What is the clinical significance of elevated Human Herpesvirus 6 (HHV6) antibody titers?

Clinical Significance of Elevated HHV6 Antibody Titers

Elevated HHV-6 antibody titers alone have limited clinical significance and should not be used as the primary diagnostic method for active HHV-6 infection, as antibody tests cannot distinguish between HHV-6A and HHV-6B variants and may reflect cross-reactivity with other herpesviruses, particularly CMV. 1

Diagnostic Value and Limitations

Limited Utility of Antibody Testing

• Antibody tests for HHV-6 have significant limitations:
  • Cannot differentiate between HHV-6A and HHV-6B subtypes 1
  • May show cross-reactivity with CMV antibodies 2
  • Not recommended for diagnosis in hematopoietic stem cell transplant (HSCT) patients 1

Cross-Reactivity Issues

• Antibodies induced by primary CMV infection often cross-react with HHV-6 proteins 2
• Studies have demonstrated that after primary CMV infection:
  • Four-fold or greater rises in HHV-6 antibody titers are common 3
  • Some antibodies to CMV glycoprotein B cross-react with HHV-6 gp116 2

Prevalence Context

• HHV-6 is nearly ubiquitous in the general population:
  • 90% of children are infected before age 1 4
  • Nearly 100% of children acquire infection by age 3 4
  • Approximately 80% of the general population has IgG antibody titers of 1:80 or higher 5

Preferred Diagnostic Approaches

PCR-Based Testing

• Quantitative PCR is the mainstay of HHV-6 diagnosis 1
  • Should distinguish between HHV-6A and HHV-6B DNA
  • More reliable than antibody testing for active infection
  • Detection of HHV-6 DNA in cell-free plasma samples is recommended 4

Chromosomally Integrated HHV-6 (CIHHV-6)

• Important to rule out CIHHV-6 when evaluating HHV-6 DNA results 1
• Characteristics of CIHHV-6:
  • Persistently high levels of HHV-6 DNA in whole blood (>5.5 log10 copies/mL)
  • Serum levels typically 100-fold lower than whole blood
  • Not affected by antiviral therapy

Clinical Contexts Where Elevated Titers May Be Significant

Immunocompromised Patients

• HHV-6 reactivation is common in transplant recipients 1, 6
• In HSCT patients, HHV-6B is associated with:
  • Encephalitis with high morbidity and mortality
  • Various post-transplant syndromes

Neurological Manifestations

• HHV-6 can cause a spectrum of neurological diseases 4:
  • Encephalitis
  • Febrile seizures

Other Conditions with Reported Elevated Titers

• Elevated HHV-6 antibody titers have been observed in 5:
  • Lymphoproliferative disorders
  • Autoimmune diseases
  • HIV-positive patients
  • Chronic Fatigue Syndrome
• However, a causal relationship between elevated titers and these conditions remains unclear

Diagnostic Criteria for True HHV-6 Infection

• A four-fold or greater increase in anti-HHV-6 antibody titers between acute and convalescent serum samples 4
• Detection of IgM anti-HHV-6 in infants and young children 4
• Detection of HHV-6 DNA by PCR (preferred method) 1, 4

Key Pitfalls to Avoid

1. Misinterpreting elevated HHV-6 antibody titers as definitive evidence of active infection
2. Failing to consider cross-reactivity with CMV antibodies
3. Not distinguishing between latent infection and active replication
4. Overlooking the possibility of CIHHV-6 when interpreting HHV-6 DNA results
5. Using antibody testing in immunocompromised patients where antibody production may be impaired