Human Herpesvirus 6 - HHV6

Human herpesvirus 6 (HHV6), a member of the β-herpesvirus subfamily, exists as two closely related variants, HHV6A and HHV6B. A large portion (>90%) of the population is infected with HHV early in life, at which time the virus can cause a mild, self-limited syndrome called roseola. In immunocompromised patients, HHV6 reactivation can cause life-threatening diseases such as myocarditis, liver failure, and encephalitis. Reactivated HHV6 can also facilitate activation of other viruses and allow the spread of fungal infection.

Diagnosis

Indications for Testing

Severe viral illness in immunocompromised patients

Laboratory Testing

  • Immunocompromised patients
    • Polymerase chain reaction (PCR)
      • More rapid and sensitive than antibody testing
      • Use in patients with suspected meningitis – cerebrospinal fluid (CSF) sample
      • Quantitative PCR may help identify acute vs. previous disease
      • Not useful for inherited chromosomally integrated human herpesvirus 6 (iciHHV6) – always positive
    • Antibody testing – traditional testing of paired acute and convalescent antibody testing samples
      • Indirect fluorescent antibody (IFA) – recommended
        • Provides quantitative testing
        • Allows for evaluation of change over time
      • Enzyme-linked immunosorbent assay (ELISA) – qualitative testing; less useful
      • Not as useful as PCR in immunocompromised diagnoses
    • Culture – not recommended due to difficulty and extended turnaround times
  • Young children – testing typically not performed; diagnosis based on clinical presentation
  • Concurrent testing for other viral etiologies based on symptoms

Differential Diagnosis

Background

Epidemiology

  • Prevalence – most children >2 years are seropositive
  • Transmission

Organism

  • DNA virus – human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7) together constitute Roseolovirus of the Herpesviridae family
    • HHV6B – most common agent
    • HHV6A – may be responsible for neuromeningitis
  • Isolated in 1986 from patients with AIDS and lymphoproliferative disease
    • Virus originally named human B-lymphotropic virus; now identified as T-lymphotropic
  • Following primary infection, the virus becomes latent in lymphocytes and monocytes
    • May persist in various tissues with a low level of replication
  • Evidence suggests HHV6 may act as an opportunistic agent with reactivation found in
    • Immunodeficient patients – after bone marrow or organ transplants
    • HIV-infected patients – as primary infection, reactivation of latent infection, or persistent infection
    • Other immunosuppressed patients 

Clinical Presentation

  • Primary infection in children
    • Fever ≥40°C persisting for 3-5 days
    • Exanthem subitum (roseola infantum or sixth disease) – develops on trunk and spreads to extremities
    • Diarrhea
    • Respiratory symptoms
  • Primary infection or reactivation in immunocompromised patients (particularly in organ transplant patients)
    • Meningitis/encephalitis – posttransplantation acute limbic encephalitis
    • Fulminant or chronic hepatitis, gastritis, colitis
    • Bone marrow suppression, hemophagocytosis syndrome
    • Pneumonitis
    • Organ transplant rejection
    • Arthritis
    • In transplant patient, increases risk for (Razonable, 2013)
      • Allograft dysfunction
      • Cytomegalovirus (CMV) disease after kidney or liver transplantation
      • Fungal disease
      • Higher mortality

ARUP Lab Tests

Detect and quantify HHV6 subtypes A and B in immunocompromised patients

The limit of quantification for this DNA assay is 3.0 log copies/mL (1,000 copies/mL)

If no virus is detected, result will be reported as “<3.0 log copies/mL (<1,000 copies/mL)”; if assay detects the presence of the virus but is not able to accurately quantify the number of copies, result will be reported as “Not Quantified”

Use in conjunction with HHV6, IgM screen with reflex to titer for diagnosis of HHV6 disease in immunocompromised adults

Consider HHV6 (HHV6A and HHV6B) by polymerase chain reaction (PCR) as an alternative, especially in cases of suspected meningitis

Use in conjunction with HHV6, IgG, for diagnosis of HHV6 disease in immunocompromised adults

Consider HHV6A and HHV6B by PCR as an alternative, especially in cases of suspected meningitis

Related Tests

May be helpful in differentiating bacterial from viral etiology

Assess metabolic derangement as cause of altered consciousness

Panel includes sodium, serum or plasma; potassium, serum or plasma; chloride, serum or plasma; carbon dioxide, serum or plasma; anion gap

Identify bacteria in CSF

May be helpful in differentiating bacterial from viral etiology

Diagnose and manage diabetes mellitus and other carbohydrate metabolism disorders

Aid in differentiating bacterial from viral meningitis

May be helpful in differentiating bacterial from viral etiology

Preferred initial serologic test to detect acute Epstein-Barr virus infectious mononucleosis

Aid in the diagnosis of infection with arboviruses

Aid in the diagnosis of lymphocytic choriomeningitis (LCM) viral infection

Evaluate viral etiology in patients with acute hepatitis

Not recommended for screening asymptomatic patients

Panel includes HAV IgM, HBV core antibody IgM, HBV surface antigen (HBsAg), HCV antibody

Reflex pattern: if results for HBsAg are repeatedly reactive with an index value between 1.00 and 50.00, then HBsAg confirmation will be added

Detect and quantify cytomegalovirus (CMV)

Aid in the diagnosis of parvovirus infection

Preferred test for detecting herpes simplex virus (HSV) infection in CSF, neonates, or when rapid diagnostic test for suspected HSV infection is necessary

Detect adenovirus groups A-F

Detect presence of IgG and IgM antibodies in individuals with a clinical suspicion of West Nile virus

Medical Experts

Contributor

Couturier

Marc Roger Couturier, PhD, D(ABMM)

Marc Roger Couturier, PhD, D(ABMM)

Associate Professor of Clinical Pathology, University of Utah

Medical Director, Microbial Immunology, Parasitology and Fecal Testing, and Infectious Disease Antigen Testing at ARUP Laboratories

Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®

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