq. J Virol. 2013 Sep 18. [Medline].
Merk J, Schmid FX, Fleck M, Schwarz S, Lehane C, Boehm S, et al. Fatal pulmonary failure attributable to viral pneumonia with human herpes virus 6 (HHV6) in a young immunocompetent woman. J Intensive Care Med. 2005 Sep-Oct. 20(5):302-6. [Medline].
Harris RC. Long-term effects of human herpesvirus 6 infection. Pediatrics. 2008 Sep. 122(3):679. [Medline].
Broccolo F, Drago F, Cassina G, Fava A, Fusetti L, Matteoli B, et al. Selective reactivation of human herpesvirus 6 in patients with autoimmune connective tissue diseases. J Med Virol. 2013 Nov. 85(11):1925-34. [Medline].
Singh N. Infections with Human Herpesvirus 6, 7, and 8 after hematopoietic stem cell or solid organ transplantation. In: Bowden R, Ljungman P, Paya C. Transplant Infections. 2nd. Philadelphia: Lippincott Williams & Wilkins; 2004:365-374.
Betts BC, Young JA, Ustun C, Cao Q, Weisdorf DJ. Human herpesvirus 6 infection after hematopoietic cell transplantation: is routine surveillance necessary?. Biol Blood Marrow Transplant. 2011 Oct. 17(10):1562-8. [Medline]. [Full Text].
Buyse S, Roque-Afonso AM, Vaghefi P, Gigou M, Dussaix E, Duclos-Vallée JC, et al. Acute hepatitis with periportal confluent necrosis associated with human herpesvirus 6 infection in liver transplant patients. Am J Clin Pathol. 2013 Sep. 140(3):403-9. [Medline].
Kunisaki Y, Goto H, Kitagawa K, Nagano M. Salazosulfapyridine induced hypersensitivity syndrome associated with reactivation of humanherpes virus 6. Intern Med. 2003 Feb. 42(2):203-7. [Medline].
Ward KN, Leong HN, Nacheva EP, Howard J, Atkinson CE, Davies NW, et al. Human herpesvirus 6 chromosomal integration in immunocompetent patients results in high levels of viral DNA in blood, sera, and hair follicles. J Clin Microbiol. 2006 Apr. 44(4):1571-4. [Medline]. [Full Text].
Hasegawa A, Yasukawa M, Sakai I, Fujita S. Transcriptional down-regulation of CXC chemokine receptor 4 induced by impaired association of transcription regulator YY1 with c-Myc in human herpesvirus 6-infected cells. J Immunol. 2001 Jan 15. 166(2):1125-31. [Medline].
Kumagai T, Yoshikawa T, Yoshida M, Okui T, Ihira M, Nagata N, et al. Time course characteristics of human herpesvirus 6 specific cellular immune response and natural killer cell activity in patients with exanthema subitum. J Med Virol. 2006 Jun. 78(6):792-9. [Medline].
Challoner PB, Smith KT, Parker JD, MacLeod DL, Coulter SN, et al. Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci U S A. 1995 Aug 1. 92(16):7440-4. [Medline]. [Full Text].
Tejada-Simon MV, Zang YC, Hong J, Rivera VM, Zhang JZ. Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis. Ann Neurol. 2003 Feb. 53(2):189-97. [Medline].
Yamanishi K, Okuno T, Shiraki K, Takahashi M, Kondo T, Asano Y, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet. 1988 May 14. 1(8594):1065-7. [Medline].
HHV-6A and HHV-6B now recognized as two distinct viruses. HHV-6 Foundation Web site. July 18, 2012. Available at http://www.hhv-6foundation.org/featured/hhv-6a-and-hhv-6b-to-be-recognized-as-two-distinct-viruses. Accessed: December 20, 2012.
Rantala H, Mannonen L, Ahtiluoto S, Linnavuori K, Herva R, Vaheri A, et al. Human herpesvirus-6 associated encephalitis with subsequent infantile spasms and cerebellar astrocytoma. Dev Med Child Neurol. 2000 Jun. 42(6):418-21. [Medline].
Epstein LG, Shinnar S, Hesdorffer DC, Nordli DR, Hamidullah A, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia. 2012 Sep. 53(9):1481-8. [Medline]. [Full Text].
De Almeida Rodrigues G, Nagendra S, Lee CK, De Magalhães-Silverman M. Human herpes virus 6 fatal encephalitis in a bone marrow recipient. Scand J Infect Dis. 1999. 31(3):313-5. [Medline].
