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Human Herpesvirus Type 6: Differential Diagnoses & Workup

Author: Michelle R Salvaggio, MD, Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Medical Director of Infectious Diseases Institute, University of Oklahoma Health Sciences Center
Coauthor(s): Peter S Miele, MD, Fellow, Department of Internal Medicine, Section of Infectious Diseases, Washington Hospital Center; Margo A Smith, MD, Associate Program Director, Department of Medicine, Washington Hospital Center; Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, George Washington University
Contributor Information and Disclosures

Updated: Oct 8, 2008

Differential Diagnoses

Bone Marrow Failure
Infectious Mononucleosis
Chronic Fatigue Syndrome
Meningitis
Cytomegalovirus
Parvovirus (B19)
Early Symptomatic HIV Infection
Pneumonia, Viral
Fever of Unknown Origin
Herpes Simplex

Other Problems to Be Considered

In infants with signs and symptoms of classic roseola infantum, human herpesvirus 6 (HHV-6) is the causative agent. However, other causes for fever and rash should be excluded.

In immunocompetent adults with symptomatic HHV-6 disease, the illness closely resembles mononucleosis. EBV infection and CMV infection should be excluded.

In immunocompromised patients with symptomatic HHV-6 disease, CMV infection is often present and needs to be diagnosed and managed accordingly.

Workup

Laboratory Studies

  • Routine laboratory studies used to evaluate for human herpesvirus 6 (HHV-6) depend on the clinical presentation and setting, such as immunocompetent versus immunocompromised host.
    • CBC count may show leukopenia and varying degrees of cytopenia (thrombocytopenia or anemia), especially in the setting of transplantation.
    • Obtain electrolytes and renal function tests, especially in renal transplant patients.
    • Liver function tests may show hepatitis or liver dysfunction.
    • Specific tests to diagnose HHV-6 infection include the following:
      • Culture: Standard peripheral cell culture, which takes 5-21 days and is labor intensive, and shell vial assay culture, which takes 1-3 days, are available for isolating HHV-6. The virus causes a characteristic finding of balloonlike syncytia on cell culture due to its cytopathic effects. The rapid shell vial assay yields a sensitivity of 86% and a specificity of 100%. Availability of culture or shell vial assays is limited.
      • Immunohistochemical stains: Immunohistochemical stains are available for detecting HHV-6 in formalin-fixed paraffin-embedded tissues. Only cells with active infection, as opposed to latent infection, stain positively with these antibodies. For biopsy and cytologic specimens, results are available in 1-3 days.
      • Serology: Primary infection can be demonstrated by seroconversion from IgG negative to positive or the presence of IgM to HHV-6. Active disease is indicated by a 4-fold increase in IgG on immunofluorescence or a 1.6-fold increase in antibody on enzyme immunoassay (EIA). Distinguishing primary infection from reactivation can be difficult. Immunofluorescent techniques include both indirect and anticomplement methods; results are operator dependent and may lack objectivity. In general, EIA methods are more easily quantified and less subjective. Note that increases in HHV-6 antibody levels have been observed in other herpesvirus infections.
      • Polymerase chain reaction (PCR): PCR can be performed on either cellular or acellular specimens. Acellular samples, including CSF, have been suggested to be more helpful in distinguishing active from latent infection. A quantitative technique to determine viral load still is investigational. A sensitive semiquantitative technique that cannot detect latent virus but that can detect actively infected cells has been described.

Imaging Studies

  • Chest radiography or CT scanning should be obtained in patients with respiratory symptoms. These may show evidence of pneumonitis or pneumonia.
  • A head CT scan, with and without contrast, should be obtained to rule out other treatable diseases.

