Human Herpesvirus 6 (HHV-6) Infection Differential Diagnoses

Updated: Aug 16, 2019
  • Author: John L Kiley, MD; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD  more...
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Diagnostic Considerations

In infants with signs and symptoms of classic roseola infantum, human herpesvirus 6 (HHV-6) can be the causative agent. However, since this diagnosis has various differential diagnoses, other causes for fever and rash should be excluded. In immunocompetent adults with symptomatic HHV-6 disease, the illness closely resembles mononucleosis. Infection with Epstein-Barr virus (EBV) or cytomegalovirus (CMV) should be excluded.

Because 30%-70% of HSCT recipients experience HHV-6 reactivation 2-4 weeks after transplantation, with viremia lasting an average of 1-2 weeks, routine screening is not recommended, but practice can vary by center. [27] Risk factors for HHV-6 reactivation in this population include steroid treatment, transplantation from unrelated mismatched donors, and umbilical cord blood transplantation. This places the burden on the clinician to assess all the relevant clues for diagnosis.

For HHV-6 encephalitis in HSCT recipients, targeted diagnostics (PCR of either serum or CSF) can usually be performed by most clinical laboratories or reference centers. This should be performed in patients in whom the diagnosis of HHV-6 encephalitis is being considered. [27]

HHV-6 encephalitis has the following features: [4, 5, 20]

  • Neurologic symptoms consistent with encephalitis
  • CSF abnormalities consistent with a viral etiology of infection (elevated CSF protein, normal CSF glucose, and pleocytosis)
  • Positive PCR of CSF for HHV-6 (excluding ciHHV-6)
  • An absence of other causes of CNS dysfunction

Some studies have suggested that patients with HHV-6 encephalitis may have normal CSF cell counts and the absence of PCR positivity in the CSF, complicating diagnosis.

Confirming the diagnosis of HHV-6 disease in patients with chromosomally integrated HHV-6 can be particularly difficult owing to persistent detection of HHV-6 via PCR in the absence of active disease. [6] Clues may include persistently high viral loads in the setting of appropriate antiviral therapy (106-107 copies per mL in whole blood), as well as detection of HHV-6 DNA in hair follicles and nail samples.

In addition to the conditions in the differential diagnoses, other problems to be considered include the following:

Differential Diagnoses