Human herpesvirus 6 causes hepatitis in transplant recipients.

Human herpesvirus 6 (HHV-6) was discovered as a novel human herpesvirus in the peripheral blood of patients with lymphoproliferative disorders and AIDS. While it was originally designated “human B-lymphotropic virus” (1), subsequent studies established that the virus was primarily T-cell lymphotropic, causing it to be classified as HHV-6. In most children, primary HHV-6B infection causes exanthem subitum (2), a common febrile illness in infants, occurs between 6 months and 1 year of age (3). Although exanthem subitum is generally benign and a self-limited disease, several severe complications, including encephalitis/encephalopathy (4), and hepatitis (5), can rarely occur. Some patients experience a mild elevation in hepatic transaminase levels during infection. Indeed, approximately 4% (4 cases) of 89 infants with primary HHV-6 infection had signs of hepatic injury during viral infection (6). In these cases, patients had a transient elevation in serum hepatic transaminase levels that completely resolved without any specific treatments. However, one case report described chronic hepatitis caused by HHV6 infection in one 20-month-old otherwise healthy boy (7). Chronic hepatitis was confirmed by pathological analysis, and viral DNA was detected in liver tissue by polymerase chain reaction (PCR) and in situ hybridization. In these samples, HHV-6 DNA localized to the nuclei of hepatocytes, the sinusoidal cells, and the nuclei of the epithelial cells of the intra-hepatic bile ducts. In addition to chronic hepatitis, HHV-6 also appears to cause some cases of fulminant hepatitis, a much more severe disease entity. We reported fatal fulminant hepatitis resulting from primary HHV-6 infection in a previously healthy 3month-old boy in 1990. Despite full supportive care and exchange transfusion, the patient died seven days after admission to our hospital (5). Aita et al observed a clinical course similar to those we have reported, and this patient recovered following supportive treatments (8). The onset of hepatic injury in these patients corresponded to the exanthematous period of the disease. Histopathological analysis was carried out in the case reported by Aita et al (8), and showed microvesicular steatosis resembling that of Reye’s syndrome. Moreover, HHV-6 DNA was detected in the endothelium of the portal vein but not in hepatocytes by in situ hybridization. HHV-6 infection has also been associated with fulminant hepatitis in adults (9). Six Japanese adults (aged between 26 and 56 years old) and 5 children (aged between 10 months and 13 years old) with non-A, non-B, non-C fulminant hepatitis were analyzed using PCR, in situ hybridization, and immunohistochemistry to identify the etiologic agent (9). HHV-6 DNA was detected in all 5 child patients and in 2 out of the 6 adult patients by PCR. Although histological analysis was performed on samples from only one child (13-year-old boy), HHV-6 DNA, RNA, and antigen were detected in the nuclei of hepatocytes suggesting active viral replication in the hepatocytes. HHV-6 probably remains latent in the body after the primary infection, then reactivates upon host immunosuppression in a manner similar to other human herpesviruses. All previously-identified human herpesviruses, especially human cytomegalovirus (HCMV), are important contributors to morbidity and mortality in immunosuppressed organ transplant recipients. As HHV-6 shares many characteristics with HCMV, including DNA sequence homology, elements of genomic organization, antigenic cross-reactivity, and in-vitro growth characteristics, HHV-6 may behave similarly as a complication of organ transplantation. Although the pathogenesis of HHV-6 is not well understood, recent evidence suggests that the virus is a serious, potentially lifethreatening pathogen in the post-transplant period (10). Although the exact frequency of reactivation is difficult to determine, approximately 40% to 50% of transplant recipients develop HHV-6 infection around 2 to 4 weeks after transplantation. The incidence appears to be dependent on the sensitivity of the procedures for the diagnosis of viral infection. Although numerous clinical syndromes have been postulated as HHV-6-associated diseases (Table 1), many of such associations have been inconclusive. Therefore, if physician observes patients with these complications, accurate