Procedures

  • Indications for procedures depend on the clinical presentation, especially in immunocompromised patients.
  • Clinicians should have a low threshold for certain procedures, including the following:
    • Bronchoscopy: In cases of respiratory distress, bronchioalveolar lavage (BAL) or biopsy samples can be sent for immunohistochemical staining to identify HHV-6 infection.
    • Lumbar puncture (LP): In patients with CNS symptoms, an LP can be used to rule out other etiologies. In cases of febrile seizures due to HHV-6 infection, the CSF may reveal a mild pleocytosis with elevated protein levels but is often noteworthy for a complete lack of inflammatory response. CSF can be sent for HHV-6 PCR studies. A positive result may indicate active HHV-6 infection in the CNS. The virus has not been shown to grow in CSF samples sent for viral culture.
    • Tissue biopsy
      • Tissue biopsy is especially relevant in solid organ or bone marrow transplant recipients who have evidence of graft rejection and in immunocompromised patients with severe hepatitis or hepatic failure. Samples should be sent for immunohistochemical staining and cell culture to identify HHV-6 infection.
      • Skin biopsies have failed to show the presence of HHV-6 in cases of rash. If the etiology of a rash is in doubt, skin biopsy should be obtained to rule out other causes.

Histologic Findings

Immunohistochemical staining can be performed on tissue and cytologic samples to identify HHV-6 infection.

More on Human Herpesvirus Type 6

Overview: Human Herpesvirus Type 6
Differential Diagnoses & Workup: Human Herpesvirus Type 6
Treatment & Medication: Human Herpesvirus Type 6
Follow-up: Human Herpesvirus Type 6
References
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References

  1. Merk J, Schmid FX, Fleck M, et al. Fatal pulmonary failure attributable to viral pneumonia with human herpes virus 6 (HHV6) in a young immunocompetent woman. J Intensive Care Med. Sep-Oct 2005;20(5):302-6. [Medline].

  2. 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.

  3. Kunisaki Y, Goto H, Kitagawa K, et al. Salazosulfapyridine induced hypersensitivity syndrome associated with reactivation of humanherpes virus 6. Intern Med. Feb 2003;42(2):203-7. [Medline].

  4. Hasegawa A, Yasukawa M, Sakai I, et al. 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. Jan 15 2001;166(2):1125-31. [Medline].

  5. 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. Aug 1 1995;92(16):7440-4. [Medline].

  6. Tejada-Simon MV, Zang YC, Hong J, et al. Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis. Ann Neurol. Feb 2003;53(2):189-97. [Medline].

  7. Mori T, Mihara A, Yamazaki R, 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].

  8. Burns WH, Sandford GR. Susceptibility of human herpesvirus 6 to antivirals in vitro. J Infect Dis. Sep 1990;162(3):634-7. [Medline].

  9. Chapnick EK, Lutwick LI. Human Herpesvirus 6 (HHV-6). Infectious Disease Practice. 1995;19:91-94.

  10. Cirone M, Cuomo L, Zompetta C, et al. Human herpesvirus 6 and multiple sclerosis: a study of T cell cross-reactivity to viral and myelin basic protein antigens. J Med Virol. Oct 2002;68(2):268-72. [Medline].

  11. Cone RW, Huang ML, Corey L, et al. Human herpesvirus 6 infections after bone marrow transplantation: clinical and virologic manifestations. J Infect Dis. Feb 1999;179(2):311-8. [Medline].

  12. Dockrell DH, Smith TF, Paya CV. Human herpesvirus 6. Mayo Clin Proc. Feb 1999;74(2):163-70. [Medline].

  13. Fox JD, Briggs M, Ward PA, et al. Human herpesvirus 6 in salivary glands. Lancet. Sep 8 1990;336(8715):590-3. [Medline].

  14. Fujita H, Maruta A, Tomita N, et al. Human herpesvirus-6-associated exanthema in a patient with acute lymphocytic leukaemia. Br J Haematol. Mar 1996;92(4):947-9. [Medline].

  15. Gutierrez J, Vergara MJ, Guerrero M, et al. Multiple sclerosis and human herpesvirus 6. Infection. Jun 2002;30(3):145-9. [Medline].

  16. Hashimoto K, Yasukawa M, Tohyama M. Human herpesvirus 6 and drug allergy. Curr Opin Allergy Clin Immunol. Aug 2003;3(4):255-60. [Medline].

