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We report a 7-month-old boy who developed vesicular lesions during the course of exanthem subitum. Human herpesvirus-6 (HHV-6) DNA was detected both in the skin lesions and in the throat, by polymerase chain reaction. IgG and IgM antibodies against HHV-6 were 1:10 and < 1:10, respectively on the tenth day of the illness, and > 1:640 and 1:10 on the twenty-second day, respectively. These results suggest that this was primary HHV-6 infection.

Human herpesvirus 7 (HHV-7) was isolated from peripheral blood mononuclear cells of two infants with typical exanthem subitum. The HindIII-, BamHI-, and EcoRI-digested DNA patterns of the isolated viruses were very similar to that of the prototype HHV-7 (RK strain), but different from that of human herpesvirus 6 (HHV-6). During the convalescent period of the first patient, the titer of antibody to HHV-7 rose from < 1:10 to 1:320 by an immunofluorescence antibody test, whereas the titer of antibody to HHV-6 remained < 1:10. In the second patient, who had two independent episodes of exanthem subitum during 2 months, both HHV-6 and HHV-7 were sequentially isolated; seroconversion to HHV-6 occurred during the first episode and to HHV-7 during the second episode. In addition, sera from another 15 children who had episodes of exanthem subitum were serologically tested for antibodies to HHV-6 and HHV-7 by immunofluorescence antibody test. Five of seven patients had seroconversion to HHV-7 just after having typical signs and symptoms of exanthem subitum. These results suggest that HHV-7 is one of the causative agents of exanthem subitum.

The mode of transmission of human herpesvirus 6 (HHV-6) was investigated by molecular epidemiological techniques in four families. HHV-6 was isolated from the peripheral blood of seven infants with exanthem subitum, including siblings, and from the saliva of two mothers. These isolates were examined for genetic relatedness by means of restriction enzymes analysis of purified DNA. While the profiles of the digestion patterns differed among families, they were very similar in a particular family. These results may suggest that HHV-6 is transmitted primarily from mother to child.

Nested primer-based polymerase chain reaction was employed to determine the frequency of latent infection with human herpesvirus 6 (HHV-6) among healthy adults from Bratislava, Slovak Republic. A 592-bp region, upstream from the gene encoding the putative large tegument protein of HHV-6, was amplified from DNA extracted from peripheral blood mononuclear cells (PBMC) of only one of 29 seropositive adults, suggesting that as few as 1 in 10(5) PBMC may be infected with the virus. Direct sequencing of the 592-bp fragment indicated that the virus harbored by the seropositive Slovak subject (designated B38) differed by only 3 nucleotides from an HHV-6 variant B strain (R-147) isolated from an American infant with a roseola-like illness and by 32 bases from the variant A strain GS isolated from a patient with lymphadenopathy (5.4% sequence divergence). None of these strains had a deoxyadenosine at base position 1251, when compared to the published sequence of strain GS clone pZVH14. Although this discrepancy did not affect the large tegument protein gene, it altered the predicted amino acid sequences of two putative proteins coded by open-reading frames 1 and 2 (ORF 1 and ORF 2) located upstream from this gene.

The explosion of immunologic testing capabilities over the past 20 years has enabled clinicians to accurately diagnose many conditions that previously were very difficult to identify solely on a clinical basis. Among these disorders are the viral exanthems. Infections with some of these viruses are of relatively little import (erythema infectiosum), whereas others have more significant consequences (HIV, cytomegalovirus). Clinical suspicions may be pursued more fully now, sometimes even in an office setting.

Objective: To clarify clinical features of patients with primary human herpesvirus 6 (HHV-6) infection (roseola infantum, exanthem subitum) in a large-scale study., Subjects and Methods: Clinical signs and symptoms were analyzed in 176 infants in whom exanthem subitum was initially suspected and primary HHV-6 infection was later confirmed. The infection was proved by isolation of the virus from blood, a significant increase in the neutralizing antibody titers to the virus, or both., Results: The primary HHV-6 infection, which occurred throughout the year, was observed in 94 boys and 82 girls (mean age, 7.3 months). Fever developed in 98% (mean maximum fever, 39.4 degrees C) and lasted for 4.1 days. Macular or papular rashes appeared in 98%, on face, trunk, or both, mostly at the time of subsidence of the fever, and lasted for 3.8 days. Other clinical manifestations occurred as follows: mild diarrhea in 68%, edematous eyelids in 30%, erythematous papules in the pharynx in 65%, cough in 50%, and mild cervical lymph node swelling in 31%. Twenty-six percent had bulging of the anterior fontanelle and 8% had convulsions., Conclusions: Clinical features of patients with virologically confirmed exanthem subitum were comparable with those described before discovery of HHV-6.

