吉川 哲史

Background. Little is known about human herpesvirus (HHV)-6 infection after liver transplantation. We present our experiences with four cases of HHV-6 infection after liver transplantation from living related donors. Methods. Peripheral blood was collected from four donor and recipient pairs at the time of transplantation and biweekly from the recipients after transplantation. We attempted to isolate HHV-6 and measure antibody titers to HHV-6 and HHV-7. Results. HHV-6 was isolated from four recipients approximately 2 weeks after transplantation. A significant rise in HHV-6 antibody titers was observed in four recipients at some point in their course, whereas HHV-7 antibody titers were increased in one recipient. Four isolates were variant B. When HHV-6 was isolated, all recipients had an unexplained fever. Conclusions. HHV-6 variant B infection after pediatric liver transplantation was confirmed. HHV-6 infection occurred approximately 2 weeks after transplantation. Moreover, there appears to be an association between HHV-6 infection and unexplained fever.

Abstract Five patients suffering from exanthem subitum with thrombocytopenia were confirmed as primary human herpesvirus 6 (HHV-6) infection by serological test. All cases had thrombocytopenia during the acute phase of exanthem subitum. The clinical features of these cases were benign, and all recovered without any specific treatment. Moreover. 4 of the 5 cases showed a mild elevation of hepatic transaminase during the same period, and other viral infections including cytomegalovirus, Epstein-Barr virus, and human herpesvirus 7 were ruled out in these patients. It was speculated that direct inhibition of platelet production by the virus or cytokine induced by the virus-infected cells was the mechanism of the thrombocytopenia induced by primary HHV-6 infection. © 1998 Wiley. All rights reserved.

The persistence of protective immunity after postexposure prophylaxis against varicella using oral aciclovir was evaluated in the family setting. Sixty one of 78 recipients of oral aciclovir were assessed by questionnaire, and 13 of 61 were evaluated for serum antibody to varicella zoster virus (VZV) using the fluorescent anti body to membrane antigen method. The observation period ranged from 33 to 50 months. None of those (n = 44) who had initially seroconverted to VZV after aciclovir prophylaxis developed breakthrough varicella. All 13 who had serology repeated still had titres ≤ 4. Antibody titres in those who had histories of re-exposure to the virus were significantly higher than in those who had not (p&lt 0.01).

An otherwise healthy 3-year-old girl developed severe varicella complicated by aseptic meningitis and received intravenous acyclovir (ACV) therapy. Her two siblings who were susceptible to varicella-zoster virus (VZV) and closely exposed to VZV in the family received oral ACV (45 or 54 mg/kg per day in four divided doses for 7 days) starting 8 days after onset of the index case for post-exposure prophylaxis of varicella. They showed only five or seven papules over the body without fever 12 days after onset of the index case, while they had one-third or half the level of antibody titer and equal sized skin reactions to VZV antigen of the index case 2.5 months later. © 1996 Japan Pediatric Society.

Pathological findings of an otherwise healthy 17 month old boy who was exposed to Varicella‐zoster virus (VZV) in his family and unexpectedly died 3 days after onset of varicella are reported. They showed a disseminated VZV infection with involvement of skin, lung, liver, spleen, gastrointestinal tract and other organs where VZV antigen was detected by the enzyme‐immunoassay with monoclonal antibodies to VZV. Since the subject was the full‐term product of an uncomplicated pregnancy, who grew and developed normally, and had no symptoms or laboratory findings suggestive of immunodeficiency until his death, these findings suggest that many organs are involved as major internal sites of viral replication before or during infection of skin with VZV in the immunocompetent host. 1993 Japan Pediatric Society

