Evaluation of liver failure in a pediatric transplant recipient of a liver allograft with inherited chromosomally integrated HHV‐6B

Abstract

Background Active infections of human herpesvirus 6B (HHV‐6B) are frequent in immunocompromised recipients after transplantation. Nevertheless, they need to be distinguished from latent inherited chromosomally integrated genomes (iciHHV‐6) present in about 1% of the population to avoid unnecessary administration of toxic antivirals. Methods A 5‐year‐old child presented with acute liver allograft rejection associated with HHV‐6 DNA in plasma, which led to an unfavorable outcome. We investigated the possibility of HHV‐6 infection derived from an iciHHV‐6 present in the donor's liver using molecular and histopathology studies in various tissues, including quantification of HHV‐6 DNA, genotyping, sequencing for antiviral resistance genes, relative quantification of viral transcripts, and detection of gB and gH viral proteins. Results The presence of iciHHV‐6B was evidenced in the donor with signs of reactivation in the gallbladder and transplanted liver (detection of HHV‐6B mRNA and late proteins). This localized expression could have played a role in liver rejection. Low viral loads in the recipient's plasma, with identical partial U39 sequences, were in favor of viral DNA released from the transplanted liver rather than a systemic infection. Conclusions Determination of iciHHV‐6 status before transplantation should be considered to guide clinical decisions, such as antiviral prophylaxis, viral load monitoring, and antiviral therapy.

Investigation of Inherited Chromosomally Integrated Human Herpesvirus-6A+ and -6B+ in a Patient with Ulipristal Acetate-Induced Fulminant Hepatic Failure

“…In immunosuppressed patients, reactivated HHV-6 from iciHHV-6 can induce acute liver failure and acute rejection, as demonstrated in a 5-year transplant recipient, by the presence of mRNA and late viral protein in the sole iciHHV-6B+ liver allograft [31]. Reactivated HHV-6 from iciHHV-6 is susceptible to antiviral drugs and can be treated with ganciclovir, valganciclovir, cidofovir, brincidofovir, or foscarnet [28,[31][32][33][34]. However, antiviral treatment, considered a therapeutic option for iciHHV-6-associated diseases, leads to variable clinical improvement [24,33,35,36].…”

“…Aside from the highest levels of gene expression in the T-cells, brain, testis, esophagus, and adrenal gland, it has been demonstrated that ciHHV-6B is able to reactivate in hepatocytes as a permissive cell [27,30]. In immunosuppressed patients, reactivated HHV-6 from iciHHV-6 can induce acute liver failure and acute rejection, as demonstrated in a 5-year transplant recipient, by the presence of mRNA and late viral protein in the sole iciHHV-6B+ liver allograft [31]. Reactivated HHV-6 from iciHHV-6 is susceptible to antiviral drugs and can be treated with ganciclovir, valganciclovir, cidofovir, brincidofovir, or foscarnet [28,[31][32][33][34].…”

Human herpesvirus 6B encephalitis in a liver transplant recipient: A case report and review of the literature

“…Recognition of ciHHV‐6 is vital for clinical strategy. ciHHV‐6–induced HHV‐6 infection after liver transplant has been reported to be associated with liver rejection and mortality 15,16 . On the other hand, misdiagnosis of ciHHV‐6 as HHV‐6 reactivation will result in unnecessary and potentially toxic antiviral therapy 17 .…”

Variation in human herpesvirus 6B telomeric integration, excision, and transmission between tissues and individuals

“…Similarly, the presence of a large viral genome within a telomere has been shown to cause localized instability that may influence telomere DNA damage signaling and function ( Huang et al, 2014 ; Wood and Royle, 2017 ; Zhang et al, 2016 ). Recent studies have also indicated an association between iciHHV-6A/6B and angina pectoris ( Gravel et al, 2015 ); unexplained infertility ( Miura et al, 2020 ); an increased risk of aGVHD following hematopoietic stem cell transplantation when either the donor or recipient has iciHHV-6A/6B ( Hill et al, 2017 ; Weschke et al, 2020 ); complications following solid organ transplantation when there was iciHHV-6A/6B donor/recipient mismatch ( Bonnafous et al, 2018 ; Bonnafous et al, 2020 ; Petit et al, 2020 ); and possibly an increased risk of pre-eclampsia ( Gaccioli et al, 2020 ).…”