Yoshizo Asano

Central nervous system complications in human herpesvirus-6 infection

Human herpesvirus-6 (HHV-6) is the causative agent of the common childhood infectious disease, exanthem subitum. After the virus was recently isolated from humans, it was found to be closely related to human cytomegalovirus (CMV), and was thus classified within the beta subgroup of human herpesviruses. HHV-6 possesses neurotropism in vitro, and it has been suggested that primary infection can cause complications of the central nervous system (CNS), including febrile seizures and encephalitis/encephalopathy. There is also speculation that the direct invasion of the virus into the CNS may play an important role in causing these neurological complications. Moreover, there are several reports which have suggested an association between HHV-6 and a variety of neurological disorders in adults. This paper will briefly review our virological understanding of the virus, and summarize recent findings regarding HHV-6 as an etiologic agent for CNS infection.

Clinical characteristics of febrile convulsions during primary HHV-6 infection

OBJECTIVE To clarify clinical characteristics of children with febrile convulsions during primary human herpesvirus 6 (HHV-6) infection. SUBJECTS AND METHODS The clinical characteristics of first febrile convulsion were compared between those with and without primary HHV-6 infection in 105 children. HHV-6 infection was verified by culture or acute/convalescent anti-HHV-6 antibody titres. RESULTS Primary infection with HHV-6 was seen in 21 of 105 patients with febrile convulsions (3 upper respiratory infection, 1 lower respiratory infection, and 17 exanthem subitum). 13 of 23 patients < 1 year, 19 of 79 patients with first febrile convulsion, and 2 of 15 with second convulsion were infected with HHV-6. The median age of patients with first febrile convulsion and HHV-6 was significantly lower than those without infection. The frequency of clustering seizures, long lasting seizures, partial seizures, and postictal paralysis was significantly higher among those with primary HHV-6 infection than among those without. The frequency of atypical seizures in 19 patients with first febrile convulsion associated with primary infection was significantly higher than in 60 patients without primary infection. The frequency in infants younger than 1 year of age was also significantly higher than that in 10 age matched infants without primary infection. CONCLUSIONS These findings suggest that primary infection with HHV-6 is frequently associated with febrile convulsions in infants and young children and that it often results in the development of a more severe form of convulsions, such as partial seizures, prolonged seizures, and repeated seizures, and might be a risk factor for subsequent development of epilepsy.

Monitoring four herpesviruses in unrelated cord blood transplantation

Cord blood transplantation, which has lower risk of graft-versus-host disease than bone marrow transplantation, might have higher risk of infections. A system to quantify four herpesviruses, CMV, human herpesvirus 6 (HHV6), EBV, varicella-zoster virus using the real-time PCR assay was established and applied for prospective viral load monitoring in three recipients undergoing cord blood transplantation. CMV and HHV6 were detected in peripheral blood from all three recipients, while EBV was detected in two. Varicella-zoster virus was not detected at all. At the peak of HHV6 or CMV, each patient showed virus-related symptoms. During the pre-transplant period, CMV DNA was detected in two recipients who later developed CMV-related diseases. These observations indicate that our system is not only useful for managing herpesviruses infections in transplant recipients, but also a powerful method for clarifying the relationships between the viral load and clinical symptoms. Bone Marrow Transplantation (2000) 26, 1193–1197.

Prospective study of persistence and excretion of human herpesvirus 6 in patients with exanthem subitum and their parents.

Objective. To elucidate persistence of human herpesvirus-6 (HHV-6) in the blood and excretion of the virus into several body fluids of patients with exanthem subitum (ES), and to examine serologic and virologic findings of the parents caring for the patients in the family setting. Materials and Methods. During a 15-month period, 20 infants from 20 families (11 boys and 9 girls; mean age, 7.7 months; range, 4–11 months) with primary HHV-6 infection and a typical clinical course of ES, and 15 parents from the 20 families (2 males and 13 females; mean age, 28.2 years; range, 21–34 years) were enrolled in the study and examined clinically and virologically. Primary infection with HHV-6 was confirmed by isolation of the virus from peripheral blood mononuclear cells (MNCs), and seroconversion or a significant increase in the antibody titers to HHV-6 by a neutralization test. Viral persistence or excretion was examined by amplifying the viral deoxyribonucleic acid (DNA) in serially collected peripheral blood MNCs, plasma, saliva, stool, and urine samples with a nested polymerase chain reaction method. Data on saliva from the parents were compared with those of 21 age-matched controls. Results. Twenty infants with virologically confirmed ES had HHV-6 DNA in MNCs persistently during and after the disease but in plasma only in the first 5 days of ES. The viral DNA was also detected persistently or intermittently in saliva and stool during and after the disease but rarely in urine. On the other hand, the 15 parents examined of the 20 infants had no HHV-6 viremia nor viral DNA in peripheral blood MNCs and plasma except 1, but half of them excreted viral DNA in saliva during and after ES. The frequency of excretion of viral DNA into saliva was not significantly different from that of 21 control parents. Only 1 of the 15 showed a fourfold increase in antibody titers to HHV-6 after possible exposure from their children. Conclusions. After systemic replication of HHV-6 in the blood of patients with ES during the first 5 days of the disease, the virus is excreted into saliva and stool persistently or intermittently but rarely into urine. The presence of HHV-6 DNA in plasma suggested active infection with the virus. Excretion of the virus into the saliva of infants with ES and their parents suggests the source and transmission route of infection with HHV-6.