Twenty‐one infants who had virologically confirmed exanthem subitum and central nervous system (CNS) complications were studied to elucidate the clinical fearures, laboratory and virological findings, and outcome. The primary infection with human herpesvirus 6 was confirmed by isolation of the virus from blood, a significant rise in the antibody titeres to the virus, or both. All convulsive seizures (15 generalized and 6 focal) occurred during the pre‐eruptive stage of exanthem subitum. Four infants with encephalities/encephalopathy had more severe clinical features with abnormalities demonstrated on electroencephalograms and cerebral computed tomograms. All infants except those with encephalities/encephalopathy recovered without any sequelae. One infant with encephalities/encephalopathy developed epilepsy and another one died. Human herpesvirus 6 DNA amplified by the nested polymerase chain reaction method was detected in the cerebrospinal fluid of 6 infants, including 3 with encephalities/encephalopathy, of 11 parients examined by the fifthy day of the illness. These findings suggest thar CNS complications including encephalitis/encephalopathy occur at the pre‐eruptive stae of exanthem subitum, that human herpesvirus 6 invades the CNS in some patients, and that the outcome is not always benign. Copyright © 1993 American Neurological Association

The isolation of human herpesvirus 7 (HHV‐7) from saliva and blood, and the prevalence of antibodies to the virus in healthy individuals were investigated in Japan. By cocultivating samples with phytohemagglutinin‐P‐stimulated cord blood mononuclear cells, HHV‐7 was isolated from the saliva of 1 of 20 children and from 4 of 38 adults but not from their blood. The isolates were confirmed as closely related to RK strain of HHV‐7, but not to U1102 (human herpesvirus 6, HHV‐6 type A) or Z29 (HHV‐6 type B) strains by restriction cleavage patterns of the DNA. The virus antibody of 330 healthy children and adults was measured with an indirect immunofluorescence assay, using one of our isolates (FG7‐6). The positivity rate of antibody was 40% in the first 2 months of life, declined during the first 6 months, then gradually increased and was 45% at 1‐4 years of age. It reached the highest level (60%) at 11‐13 years of age and was maintained until the end of the third decade, then decreased thereafter. Additionally, no simultaneous rise in the antibody titers was observed in 7 virologically confirmed exanthem subitum patients. Copyright © 1993 Wiley‐Liss, Inc., A Wiley Company

The involvement of human herpesvirus-6 (HHV-6) and herpes simplex virus infections was evaluated virologically and serologically in a 13-month-old girl with meningoencephalitic illness occurring in the pre-eruptive stage of exanthem subitum. An isolation of HHV-6 from blood and seroconversion to the virus confirmed the primary infection with the virus. HHV-6 gene sequences were detected in cerebrospinal fluid of acute stage of the disease by polymerase chain reaction. There was no evidence of herpes simplex virus infection in blood and cerebrospinal fluid. The patient recovered from the disease without any sequelae, although abnormal electroencephalography and cerebral computed tomography findings were observed temporally in the acute stage of the disease. These findings strongly suggest that HHV-6 invades the central nervous system and causes meningoencephalitis.

Virological and serological studies were carried out prospectively to evaluate the possible activation of human herpesvirus‐6 (HHV‐6) in 50 infants and children with acute measles by isolation of HHV‐6 from peripheral blood and by determining neutralizing antibodies to the virus. All but 5 patients (90%) were seropositive to HHV‐6 in the acute stage of measles and 18 (40%) had a significant increase in HHV‐6 antibody titers thereafter, whereas only 2 of 27 patients who were initially seropositive to Epstein‐Barr virus (EBV) viral capsid antigen (VCA) had a significant rise in antibody titers to EBV VCA. Among 18 patients with a significant increase in HHV‐6 titers, the virus was isolated from the peripheral blood mononuclear cells of three patients in the early convalescent stage of measles. These results indicate that activation of HHV‐6 may occur frequently a few weeks after primary infection with the measles virus. © 1992 Wiley‐Liss, Inc. Copyright © 1992 Wiley‐Liss, Inc., A Wiley Company

