What is Human Herpesvirus 6 (HHV-6)?

Human Herpesvirus 6 (HHV-6): Clinical Overview

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, establishes lifelong latency, and can cause significant morbidity and mortality through reactivation, particularly in immunocompromised patients. 1, 2

Variants and Epidemiology

• HHV-6B: The predominant variant in clinical settings

  • Causes exanthem subitum (roseola infantum or sixth disease) in children
  • Primary infection typically occurs in the first 2 years of life
  • Nearly 90% of children are infected by 12 months and virtually 100% by age 3 1

• HHV-6A: Less common variant

  • No specific disease has been causally linked to HHV-6A
  • Natural history remains largely unknown 1

Transmission and Infection

• Primary transmission occurs through contact with saliva of infected adults
• Approximately 85% of adults, regardless of HIV status, shed HHV-6 intermittently in saliva 1
• After primary infection, the virus establishes latency in:
  • CD4+ T lymphocytes
  • Monocytes/macrophages
  • Salivary glands
  • Brain tissue
  • Kidneys 1

Unique Feature: Chromosomal Integration

• In approximately 1% of humans, complete HHV-6 genome is integrated into chromosomal telomeres (CIHHV-6)
• CIHHV-6 is inherited through Mendelian inheritance
• Distribution between variants in CIHHV-6:
  • HHV-6A: ~1/3 of CIHHV-6 cases
  • HHV-6B: ~2/3 of CIHHV-6 cases 1

Clinical Manifestations

Primary Infection

• HHV-6B: Causes exanthem subitum (roseola) in children
  • High fever for 3-5 days followed by characteristic rash upon fever resolution
  • Can cause febrile seizures and encephalitis in some cases 1

Reactivation in Immunocompromised Hosts

• Most concerning in hematopoietic stem cell transplant (HSCT) recipients

• HHV-6B is associated with:

  • Encephalitis (high morbidity and mortality)
  • Various post-transplant syndromes 1

• In HIV-infected patients:

  • Not identified as an important opportunistic pathogen
  • Some studies suggest possible role in HIV disease progression, but this remains unconfirmed 1

Diagnosis

Recommended Diagnostic Approach

• Quantitative PCR is the mainstay of diagnosis
  • Should distinguish between HHV-6A and HHV-6B
  • Detection in cell-free plasma suggests active replication 1, 2

Diagnostic Pitfalls

• Antibody testing limitations:

  • Cannot distinguish between HHV-6A and HHV-6B
  • Not recommended in HSCT patients
  • May be unreliable in immunocompromised patients 1, 2

• CIHHV-6 considerations:

  • Persistently high viral DNA levels (>5.5 log10 copies/mL) in whole blood
  • DNA detected in "cell-free" samples like serum and CSF due to cellular DNA release during sample preparation
  • Can be misinterpreted as active infection 1, 2

Treatment

• Antiviral susceptibility patterns of HHV-6 resemble those of CMV

• HHV-6 replication is inhibited by:

  • Foscarnet
  • Cidofovir
  • Ganciclovir 1

• For confirmed HHV-6 disease in immunocompromised patients:

  • Consider ganciclovir or foscarnet using treatment schedules similar to those for CMV disease 1
  • Resistance mutations to these antivirals have been described 1

Clinical Implications

• Most HHV-6 infections in immunocompetent individuals are asymptomatic or self-limiting
• In allogeneic HSCT recipients, HHV-6B is associated with significant morbidity and mortality, particularly encephalitis 1
• Limited evidence suggests CIHHV-6 may be associated with acute GvHD and CMV reactivation in HSCT recipients, but without effect on overall mortality 1

Prevention

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

Understanding the distinction between latent infection, active replication, and chromosomal integration is crucial for accurate diagnosis and appropriate management of HHV-6 infections, particularly in immunocompromised patients where the consequences can be severe.