Twenty-one infants who had virologically confirmed exanthem subitum and central nervous system (CNS) complications were studied to elucidate the clinical features, 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 titers 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 encephalitis/encephalopathy had more severe clinical features with abnormalities demonstrated on electroencephalograms and cerebral computed tomograms. All infants except those with encephalitis/encephalopathy recovered without any sequelae. One infant with encephalitis/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 encephalitis/encephalopathy, of 11 patients examined by the fifth day of the illness. These findings suggest that CNS complications including encephalitis/encephalopathy occur at the pre-eruptive stage of exanthem subitum, that human herpesvirus 6 invades the CNS in some patients, and that the outcome is not always benign.

To determine the relationship of human herpesvirus-6 (HHV-6) infection to febrile convulsions, cerebrospinal fluid (CSF) from patients with a history of febrile convulsion were tested by polymerase chain reaction (PCR) amplification for HHV-6 DNA. HHV-6 DNA was detected in 9 of 10 samples from patients with exanthem subitum who showed neurologic symptoms. Also, 8 of 10 CSF samples from 8 patients who had three or more febrile convulsions and 1 of 7 CSF samples from patients who had a single febrile convulsion contained HHV-6 DNA. These data suggest that HHV-6 may invade the brain during the acute phase of exanthem subitum and that recurrence of febrile convulsions may be associated with reactivation of HHV-6.

Exanthema subitum had been speculated to be a viral disease although its pathogen is unknown. Human herpesvirus 6 (HHV-6), first isolated in 1986, was proved by Yamanishi et al. to be the causal agent of exanthema subitum. To evaluate the role of HHV-6 as the causal agent in clinically diagnosed exanthema subitum, we tested for HHV-6 antibody in 57 infants with clinical exanthema subitum and exanthema subitum-like rash without fever. Of the 53 patients with clinical exanthema subitum 43 showed seroconversion or a significant rise in antibody titer to HHV-6, 7 were seropositive without significant rise and 3 remained seronegative. The clinical manifestations of these 43 infants with serologically confirmed HHV-6 infection were consistent with the classical characteristics of exanthema subitum. The 4 patients with atypical exanthema subitum showed significant rises in antibody titer. Our results therefore show that the majority of cases with typical clinical manifestations of exanthema subitum had HHV-6 infection. Most cases with HHV-6 infection had the typical clinical course of exanthema subitum, and a few cases might show an afebrile exanthema subitum-like rash.

Human Herpesvirus 6 (HHV-6) is the sixth human pathogenic Herpesvirus. It was isolated for the first time in 1986. The virus is isolated from blood and saliva and it is probable that it is latent in salivary glands and possibly also in blood. The most probable route of infection is droplet infection via saliva and thereafter possibly by blood. Sero-epidemiological investigations demonstrate that newly born infants are practically all passively immunised via maternal antibodies. At about the age of six months, HHV-6 antibody can be demonstrated in a minority of children. From the age of two years and until 50 years, HHV-6 antibody is present in 90-100% of the population. This is in agreement with the extensive HHV-6 infection in the age group from six months to two years. It is demonstrated that HHV-6 is the cause of exanthema subitum. It is uncertain whether HHV-6 is of pathogenetic significance for other diseases.

The existence of catharreal respiratory symptoms (such as pharyngitis, tracheitis, bronchitis etc.) is established as the usual manifestation of "exanthema subitum" due to acute human herpesvirus-6 (HHV-6) infection. But so far pneumonia, purulent sinusitis, purulent otitis media and/or acute obstructive bronchitis (bronchiolitis) in infants and children have not been described. Here we report the results of observations of 2 children with bronchopneumonia/sinusitis maxillaris and severe bronchiolitis associated with an acute HHV-6 infection. Other respiratory viruses were excluded as agents causing the ARD.

Human herpesvirus-6 (HHV-6), a mature T-cell lymphotropic virus, is a newly recognized member of the herpes virus family and shares limited homology with human cytomegalovirus. HHV-6 has been identified as the etiologic agent of the childhood illness exanthem subitum (roseola infantum). Widespread acquisition of this virus has been demonstrated to occur early in childhood, with fever as the most consistent manifestation of primary infection. Reactivation of latent infection has been postulated and may be associated with lymphoproliferative disorders or other diseases of immune function.

An encephalitic illness with a fatal outcome occurred in a 9 month old girl with virologically confirmed exanthem subitum. Human herpes-virus-6 (HHV-6) DNA was found in the cerebrospinal fluid at the acute stage of the disease by the polymerase chain reaction, but the virus antigen was not detected in her brain tissue. This suggests that HHV-6-induced encephalitis/encephalopathy may be due to a non-infectious process.

