A Japanese study found that unexplained fever and biliary atresia are associated with HHV-6B infection in pediatric transplant patients. 100% of seronegative infants developed a primary infection.
In an effort to elucidate the risk factors for clinical features of HHV-6B infection in pediatric living donor liver transplant (LDLT) recipients, researchers from Fujita Health University School of Medicine performed pre-transplant HHV-6 testing and weekly HHV-6B monitoring for pediatric LDLT patients until day +90 post-transplant. They reported that young age (OR 0.975, p=0.041), and biliary atresia (OR 16.48, p=0.013) were independent predictors of HHV-6B infection. Further, the occurrence of unexplained fever was higher in recipients with HHV-6B infection compared to uninfected recipients (78.6% vs. 31.6%, p=0.013) as was ALT levels at 8 and 9 weeks post-transplant.
This retrospective cohort study included 33 pediatric (<16 years old) patients who received a LDLT from their parents between 2004 and 2015. The researchers defined infection as ≥104 copies/µg DNA and if patients were seronegative prior to transplant, they were diagnosed with primary infection as opposed to a diagnosis of reactivation if the patient were seropositive. Fourteen of the 33 patients (42.4%) developed HHV-6B infection and HHV-6B was isolated via co-culture from 10 of these 14 patients, leading the authors to conclude that 104 copies/µg DNA was an appropriate threshold to differentiate between active and latent viral infections when using PCR.
Of note, all 8 HHV-6 seronegative patients developed a primary HHV-6B infection, though this observation was not statistically significant in multivariate analysis due to the lack of seronegative patients who did not develop HHV-6B infection. Regardless, the authors still pondered whether younger LDLT recipients, who have a higher frequency of seronegativity, have a higher risk of acquiring HHV-6B infections, as has been reported in past studies (Yoshikawa 2000).
Five of the 33 recipients required ganciclovir after testing positive for active infection using a CMV antigenemia assay, which identifies immediate early antigens in the peripheral blood. Levels of CMV antigenemia dropped rapidly in response to antiviral therapy. On the other hand, peripheral blood HHV-6B DNA loads did not change in 4 of these 5 patients, presumably because latent DNA in PBMCS is included in this measure.
Most US laboratories use HHV-6 DNA in the plasma as an indicator of active infection, to avoid picking up latent HHV-6 DNA. This can result in false negatives, however, since HHV-6 can reactivate locally in the liver allograft and cause liver failure, often without detectable plasma viremia (Phan 2018) or change in peripheral blood DNA levels (Buyse 2013). Liver biopsies were not routinely performed during the study period; thus, it is unknown if these rejections and/or elevations in ALT are due to a localized HHV-6 infection that could not be detected in peripheral blood mononuclear cells in the background of a high load of latent HHV-6 DNA.
Between the 2 groups (HHV-6+ vs. HHV-6-), there were no differences in mortality (p=0.313), CMV and EBV infections. Overall, all of the active HHV-6B infections were resolved without antiviral drugs, which suggested that HHV-6B infection is self-limiting in pediatric LDLT recipients. The authors suggested that HHV-6B monitoring may help reduce unnecessary antimicrobial therapies to febrile patients around 2-4 weeks after LDLT.
Biliary atresia is a childhood disease in which one or more bile ducts becomes abnormally blocked. Both CMV and HHV-6 were found in biliary atresia biopsies in a previous study (Domiati-Saad 2000).
Read the paper here: Yasui 2018.