Human herpesvirus 6 infection after living related liver transplantation

The aim of the study was to investigate human herpesvirus‐6 (HHV‐6) infection after liver transplantation from living related donors, and to evaluate the reliability of the presence of HHV‐6 DNA in plasma by the polymerase chain reaction (PCR) for monitoring active HHV‐6 infection. EDTA peripheral blood was collected from 47 donor and recipient (16 males and 31 females, age 1–320 months) pairs at the time of transplantation and biweekly from these recipients after transplantation until 2 months after operation. Isolation of HHV‐6 and serological assays were carried out to evaluate active HHV‐6 infection in this study. The presence of the viral DNA in plasma was tested by nested PCR. Four clinical events, such as unexplained fever, thrombocytopenia, rejection, and central nervous system (CNS) involvement, were evaluated for clinical features of the virus infection. Risk factors for the virus activity after liver transplantation were also examined. HHV‐6 activity was detected in 23 (49%) of the 47 recipients approximately 2–4 weeks after transplantation. All 9 isolates were HHV‐6 variant B. The presence of the viral DNA in plasma correlated well with virus isolation and serology (P < 0.01). Only unexplained fever was associated statistically with HHV‐6 activity after liver transplantation (P < 0.01). If the recipient was seronegative to HHV‐6 before transplantation, the recipient was more likely to develop the active virus infection after liver transplantation (P = 0.11). HHV‐6 activity occurred in one‐half of the recipients approximately 2–4 weeks after liver transplantation, and there was a close association between HHV‐6 activity and unexplained fever following transplantation. Detection of the viral DNA in plasma by PCR is useful for monitoring active HHV‐6 infection in these patients. Seronegative recipients were more likely to have evidence of active HHV‐6 infection after liver transplantation. J. Med. Virol. 62:52–59, 2000.

Invasion by human herpesvirus 6 and human herpesvirus 7 of the central nervous system in patients with neurological signs and symptoms

METHODS A total of 43 children with neurological signs and symptoms were enrolled in the study. All children were suspected of having meningitis, and lumbar punctures were performed. Human herpesvirus 6 (HHV-6) and HHV-7 DNA was detected in cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMC) by nested polymerase chain reaction. RESULTS Most patients had detectable serum antibody to both HHV6 and 7. HHV6 DNA was detected in PBMC of 15 patients and in CSF cell pellet of seven. Corresponding figures for HHV7 were 28 and 6.2/7, and 5/6 with CSF viral DNA also had it in PBMC, respectively. No viral DNA was detected in CSF supernatants. The seven HHV6 CSF viruses were all variant B. CONCLUSION These data suggest that HHV-7 may invade the CNS.

Human herpesvirus-7 (HHV-7): current status

BACKGROUND Human herpesvirus-7 (HHV-7) is a newly discovered virus and very little is known about its prevalence, biologic, immunologic and molecular biology aspect. Besides the HHV-7 etiologic role in a few cases of exanthem subitum, its association with other diseases has not been reported. OBJECTIVES To review what is currently known about HHV-7. RESULTS HHV-7 was first isolated in 1990 from purified T-cells from a healthy individual. Following this report, an independent isolation of HHV-7 was reported from the mononuclear cells (PBMC) of a chronic fatigue syndrome patient. HHV-7 is closely related to human herpesvirus-6 (HHV-6) and human cytomegalovirus (HCMV), but is distinct from Epstein-Barr virus (EBV), herpes simplex virus and varicella zoster virus. Using polyvalent and monoclonal antibodies, several HHV-7 viral proteins were identified, ranging from 136 to 30 kDa. HHV-7 infection occurs later than HHV-6, which appears in early childhood. HHV-7 is ubiquitous, and its prevalence rate is >85% in the US population, although its rates of prevalence in Japan is lower than in the USA and Europe. HHV-7 is frequently isolated from saliva; however, HHV-7 has been consistently isolated from PBMC from young children as well. Several cases of exanthem subitum have been linked to primary infection of HHV-7, suggesting that it may also cause exanthem subitum. Primary infection with HHV-7 was also reported from a patient with features of hepatitis and exanthem subitum. This virus was also isolated from tissues from a case of hepatosplenomegaly and pancytopenia lacking either EBV or HCMV. Thus far, no other disease associated with HHV-7 has been reported. Only one continuous T-cell line (SupT1) can support the replication of HHV-7, but the virus yield is extremely low. CONCLUSIONS It has been about 4 years since this member of the human herpesvirus family was reported. In the coming years, more data will be available on the epidemiology, biology, immunology, molecular biology, and pathogenesis of HHV-7. The finding of reciprocal interference between HHV-7 and HIV-1, suggesting competition at the receptor level is important, needs further work and here HHV-7 may play a role as a negative cofactor in the natural history of HIV infection. Because of HHV-7 interaction with HIV-1, the possibility of its vertical transmission needs to be investigated. This review on HHV-7 is intended to provide current information on HHV-7.

A Live Varicella Vaccine

A live varicella vaccine has been developed, and its safety and immunogenicity have been established in normal children as well as in high-risk children.

Four cases of human herpesvirus 6 variant B infection after pediatric liver transplantation

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.

Persistence of protective immunity after postexposure prophylaxis of varicella with oral aciclovir in the family setting

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 antibody 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<0.01).