The human herpes virus 6 (HHV6) is the causal agent of exanthem subitum (rose rash of infants). In addition, however, a wide range of other clinical manifestations are possible, the more common of these include: Untypical exanthem or uncharacteristic rash (with and without fever), acute respiratory disease (ARD) acute gastroenteritis and febrile convulsions (with and without exanthem). More uncommon, and in part unknown, clinical manifestations associated with HHV6 infection are discussed in Part 2 of this paper. In common with other herpes viruses, HHV6 also tends to show persistence and intermittent or chronic shedding in the normal population, making the unusually early infection of children (seroconversion in the first year of life in up to 80% of all children) understandable. This means that HHV6 infections manifesting in close temporal association with recommended vaccinations may be misinterpreted as complications of the vaccination. Today, the situation can be clarified by employing special virological-serological laboratory tests, which are available throughout the country.

A 13-month-old immunocompetent girl had fever, rash, and multisystem disease, and she eventually died of cardiac failure. Autopsy revealed intracellular viral inclusions of the herpesvirus group, with results of in situ hybridization positive for human herpesvirus-6. This is apparently the first case of fatal disseminated herpesvirus-6 infection.

Human herpesvirus 6 (HHV 6) was isolated from patients with exanthema subitum (ES) with a high frequency, and it is now believed that this virus causes ES as a primary infection in childhood. HHV 6 infection is highly prevalent in early childhood and this virus may infect infants through the saliva mainly from mother to child. HHV 6 has a tropism to CD4+ cells and destroys cells in vitro. Although children recover from ES without any sequelae, neurological symptoms associated with exanthema subitum are often observed, and we could detect HHV 6 in the cerebrospinal fluid of ES patients. This result suggests that HHV 6 may invade the central nervous system and cause neurological symptoms.

Early immune response was studied by assessing interferon (IFN) and natural killer cell activity in 13 patients with exanthem subitum associated with human herpesvirus 6 infection during the acute and convalescent phases. Only IFN-alpha showed a significant increase in the plasma of patients during the acute febrile phase compared with the convalescent period. The inhibitory effect of IFN-alpha and IFN-beta on human herpesvirus 6 replication was demonstrated in vitro with cord blood mononuclear cells. Natural killer cell activity was also significantly augmented in the acute phase, especially in the exanthem period, rather than in the convalescent phase (P less than 0.01). These results suggest that the enhanced IFN-alpha response and natural killer cell activity in the acute early phase of the disease may play pivotal roles in the recovery from exanthem subitum.

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.

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.

Twenty-five patients with clinical exanthema subitum (roseola infantum) were enrolled into a study, where acute-phase and convalescent sera were examined for antibodies to human herpesvirus 6 (HHV-6), several other viruses, and other microbes. In addition, an acute-phase fecal specimen was examined for viruses by electron microscopy. Confirmative or suggestive serologic evidence for recent HHV-6 infection was obtained in 23 (92%) cases. Conversion to HHV-6 was found in 19 (76%), a diagnostic (greater than or equal to 4-fold) titer rise in 2, a twofold titer rise in 1, and a stable relatively high titer in 1 of the patients; only 2 (8%) individuals remained negative. The other microbial assays produced only two slight mycoplasma antibody rises and one rotavirus identification in the fecal specimen. It is concluded that if the clinical diagnosis of exanthema subitum is deemed doubtful, HHV-6 infection is verifiable in about 75% of the cases by serology.

Exanthema subitum was described in 1910 by John Zahorsky/USA; in 1986 and 1988 the human herpesvirus 6 (HHV 6) was discovered as the causative agent of the disease and serologic tests were established for diagnostics (specific IgM and IgG antibodies). Up to this time the diagnosis was based on the typical clinical course: the prodromal febrile stage (3 days) followed by the onset of a (more or less characteristic) rash closely connected with the normalisation of the body temperature. Usually a typical white blood cell count was described for diagnostics on the first day of exanthema: leukocytopenia with eosino- and granulocytopenia associated with consequent lymphocytosis. We analysed the hematologic data for children with a serologically documented HHV6 infection including exanthema (group 1: n = 9), without exanthema (group 2: n = 11) or with a serologically unexplained febrile rash (group 3: n = 13). In children with exanthematous HHV6 infection (exanthema subitum) granulocytopenia and a decreased thrombocyte count (mean values) is the rule. But the total white blood cell count and the mean values for eosinophils did not differ between the groups studied.

