Keiko Tanaka-Taya

Human herpesvirus 7 infection associated with central nervous system manifestations

The clinical features of infection with human herpesvirus 7 (HHV-7) are not well described. Exanthem subitum is the only illness that is confirmed to be caused by HHV-7. We report two children who had exanthem subitum associated with central nervous system manifestations. Two strains of HHV-7 were isolated sequentially from peripheral blood mononuclear cells and saliva of the some child who had exanthem subitum complicated with acute hemiplegia in childhood. Two strains were confirmed to be HHV-7 by means of monoclonal antibodies to human herpesvirus 6 (HHV-6) and HHV-7, polymerase chain reaction, and DNA analysis. During the convalescent period, the antibody titer to HHV-7 rose from less than 1:10 to 1:320, whereas the antibody titer to HHV-6 remained less than 1:10. Another child with exanthem subitum complicated by acute hemiplegia had serologic evidence of primary HHV-7 infection. These two cases demonstrate a new relationship between HHV-7 and central nervous system symptoms.

Seroepidemiological study of human herpesvirus-6 and -7 in children of different ages and detection of these two viruses in throat swabs by polymerase chain reaction

The presence of human herpesvirus 6 (HHV‐6) and human herpesvirus 7 (HHV‐7) in throat swabs of 62 children of different age groups (group I, ages 0–5 month; group II, ages 6–11 months, group III, ages 12–23 months, group IV, age 2–8 years) and 28 adults was detected by polymerase chain reaction. The detection rate of HHV‐6 DNA was the highest (87%) in children aged 1‐year‐old and decreased with age, whereas the detection rate of HHV‐7 increased with age and reached a maximum in adults. HHV‐6B was detected in almost all samples except for two children who secreted only HHV‐6A. When the antibody prevalence was determined in the four groups of children, HHV‐6 antibody was detected in 8/12 (66.7%), 10/12 (83.3%), 15/16 (93.8%), and 13/14 (92.9%), respectively. Antibody to HHV‐7 in these groups was detected in 6/12 (50.0%), 4/12 (33.3%), 12/16 (75.0%), and 13/14 (92.9%), respectively. Detection of HHV‐6 DNA in throat swabs of triplets who had the sequential onset of exanthem subitum was attempted by using samples sequentially collected from these children after the onset of the disease in the first patient. HHV‐6 DNA with high copy numbers was detectable during the acute and convalescent phases of the disease in all patients, but no DNA was detected in samples collected before the onset of disease.

Ganciclovir is effective for prophylaxis and treatment of human herpesvirus-6 in allogeneic stem cell transplantation

Human herpesvirus 6 (HHV-6) infection and disease are serious complications of allogeneic hematopoietic stem cell transplantation (allo-SCT). Ganciclovir (GCV) is effective against HHV-6 in vitro but the antiviral susceptibility of HHV-6 has not been well characterized in vivo. We retrospectively compared the HHV-6 reactivation rate in pediatric allo-SCT recipients with and without GCV prophylaxis. The HHV-6 reactivation rate at 3 weeks after allo-SCT in patients without prophylactic GCV administration was significantly higher than that in those receiving prophylactic GCV (11/28 vs 0/13, P < 0.01). Five of 36 patients without prophylactic GCV showed clinical manifestations including skin rash, interstitial pneumonitis, persistent thrombocytopenia, enterocolitis and thrombotic microangiopathy, respectively. HHV-6-associated symptoms were observed in one of the 13 patients receiving prophylactic GCV. This patient showed fever, diarrhea and graft rejection concomitantly with a sudden increase of HHV-6 DNA copy number. Patients who received GCV for treatment of HHV-6 infection showed an improvement in symptoms and/or decrease of HHV-6 copy number. Thus, GCV is effective for treating HHV-6 disease after allo-SCT in vivo.

Prevalence of Epstein–Barr virus in Japan: Trends and future prediction

Epstein–Barr virus (EBV) is the causative agent of infectious mononucleosis and some malignancies including EBV‐associated‐lymphomas. A large portion of adults all over the world are infected with EBV. In children, however, there are geographic variations. Most of the children in Asia and in other developing countries are infected in their early life, before 1 year of age (>90% of 5–9‐year‐old children are infected), while the age of primary infection is delayed in Western countries (approx. 50% of 5–9‐year‐old children are infected). The purpose of the present paper was to investigate the recent time trend of the EBV seropositivity among 5–7‐year‐old children living in Tokyo and its neighboring prefectures. Indirect immunofluorescein study for IgG antibody to viral capsid antigen was performed on 442 archival sera. Before the early 1990s, >80% of 5–7‐year‐old children were found to be seropositive, while the positivity rate decreased to 59% (P < 0.001) for the years 1995–1999. These results also showed that the delay in the age of primary infection is continuing and that the rate is estimated to be <50% in 2006. This result suggests that the delay will affect the incidence of EBV‐associated disorders in Japan.

