What is Human Herpesvirus 6 (HHV6)?

Human Herpesvirus 6 (HHV-6)

Human Herpesvirus 6 (HHV-6) is a ubiquitous betaherpesvirus with two distinct variants (HHV-6A and HHV-6B) that infects nearly 100% of children by age 3, establishing lifelong latency, and can cause significant morbidity and mortality through reactivation, particularly in immunocompromised patients. 1

Basic Characteristics

• HHV-6 belongs to the Roseolovirus genus of the betaherpesvirus subfamily and is closely related to human cytomegalovirus
• Two distinct species exist:
  • HHV-6A: No disease has been causally linked to this variant, and its natural history remains unknown 2
  • HHV-6B: Causes exanthem subitum (roseola infantum or sixth disease) in children; primary infection is ubiquitous in the first two years of life 2, 1

Transmission and Infection

• Primary transmission occurs through contact with saliva of infected adults 1
• Nearly 90% of children are infected by 12 months and virtually 100% by age 3 1
• After primary infection, the virus establishes latency in:
  • CD4+ T lymphocytes
  • Monocytes/macrophages
  • Salivary glands
  • Brain tissue
  • Kidneys 1

Chromosomally Integrated HHV-6 (CIHHV-6)

• In approximately 1% of humans, the complete HHV-6 genome is integrated into chromosomal telomeres 2, 1
• This integration is inherited through Mendelian inheritance 2
• Distribution of variants in CIHHV-6:
  • HHV-6A: ~1/3 of CIHHV-6 cases
  • HHV-6B: ~2/3 of CIHHV-6 cases 2
• In individuals with CIHHV-6, viral DNA is persistently detected at high levels in whole blood and "cell-free" samples like serum and cerebrospinal fluid 2

Clinical Manifestations

Primary Infection

• HHV-6B causes exanthem subitum (roseola) in children:
  • High fever for 3-5 days
  • Characteristic rash appears upon fever resolution
  • Can cause febrile seizures and encephalitis in some cases 1, 3

In Immunocompromised Patients

• HHV-6B is associated with significant morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients:
  • Encephalitis with high morbidity and mortality
  • Various post-transplant syndromes 2, 1
• In solid organ transplant recipients:
  • Only about 1% develop clinical illness (mostly due to HHV-6B)
  • Manifestations include fever, myelosuppression, hepatitis, and encephalitis
  • Associated with higher rates of CMV disease, graft rejection, and opportunistic infections 4

Diagnosis

• Quantitative PCR is the mainstay of diagnosis:
  • Should distinguish between HHV-6A and HHV-6B
  • Detection in cell-free plasma suggests active replication 1
• Diagnostic challenges:
  • Distinguishing between active infection and latent virus
  • Identifying CIHHV-6 (which can lead to false positives) 5
• Antibody testing has limitations:
  • Cannot distinguish between HHV-6A and HHV-6B
  • Not recommended in immunocompromised patients 1

Treatment

• Antiviral susceptibility patterns of HHV-6 resemble those of CMV 1
• Effective antivirals include:
  • Foscarnet
  • Ganciclovir (first-line agent for immunocompromised patients)
  • Cidofovir 1, 3
• Treatment is indicated for established end-organ disease such as encephalitis 4

Prevention

• Due to the ubiquity of HHV-6, prevention of primary infection is not feasible 1
• No data support prophylactic antiviral use to prevent HHV-6 reactivation 1

Clinical Significance and Monitoring

• Most HHV-6 reactivations are asymptomatic, but can cause severe disease in immunocompromised patients 5
• Monitoring is particularly important in transplant recipients, where HHV-6 reactivation is associated with increased all-cause mortality 4