Mendez JC, Dockrell DH, Espy MJ, Smith TF, Wilson JA, Harmsen WS, et al. Human beta-herpesvirus interactions in solid organ transplant recipients. J Infect Dis. 2001 Jan 15. 183(2):179-184. [Medline].
Broccolo F, Drago F, Careddu AM, Foglieni C, Turbino L, Cocuzza CE, et al. Additional evidence that pityriasis rosea is associated with reactivation of human herpesvirus-6 and -7. J Invest Dermatol. 2005 Jun. 124(6):1234-40. [Medline].
Mardivirin L, Valeyrie-Allanore L, Branlant-Redon E, et al. Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on Human Herpesvirus 6 replication in vitro. Eur J Dermatol. 2010 Jan-Feb. 20(1):68-73. [Medline].
Peppercorn AF, Miller MB, Fitzgerald D, Weber DJ, Groben PA, Cairns BA. High-level human herpesvirus-6 viremia associated with onset of Stevens-Johnson syndrome: report of two cases. J Burn Care Res. 2010 Mar-Apr. 31(2):365-8. [Medline].
Cuende JI, Civeira P, Diez N, Prieto J. [High prevalence without reactivation of herpes virus 6 in subjects with chronic fatigue syndrome]. An Med Interna. 1997 Sep. 14(9):441-4. [Medline].
Weber T, Theurich S, Christopeit M, Klapperstueck T, Behre G. Human herpesvirus-6 as an inducer of porphyria cutanea tarda: implications from a case. Transpl Infect Dis. 2010 Oct. 12(5):432-6. [Medline].
Bates M, Monze M, Bima H, Kapambwe M, Clark D, Kasolo FC, et al. Predominant human herpesvirus 6 variant A infant infections in an HIV-1 endemic region of Sub-Saharan Africa. J Med Virol. 2009 May. 81(5):779-89. [Medline].
Magalhães IM, Martins RV, Cossatis JJ, Cavaliere RM, Afonso LA, et al. Detection of human herpesvirus 6 and 7 DNA in saliva from healthy adults from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2010 Nov. 105(7):925-7. [Medline].
Zerr DM, Meier AS, Selke SS, Frenkel LM, Huang ML, Wald A, et al. A population-based study of primary human herpesvirus 6 infection. N Engl J Med. 2005 Feb 24. 352(8):768-76. [Medline].
Chang YL, Parker ME, Nuovo G, Miller JB. Human herpesvirus 6-related fulminant myocarditis and hepatitis in an immunocompetent adult with fatal outcome. Hum Pathol. 2009 May. 40(5):740-5. [Medline].
Prezioso PJ, Cangiarella J, Lee M, Nuovo GJ, Borkowsky W, Orlow SJ, et al. Fatal disseminated infection with human herpesvirus-6. J Pediatr. 1992 Jun. 120(6):921-3. [Medline].
Hoang MP, Ross KF, Dawson DB, Scheuermann RH, Rogers BB. Human herpesvirus-6 and sudden death in infancy: report of a case and review of the literature. J Forensic Sci. 1999 Mar. 44(2):432-7. [Medline].
Aoki J, Numata A, Yamamoto E, Fujii E, Tanaka M, Kanamori H. Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2015 Nov. 21 (11):2017-22. [Medline].
Yoshida M, Nakamae H, Okamura H, Nishimoto M, Hayashi Y, Koh H, et al. Pericarditis Associated With Human Herpesvirus-6 Reactivation in a Patient After Unrelated Cord Blood Transplant. Exp Clin Transplant. 2015 Oct 14. [Medline].
Laina I, Syriopoulou VP, Daikos GL, Roma ES, Papageorgiou F, Kakourou T, et al. Febrile seizures and primary human herpesvirus 6 infection. Pediatr Neurol. 2010 Jan. 42(1):28-31. [Medline].
Yao K, Honarmand S, Espinosa A, Akhyani N, Glaser C, Jacobson S. Detection of human herpesvirus-6 in cerebrospinal fluid of patients with encephalitis. Ann Neurol. 2009 Mar. 65(3):257-67. [Medline]. [Full Text].
Mori T, Mihara A, Yamazaki R, Shimizu T, Aisa Y, Suzuki S, et al. Myelitis associated with human herpes virus 6 (HHV-6) after allogeneic cord blood transplantation. Scand J Infect Dis. 2007. 39(3):276-8. [Medline].
Lautenschlager I, Razonable RR. Human herpesvirus-6 infections in kidney, liver, lung, and heart transplantation: review. Transpl Int. 2012 May. 25(5):493-502. [Medline].
