Diagnostic value of HHV-6A/B genotyping in immunocompromised adults

Human herpesvirus 6 (HHV-6) comprises two genetically and biologically distinct species, HHV-6A and HHV-6B, yet species-level differentiation is rarely performed in clinical practice. We conducted a retrospective study of 119 immunocompromised adults with detectable HHV-6 DNA between 2020 and 2025 to characterize species distribution, compare epidemiological, clinical, and virological features, and evaluate the diagnostic relevance of genotyping. Viral species were detected by real-time polymerase chain reaction (PCR) across multiple sample types, and suspected chromosomal integration was confirmed through detection of endogenous HHV-6 (eHHV-6) DNA in hair follicles by quantitative real-time PCR. HHV-6B accounted for ~96% of infections and was significantly associated with organ involvement, predominantly gastrointestinal disease, irrespective of plasma viral load. In contrast, HHV-6A was less frequently detected in tissues and was consistently associated with viremia and chromosomal integration, independent of viral load. Genotypic concordance across plasma, biopsy, cerebrospinal fluid, bronchoalveolar lavage, and hair follicle samples from the same patient was complete. Incorporating species-level genotyping and targeted testing for chromosomal integration (eHHV-6) into diagnostic workflows may improve interpretation of viral detection and help prevent unnecessary antiviral therapy.IMPORTANCESpecies-specific identification of human herpesvirus 6 (HHV-6A/B) has critical diagnostic implications in immunocompromised patients, although it is rarely performed in diagnostic laboratories. Our study showed that HHV-6A detection is associated with chromosomal integration, whereas HHV-6B is the main species linked to clinically relevant disease and invasive tissue infection. This study emphasizes that implementing species-specific PCR and testing for eHHV-6 in clinical microbiology laboratories may help interpret viral DNA detection, prevent misclassification of integrated virus as active infection, and avoid unnecessary antiviral therapy.