What are the symptoms of Human Herpesvirus 6 (HHV6) infection?

Symptoms of Human Herpesvirus 6 (HHV-6) Infection

The primary symptoms of HHV-6 infection include fever, rash, confusion, encephalopathy, short-term memory loss, seizures, and insomnia, with manifestations varying significantly between primary infection in children and reactivation in immunocompromised adults. 1

Primary HHV-6 Infection

In Children

HHV-6 is primarily known for causing:

• Fever (high)
• Roseola infantum (characteristic rash that appears after fever subsides)
• Febrile seizures
• Most infections occur in healthy infants, with HHV-6B being the predominant variant 2

In Adults

Primary infection in adults is rare but can present as:

• Mononucleosis-like illness
• Fever
• Rarely, severe disease including encephalitis 3

HHV-6 Reactivation in Immunocompromised Patients

Reactivation is most common in:

• Hematopoietic stem cell transplant (HSCT) recipients
• Solid organ transplant recipients
• Other immunocompromised individuals

Common Symptoms of Reactivation

• Fever
• Rash
• Encephalitis/encephalopathy
• Bone marrow suppression (myelosuppression)
• Delayed engraftment (particularly affecting platelets) 1

Neurological Manifestations (HHV-6 Encephalitis)

HHV-6 encephalitis typically presents with:

• Confusion
• Encephalopathy
• Short-term memory loss
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
• Seizures (particularly temporal lobe seizures)
• Insomnia 1

In HSCT recipients, HHV-6 encephalitis often presents as post-transplant acute limbic encephalitis (PALE) with:

• Disease onset typically 2-6 weeks post-transplantation
• Memory defects and neuropsychological sequelae in 20-60% of cases
• Potential mortality rate of up to 25% in HSCT recipients and up to 50% in cord blood recipients 1

Other Potential Manifestations

• Pneumonitis
• Hepatitis
• Myelitis
• Cerebellar ataxia 4
• Headache
• Delirium
• Neurocognitive decline 1

Diagnostic Findings

Cerebrospinal Fluid (CSF)

• HHV-6B DNA in CSF
• Often unremarkable protein and cell counts
• Mild protein elevation in some cases
• Mild lymphocytic pleocytosis in some cases 1

Neuroimaging

• MRI may be negative at disease onset
• Changes in temporal lobe in approximately 60% of cases
• Typically circumscribed, non-enhancing, hyperintense lesions in the medial temporal lobes (especially hippocampus and amygdala) 1
• Lesions can also occur in other areas such as the midbrain 4

Risk Factors for Severe HHV-6 Disease

The highest risk is seen in:

• Cord blood transplant recipients
• T-cell depleted transplant recipients
• HLA-mismatched unrelated donors
• Haploidentical transplant recipients 1

Clinical Pitfalls and Caveats

1. HHV-6 DNA can be found in CSF in patients without CNS symptoms, making interpretation challenging 1

2. Chromosomally integrated HHV-6 (CIHHV-6) must be excluded when diagnosing HHV-6 encephalitis, as it can lead to false positive results 1

3. HHV-6 encephalitis can be misdiagnosed as other forms of limbic encephalitis, as similar MRI findings can occur with other infectious agents 1

4. Only one-third of HHV-6 encephalitis patients may present with the typical features of post-transplant acute limbic encephalitis 1

5. Long-term neurological sequelae, including temporal lobe epilepsy in adults and cognitive regression in children, can occur even after successful treatment 1