Corti M, Villafañe MF, Trione N, Mamanna L, Bouzas B. Human herpesvirus 6: report of emerging pathogen in five patients with HIV/AIDS and review of the literature. Rev Soc Bras Med Trop. 2011 Jul-Aug. 44(4):522-5. [Medline].
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 Mar 6. 10:49. [Medline]. [Full Text].
Eshki M, Allanore L, Musette P, Milpied B, Grange A, et al. Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure. Arch Dermatol. 2009 Jan. 145(1):67-72. [Medline].
Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L, et al. The DRESS syndrome: a literature review. Am J Med. 2011 Jul. 124(7):588-97. [Medline].
Watanabe T, Nakashima H, Ohmatsu H, Sakurai N, Takekoshi T, Tamaki K. Detection of human herpesvirus-6 transcripts in carbamazepine-induced hypersensitivity syndrome by in situ hybridization. J Dermatol Sci. 2009 May. 54(2):134-6. [Medline].
Sato T, Kuniba H, Matsuo M, Matsuzaka T, Moriuchi H. [Case of drug-induced hypersensitivity syndrome due to lamotrigine: demonstration of sequential reactivation of herpesviruses]. No To Hattatsu. 2012 Jan. 44(1):69-72. [Medline].
Morimoto M, Watanabe Y, Arisaka T, Takada A, Tonogi M, Yamane GY, et al. A case of drug-induced hypersensitivity syndrome due to carbamazepine. Bull Tokyo Dent Coll. 2011. 52(3):135-42. [Medline].
Watanabe H. Hypersensitivity syndrome due to trichloroethylene exposure: a severe generalized skin reaction resembling drug-induced hypersensitivity syndrome. J Dermatol. 2011 Mar. 38(3):229-35. [Medline].
Fujiwara N, Namba H, Ohuchi R, Isomura H, Uno F, Yoshida M, et al. Monitoring of human herpesvirus-6 and -7 genomes in saliva samples of healthy adults by competitive quantitative PCR. J Med Virol. 2000 Jun. 61(2):208-13. [Medline].
Sanders VJ, Felisan S, Waddell A, Tourtellotte WW. Detection of herpesviridae in postmortem multiple sclerosis brain tissue and controls by polymerase chain reaction. J Neurovirol. 1996 Aug. 2(4):249-58. [Medline].
Härmä M, Höckerstedt K, Lyytikäinen O, Lautenschlager I. HHV-6 and HHV-7 antigenemia related to CMV infection after liver transplantation. J Med Virol. 2006 Jun. 78(6):800-5. [Medline].
Engelmann I, Petzold DR, Kosinska A, Hepkema BG, Schulz TF, Heim A. 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 Mar. 80(3):467-77. [Medline].
Caserta MT, Hall CB, Schnabel K, Lofthus G, Marino A, Shelley L, et al. Diagnostic assays for active infection with human herpesvirus 6 (HHV-6). J Clin Virol. 2010 May. 48(1):55-7. [Medline]. [Full Text].
Ihira M, Enomoto Y, Kawamura Y, Nakai H, Sugata K, Asano Y, et al. Development of quantitative RT-PCR assays for detection of three classes of HHV-6B gene transcripts. J Med Virol. 2012 Sep. 84(9):1388-95. [Medline].
CARI. Donor sepsis. Nephrology. 2005;10(Suppl 4):S129-32.
Ljungman P, Dahl H, Xu YH, Larsson K, Brytting M, Linde A. Effectiveness of ganciclovir against human herpesvirus-6 excreted in saliva in stem cell transplant recipients. Bone Marrow Transplant. 2007 Apr. 39(8):497-9. [Medline].
Galarraga MC, Gomez E, de Oña M, Rodriguez A, Laures A, Boga JA, et al. Influence of ganciclovir prophylaxis on citomegalovirus, human herpesvirus 6, and human herpesvirus 7 viremia in renal transplant recipients. Transplant Proc. 2005 Jun. 37(5):2124-6. [Medline].
Drago F, Vecchio F, Rebora A. Use of high-dose acyclovir in pityriasis rosea. J Am Acad Dermatol. 2006 Jan. 54(1):82-5. [Medline].
Ohye T, Kawamura Y, Inagaki H, Yoshikawa A, Ihira M, Yoshikawa T, et al. A simple cytogenetic method to detect chromosomally integrated human herpesvirus-6. J Virol Methods. 2015 Nov 5. [Medline].