Severity of viremia and neutralizing antibody responses were compared between nine young infants ( 10 months) with measles and 18 infants and children ( 11 months) with ordinary measles. Peripheral blood mononuclear cell (PBMC)‐associated viremia was detected between the first day of elevation of fever (day 0) and day 5 of the disease in the former group, whereas PBMC‐associated and cell‐free viremia were detected between day 0 and day 14 in the latter group. The number of infected PBMC during the first 7 days of the disease was 3.22 ± 1.07 (log10, mean ± s.d.) per 10 million PBMC in the former group, which was significantly smaller (P= 0.02) than that of the latter group (4.21 ± 1.18). The former group reached the maximum level of antibody earlier than the latter group. Copyright © 1992, Wiley Blackwell. All rights reserved

Human herpesvirus-6 (HHV-6) is ubiquitous in the human population and causes exanthem subitum, a benign disease seen in infancy. However it also produces a wide spectrum of clinical manifestations including cases with a fatal outcome. The virus remains latent in several organs, including the kidneys, liver, lymph/nodes and salivary glands, after the primary infection and reactivates when immune function is impaired. Reactivation of the virus occurred in a half of the bone marrow recipients 2 to 4 weeks after bone marrow transplantation (BMT). It remains to be established whether HHV-6 in fact causes the fever and rash observed in recipients who have reactivation of the virus. The data reviewed here will be required to compare with those of human herpesvirus 7 and a different group of HHV-6. © 1992 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

The assay for detecting IgM neutralizing (NT) antibody activity to human herpesvirus‐6 (HHV‐6) was developed by using pretreatment of blood sample with staphylococcal protein A. The activity was mostly present in IgM fractions of serum but not in IgA fractions separated by ultracentrifugation. The assay was used for seroepidemiological studies for HHV‐6 infection. In primary HHV‐6 infection, IgM NT antibodies appeared 5 to 7 days after onset of exanthem subitum, reached maximum titers at 2 to 3 weeks, and tended to decline to undetectable levels after 2 months. In contrast, reactivation of HHV‐6 observed in organ transplants showed somewhat greater degree of IgM NT antibody responses that persisted for 2 to 3 months and became undetectable 5 to 6 months after transplantation. The level and persistence of NT antibody titers measured by the conventional method was generally greater than those of the IgM titers. The prevalence of the IgM NT antibodies was examined in healthy individuals. The antibody was first detected at 4 to 7 months of age (5%), reached maximum level at 8 to 11 months (40%), and was detectable by 4 to 6 years (17%). A few (4 to 5%) of adolescents and adults were positive for the antibody. © owned by Center for Academic Publications Japan (Publisher)

Three strains of human herpesvirus‐6 (HHV‐6) were isolated from peripheral blood mononuclear cells of a leukemic child with the antibody of HHV‐6 before and after bone marrow transplantation (BMT) two strains were obtained before BMT and one after BMT. The DNA extracted from the three isolates was analyzed by six different restriction endonucleases. The cleavage profiles of two strains obtained before BMT were different, but the third strain isolated after BMT was identical with one of the two, which suggest reactivation of HHV‐6 from the recipient's own body after BMT and possible mutation or superinfection of the virus in an immunocompromized patient. © 1992 Wiley‐Liss, Inc. Copyright © 1992 Wiley‐Liss, Inc., A Wiley Company

Sixty-five kidney transplant recipients and their (22 living related and 43 cadaveric) donors were studied prospectively to determine the relationship between kidney transplantation and human herpesvirus-6 (HHV-6) infection. The virus isolation from peripheral blood and other tissues and sequential determination of neutralizing antibodies to HHV-6 were performed during 3 months following the transplantation. All of the donors and their recipients examined had neutralizing antibodies to HHV-6 at the time of renal transplantation and the virus was not isolated from them. HHV-6 was isolated from 3 renal tissues (2 living related and 1 cadaveric) obtained during transplant surgery, but not from their blood at that time. HHV-6 viremia occurred in 9 (14%) of the 65 recipients around 2 to 4 weeks after the transplantation. An additional 27 recipients showed a significant rise in the antibody titer. Thus, the infection with HHV-6 was confirmed in 36 (55%) of the 65. These results indicate that the virus is activated in many cases in the early posttransplant period and that HHV-6 establishes in vivo latency in the kidney tissue. There was no correlation between HHV-6 infection and acute rejection or the antirejection prophylaxis. © 1992 by Williams &amp Wilkins.