  17. Hukin J, Farrell K, MacWilliam LM, et al. Case-control study of primary human herpesvirus 6 infection in children with febrile seizures. Pediatrics. Feb 1998;101(2):E3. [Medline].

  18. Janoly-Dumenil A, Galambrun C, Basset T, et al. Human herpes virus-6 encephalitis in a paediatric bone marrow recipient: successful treatment with pharmacokinetic monitoring and high doses of ganciclovir. Bone Marrow Transplant. Dec 2006;38(11):769-70. [Medline].

  19. Kimberlin DW, Whitley RJ. Human herpesvirus-6: neurologic implications of a newly-described viral pathogen. J Neurovirol. Oct 1998;4(5):474-85. [Medline].

  20. Knox KK, Carrigan DR. Disseminated active HHV-6 infections in patients with AIDS. Lancet. Mar 5 1994;343(8897):577-8. [Medline].

  21. Liedtke W, Malessa R, Faustmann PM, et al. Human herpesvirus 6 polymerase chain reaction findings in human immunodeficiency virus associated neurological disease and multiple sclerosis. J Neurovirol. Sep 1995;1(3-4):253-8. [Medline].

  22. Singh N, Carrigan DR. Human herpesvirus-6 in transplantation: an emerging pathogen. Ann Intern Med. Jun 15 1996;124(12):1065-71. [Medline].

  23. Swanborg RH, Whittum-Hudson JA, Hudson AP. Infectious agents and multiple sclerosis--are Chlamydia pneumoniae and human herpes virus 6 involved?. J Neuroimmunol. Mar 2003;136(1-2):1-8. [Medline].

  24. Tokimasa S, Hara J, Osugi Y, et al. Ganciclovir is effective for prophylaxis and treatment of human herpesvirus-6 in allogeneic stem cell transplantation. Bone Marrow Transplant. Apr 2002;29(7):595-8. [Medline].

  25. Tyler KL. Human herpesvirus 6 and multiple sclerosis: the continuing conundrum. J Infect Dis. May 1 2003;187(9):1360-4. [Medline].

  26. Villoslada P, Juste C, Tintore M, et al. The immune response against herpesvirus is more prominent in the early stages of MS. Neurology. Jun 24 2003;60(12):1944-8. [Medline].

  27. 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. Sep 2004;126(5):690-6. [Medline].

  28. Yamanishi K. Human herpesvirus 6 and human herpesvirus 7. In: Clinical Virology. First ed. New York, NY: Churchill Livingston; 1997:471-81 TEXTBOOK.

  29. Zerr DM, Corey L, Kim HW, et al. Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. Clin Infect Dis. Apr 1 2005;40(7):932-40. [Medline].

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Further Reading

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Keywords

human herpesvirus 6, human herpesvirus type 6, HHV-6, HHV6, human herpes virus 6, HHV-6A, HHV-6B, roseola infantum, exanthema subitum, sixth disease

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Contributor Information and Disclosures

Author

Michelle R Salvaggio, MD, Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Medical Director of Infectious Diseases Institute, University of Oklahoma Health Sciences Center
Michelle R Salvaggio, MD is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Merck Honoraria Speaking and teaching

Coauthor(s)

Peter S Miele, MD, Fellow, Department of Internal Medicine, Section of Infectious Diseases, Washington Hospital Center
Peter S Miele, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Margo A Smith, MD, Associate Program Director, Department of Medicine, Washington Hospital Center; Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, George Washington University
Margo A Smith, MD is a member of the following medical societies: American Society for Microbiology
Disclosure: Nothing to disclose.

Medical Editor

Thomas J Marrie, MD, Chair, Professor, Department of Medicine, Division of Infectious Diseases, University of Alberta College of Medicine
Thomas J Marrie, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society for Microbiology, Canadian Infectious Disease Society, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Ronald A Greenfield, MD, Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine
Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology
Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Wyeth Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist  Speaking and teaching

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

 
 
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