Human herpesvirus 6 (HHV-6) is a ubiquitous betaherpesvirus, typically acquired in early childhood, that establishes lifelong latency analogous to other human herpesviruses. It comprises two closely related species, HHV-6A and HHV-6B, which differ in epidemiology and clinical associations. In immunocompetent hosts, symptomatic infection is predominantly caused by HHV-6B and classically presents as roseola infantum (exanthema subitum). This self-limited illness is characterized by high fever followed by an erythematous maculopapular rash once the fever subsides. By contrast, primary HHV-6A infection is less frequent and is often clinically silent, contributing to its less well-defined disease associations.
Following primary infection, HHV-6 establishes latency in various cell types, including mononuclear cells, with the potential for periodic reactivation. Reactivation is usually subclinical in healthy individuals but becomes clinically significant in the context of impaired cellular immunity. Recipients of hematopoietic stem cell transplantation (HSCT) are at substantial risk of HHV-6 reactivation, which has been implicated in encephalitis, bone marrow suppression, and graft dysfunction, among other complications. In this population, the distinction between latent, chromosomally integrated virus and active replication is critical yet challenging.
A unique feature of HHV-6 is its ability to integrate into human chromosomal telomeric regions, resulting in chromosomally integrated HHV-6 (ciHHV-6), which is present in the germline and therefore inherited. Individuals with ciHHV-6 have high viral DNA loads in blood and tissues even in the absence of active replication, which can confound nucleic acid–based diagnostic assays. Consequently, detection of HHV-6 DNA alone is insufficient to diagnose active infection, and misinterpretation may lead to unnecessary or inappropriate antiviral therapy.
Timely and accurate diagnosis is central to effective management, especially in high-risk groups such as HSCT recipients, where delayed treatment can result in severe and potentially irreversible complications. This review evaluates the performance characteristics of available diagnostic modalities, including PCR, viral culture, antigen detection, and serology, emphasizing their respective strengths and limitations. Particular attention is given to how assay design, specimen type, and result interpretation can inadvertently promote misdiagnosis or overdiagnosis of HHV-6 disease. The review underscores the need for integrated diagnostic strategies that account for ciHHV-6, host immune status, and clinical context to distinguish true active infection from latent or integrated virus, thereby optimizing patient management and reducing the burden of HHV-6–associated morbidity.
Original article:
Gough KL, Anderson TK, Whiley DM, Sweeney EL. The diagnostic complexities of human herpesvirus 6 (HHV-6) infections. J Clin Virol. 2026 Feb;182:105905. doi: 10.1016/j.jcv.2025.105905.