Human Herpesvirus 6 Infection Workup
- Author: Michelle R Salvaggio, MD, FACP; Chief Editor: Burke A Cunha, MD more...
Human herpesvirus 6 (HHV-6) may be diagnosed by means of viral culture, serologic testing, or polymerase chain reaction (PCR) assay.[50, 51, 52] However, because of the self-limiting nature of primary HHV-6 infection, laboratory diagnosis is rarely required in patients who are immunocompetent. Most often, such infection is diagnosed on the basis of its clinical features. Leukopenia with lymphocytosis may suggest the diagnosis. Transaminase elevations, cholestasis, and thrombocytopenia may be noted.
Diagnoses in patients who are recipients of organ transplants or patients with immunodeficiency, encephalitis, or hepatitis are performed by different laboratory methods.
HHV-6 can be isolated from the blood for the first 5 days and later is found intermittently or persistently in saliva, stool, and, rarely, urine. One study showed that HHV-6 and HHV-7 antigenemia usually occurred together with symptomatic cytomegalovirus (CMV) infection after liver transplantation. HHV-6 infection preceded CMV infection, but HHV-7 infection appeared together with CMV infection. However, further investigation of the clinical significance of HHV-6 and HHV-7 antigenemia in organ transplant patients is necessary.
Other studies used in the diagnosis of HHV-6 infection include diagnostic imaging, bronchoscopy, lumbar puncture (LP), and tissue biopsy.
Routine laboratory studies used to evaluate for HHV-6 depend on the clinical presentation and setting—for example, whether the host is immunocompetent or immunocompromised.
The complete blood count (CBC) may show leukopenia and varying degrees of cytopenia (thrombocytopenia or anemia), especially in the setting of transplantation. In active infection, a CBC with differential shows leukopenia with relative leukocytosis.
Electrolyte concentrations should be evaluated and renal function tests performed, especially in renal transplant patients. Liver function tests may reveal hepatitis or liver dysfunction.
Standard peripheral cell culture, which takes 5-21 days and is labor-intensive, and shell vial assay culture, which takes 1-3 days, are available (albeit on a limited basis) for isolating HHV-6. The virus causes a characteristic finding of balloonlike syncytia on cell culture as a consequence of its cytopathic effects. The rapid shell vial assay yields a sensitivity of 86% and a specificity of 100%.
Immunohistochemical stains are available for detecting HHV-6 in formalin-fixed paraffin-embedded tissues. Only cells with active infection, as opposed to latent infection, stain positively with these antibodies. Immunohistochemical staining can be performed on tissue and cytologic samples. For biopsy and cytologic specimens, results are available in 1-3 days.
Primary infection can be demonstrated by seroconversion from immunoglobulin G (IgG)-negative to IgG-positive or by the presence of immunoglobulin M (IgM) to HHV-6. Active HHV-6 disease (primary or reactivated) is indicated by a 4-fold increase in IgG on immunofluorescence or a 1.6-fold increase in antibody on enzyme immunoassay (EIA). Distinguishing primary infection from reactivation can be difficult.
Immunofluorescent techniques include both indirect and anticomplement methods; results are operator-dependent and may lack objectivity. In general, EIA methods are more easily quantified and less subjective. Note that increases in HHV-6 antibody levels have been observed in other herpesvirus infections. CMV antibodies can cross-react with HHV-6 antibodies; hence, exclusion of CMV is required. CMV and HHV-6 are closely related on a genomic level.
Polymerase chain reaction assay
PCR assays can be performed on either cellular or acellular specimens. Acellular samples, including CSF, have been suggested to be more helpful in distinguishing active from latent infection.
Rapid diagnosis of HHV-6 primary infections or reactivations can be facilitated by using quantitative PCR assays. Detection of co-infections with multiple herpesviruses can also be accomplished, with quantitative results enabling monitoring of virus load during antiviral therapy.
Neither qualitative nor quantitative PCR of plasma is sufficient to distinguish between active viral replication and chromosomal integration with HHV-6. A higher specificity may be obtained by using reverse transcriptase PCR (RT-PCR) when evaluating samples for active HHV-6 replication.[55, 56]
Radiography and Computed Tomography
Chest radiography or computed tomography (CT) of the chest should be performed in patients with respiratory symptoms. These may show evidence of pneumonitis or pneumonia.
A head CT scan, with and without contrast, should be obtained to rule out other treatable diseases.
Indications for these and other diagnostic procedures depend on the clinical presentation, especially in immunocompromised patients.
Clinicians should have a low threshold for ordering certain diagnostic procedures, including bronchoscopy, LP, and tissue biopsy.
In cases of respiratory distress, bronchoalveolar lavage (BAL) or biopsy samples can be sent for immunohistochemical staining to identify HHV-6 infection.
In patients with central nervous system (CNS) symptoms, LP can be performed to rule out other etiologies. In cases of febrile seizures due to HHV-6 infection, the cerebrospinal fluid (CSF) may reveal a mild pleocytosis with elevated protein levels, but it is often noteworthy for a complete lack of inflammatory response. CSF can be sent for HHV-6 PCR studies. A positive result may indicate active HHV-6 infection in the CNS. The virus has not been shown to grow in CSF samples sent for viral culture.
Tissue biopsy is especially relevant in solid-organ or bone-marrow transplant recipients who have evidence of graft rejection and in immunocompromised patients with severe hepatitis or hepatic failure. Samples should be sent for immunohistochemical staining and cell culture to identify HHV-6 infection. Skin biopsies have failed to show the presence of HHV-6 in cases of rash. If the etiology of a rash is in doubt, skin biopsy should be obtained to rule out other causes.
On histologic analysis, typical balloonlike cells (cells that show cytoplasmic swelling with a loss of intercellular bridges) may be seen in all affected organs.
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