A lysate of human herpesvirus 6 (HHV‐6)‐infected cord blood mononuclear cells was used as antigen for enzyme‐linked immunosorbent assay for the detection of lgG antibody to HHV‐6. Antibody responses after exanthem subitum were well correlated with clinical recovery from the disease and the level of antibody activities was well correlated with indirect immunofluorescence assay and the neutralization test. Seroconversion to other human herpesvirus, including cytomegalovirus, was not observed in infants with exanthem subitum. All of the infants had by the age of 1 month antibodies to HHV‐6, which decreased with age to the lowest level at the age of 3 to 6 months and then increased and reached the maximum level by 1 to 2 years of age. After 3 years of age, the prevalence was almost stable. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company

The number of varicella zoster virus-infected mononuclear cells in blood samples obtained during 3 days before appearance of vesicular skin rashes could be estimated in 13 of 21 immunocompetent children with varicella and viremia (range, 1-83 per 107 mononuclear cells). The virus was isolated from 5% of adherent cells (1/21),71% ofnonadherent cells (12/17),43% ofT lymphocytes (9/21), and 33% ofB lymphocytes (7/21). The number of vesicleson the body correlated with the maximum body temperature, duration of fever, and number of infected cells in the blood. These results indicate that varicella zoster virus infection in immunocompetent children is disseminated by circulating T and B lymphocytes and the severity of the viremia is reflected in the severity of the disease. © 1990, University of Chicago. All rights reserved.

Antibody to human herpesvirus‐6 (HHV‐6) was measured in cord blood mononuclear cell cultures by a neutralization (NT) test, in which the presence or absence of characteristic large cell formation in cells infected with HHV‐6 was used as an indicator for neutralization of the virus. The NT test could measure antibodies during and just after the appearance of the skin rash in patients with exanthem subitum. The levels of antibodies measured by the NT test was generally higher than that by an indirect immunofluorescence assay. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company

Two infants (4 and 5 months of age) with a febrile episode for 3 and 5 days, respectively, developed skin rashes after the fever subsided and were diagnosed as exanthem subitum. The rash continued for 5 days followed by mild‐to‐moderate pigmentation. Human herpesvirus‐6 and measles virus, which were confirmed by a specific immunofluorescence assay and by electron microscopy, were isolated simultaneously from blood in the acute stage of the disease but not from the convalescent stage. The titer of the herpesvirus‐6 in blood was greater then that of measels. Specific serologic assays showed marked seroconversion against human herpesvirus‐6 but not to measles virus. The results suggest that dual infection with human herpesvirus‐6 and measles virus results in atypical exanthem subitum or modified measels with unique immunologic responses. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company

Mononuclear cell-associated viremia caused by human herpesvirus type 6 was detected in 39 (66%) of 59 blood samples from 38 children with exanthem subitum between day 0 and day 7 of the disease. The rate of virus isolation from mononuclear cells was 100% (26/26) on days 0 to 2 (just before appearance of skin rash), 82% (9/11) on day 3,20% (2/10) on day 4,7% (2/12) on days 5 to 7, and 0% (0/37) on day 8 and thereafter. The cell-free virus was detected in blood in 10 (21%) of 47 blood samples during the same period. The antibody activity to the virus, evaluated by a newly developed neutralization assay, was first detected on day 3 of the disease with a positive rate of 18% (2/11). It became 60% (6/10) on day 4, 75% (9/12) on days 5 to 7, and 100% on day 8 and thereafter. Thus the disappearance of the virus from blood was associated with the induction of specific immunity to the virus. © 1989 The C. V. Mosby Company.