Thrombotic microangiopathy associated with reactivation of human herpesvirus-6 following high-dose chemotherapy with autologous bone marrow transplantation in young children

Thrombotic microangiopathy (TMA) is a serious complication of BMT. Several factors are important in the etiology of TMA, such as cyclosporin A, GVHD, irradiation, intensive conditioning chemotherapy and infection, which cause damage to vascular endothelial cells leading to activation of these cells. We describe two young children with TMA following high-dose chemotherapy with autologous BMT. Development of TMA was accompanied by reactivation of HHV-6, which was identified by both an increase in the copy number of HHV-6 DNA in the peripheral blood and a significant increase in antibody titers to HHV-6. Thus, it was suggested that reactivation of HHV-6 together with high-dose chemotherapy played an important role in the pathogenesis of TMA in these patients. Since HHV-6 is known to infect vascular endothelial cells, and CMV which is virologically closely related to HHV-6, has been reported to be a pathogen that causes TMA, infection with HHV-6 of vascular endothelial cells may induce TMA via damage and activation of these cells.

Identification of Human Herpesvirus 6 Latency-Associated Transcripts

ABSTRACT Four kinds of latency-associated transcripts of human herpesvirus 6 were identified which were detected only in latently infected cells. Although they were oriented in the same direction as the immediate-early 1 and 2 (IE1/IE2) genes and shared their protein-coding region with IE1/IE2, their transcription start sites and exon(s) were latency associated.

Reactivation of human herpesvirus 6 by infection of human herpesvirus 7.

We have attempted to reactivate human herpesvirus 6 (HHV‐6) by infection with HHV‐7 using childhood exanthem subitum patients in vitro. Peripheral blood mononuclear cells (PBMCs) were collected from children who had a history of exanthem subitum(ES) by HHV‐6 and were infected by human herpesvirus 7 (HHV‐7) in vitro. The antigen positive rate to HHV‐6 started to increase 7 days after the infection and reached a maximum by Day 15 using an immunofluorescence antibody test. The copy number of HHV‐6 DNA also increased in the samples in 10 days after infection in vitro. No antigen or increase in DNA was detected in PBMCs, that were mock‐infected or infected with supernatant of stock virus after ultracentrifugation, suggesting that an infection by HHV‐7 is necessary to reactivate HHV‐6. In the paired sera samples during the acute and the convalescent phases of ES, seven to ten bands, that were specific for HHV‐6, were recognized in samples from the acute phase, and at least 5 dominant polypeptides were found more intensively after HHV‐7 infection. J. Med. Virol. 60:284–289, 2000.

Detection of human herpesvirus 7 (HHV‐7) DNA in breast milk by polymerase chain reaction and prevalence of HHV‐7 antibody in breast‐fed and bottle‐fed children

Twenty‐nine breast milk mononuclear cell samples were analyzed for human herpesvirus 7 (HHV‐7) DNA, human herpesvirus 6 (HHV‐6) DNA, and human cytomegalovirus (HCMV) DNA by polymerase chain reaction (PCR). In addition, peripheral blood mononuclear cell samples from 13 puerperants were analyzed for HHV‐7 DNA by PCR, and seropositivity of HHV‐7 was also analyzed in breast‐fed and bottle‐fed children. HHV‐7 DNA was detected in 3 of 29 breast milk samples. HCMV DNA was also detected in 3 of 29 breast milk samples, but HHV‐6 DNA was not detected. HHV‐7 DNA was detected in 11 of 13 samples of peripheral blood mononuclear cells. Though the seropositivity rate for HHV‐7 in breast‐fed children was slightly higher than that in bottle‐fed children at 18 and 24 months old, the difference was not statistically significant. From these results, we speculate that breast‐feeding may be one of the transmission routes of HHV‐7, although this is not the main route. J. Med. Virol. 56:275–279, 1998.

Human Herpesvirus 6B Infection of the Large Intestine of Patients with Diarrhea

Four patients had severe diarrhea after undergoing stem cell transplantation. Human herpesvirus 6B (HHV-6B) DNA was detected in large intestine tissue specimens and in peripheral blood mononuclear cells. In situ hybridization was positive for HHV-6B DNA in the nuclei of goblet cells and, sometimes, in the histiocytes in the submucous region of the large intestine, which suggests that HHV-6B may infect and reactivate in these cells.

Chronic hepatitis in an infant, in association with human herpesvirus-6 infection

A 20-month-old boy was investigated for persistent liver dysfunction. Liver histologic findings showed chronic hepatitis. The presence of human herpesvirus-6 DNA in liver tissue was demonstrated both by in situ hybridization and by polymerase chain reaction. Human herpesvirus-6 may be a causative agent of chronic hepatitis in this case.