Of 50 patients in Thailand suspected clinically of having exanthem, subitum, 31 (62%) were serodiagnosed as HHV-6 infection. Sixteen strains of HHV-6 from 31 patients (52%) whose antibody titers had converted during convalescence were isolated during the acute phase. The disease occurred in infants from 3 months to 1 year of age and most frequently at age 4-6 months. Antibody only to HHV-6 converted in 23 of 50 patients (46%), and seroconversion to HHV-6 and dengue virus was observed in 7 patients (14%), and to HHV-6 and Coxsackie B virus in 1 case (2%). In the 23 patients in whom seroconversion only to HHV-6 was observed, all had fever and rash which appeared after subsidence of the fever. Lymphadenopathy and relative lymphocytosis were recognized, associated with diarrhea, vomiting, running nose, cough and hepatomegaly. Febrile convulsions were seen in some cases. All patients recovered completely within a week.

The degree of viremia with human herpesvirus-6 was evaluated in 176 blood samples from 89 infants with exanthem subitum and viremia, and compared with the severity of clinical features and complications of the disease. Fever persisted for 3 to 4 days in 73% of infants and for more than 5 days in 22%, followed by a rubella- or measles-like rash. The viremia was observed between the first day of fever (day 0) and day 4 of the disease. The number of infected cells per 10 million mononuclear cells was 3.45 +/- 1.00 (log10, mean +/- SD) on days 0 to 2, 3.30 +/- 1.14 on day 3, and 3.09 +/- 2.05 on day 4 of the disease. The number of infected cells on days 3 to 4 in infants with a febrile period longer than 4 days and free virus in plasma was significantly greater than that in infants with a febrile period of less than 3 days and without free virus in plasma. The amount of virus in blood on days 0 to 2 did not relate to the duration of fever, and that on days 0 to 4 did not relate to the presence or absence of diarrhea, bulging fontanelle, or bronchopneumonia. These findings suggest that the magnitude of the virus replication in infants with exanthem subitum is reflected in the severity of the disease.

Roseola infantum is not an uncommon disease in children. The etiology was not known until 1988 when Yamanishi et al in Japan first demonstrated that human herpesvirus-6 (HHV-6) was the causative agent. In the fall of 1989, we began to study the role of HHV-6 in roseola infantum in Taiwan. A total of 7 cases of suspected roseola infantum were studied and all were proven to have primary HHV-6 infections. Six were classic cases of roseola infantum, while one had only fever without the rash. Two cases developed complications; one had leukopenia and thrombocytopenia and the other had aseptic meningitis and mononucleosis. This is the first report to substantiate that HHV-6 is an important cause of roseola infantum in Taiwan, and that the virus could cause meningitis and thrombocytopenia.

We describe the unusual clinical course in a case of exanthema subitum with affection of the liver and central nervous system in a 10-months-old girl. HHV-6 infection was confirmed serologically (positive HHV-6 IgM from 10th to 29th day, increasing IgG-titres). At the beginning of the illness convulsions with preference to the right side were noticed, which were consistent with an encephalitis (on top to a suspected pre/perinatal lesion) and resulting in spastic triplegia. Nuclear magnetic resonance imaging and cranial computertomographic results showed severe, predominantly left-sided cerebral lesions. In addition there was clinical and biochemical evidence of an associated hepatitis. Human herpesvirus-6 has been identified as the cause of exanthema subitum. In addition, the virus is known to cause other clinical entities (lymphadenopathy, febril seizures, hepatitis, postinfectious chronic fatigue a.o.) and has been identified in brain tissues. Our observations show that the course of exanthema subitum can be complicated by affection of the liver and central nervous system. At present it is impossible to estimate the clinical outcome in our patient.

Human herpesvirus-6 (HHV-6) can be regularly isolated from peripheral blood mononuclear cells (PBMC) of children suffering from exanthema subitum, but only rarely from PBMC of adults. Although the high prevalence of HHV-6 infection in early childhood seems to result from cell-free infectious virus shedded in saliva of healthy adults, latent HHV-6 infection is supposed to occur in lymphocytes. Therefore, we performed polymerase chain reaction (PCR) with DNA from PBMC of 44 healthy adults, 31 HIV-seropositive individuals and 33 patients with leukaemia or lymphoproliferative disorders. As positive control served PBMC from 11 children with exanthema subitum and as negative control PBMC from 20 newborns. Whereas HHV-6-specific sequences were detected in PBMC from all children with exanthema subitum and never in PBMC from newborns, they were found in PBMC of 9% of healthy adults and HIV-seropositive individuals and in 16% of the patients with lymphoproliferative disorders. Apparently detection of HHV-6 DNA in PBMC was neither limited by low sensitivity of the HHV-6 PCR assay, which detected less than ten copies of cloned HHV-6 DNA, nor by a low rate of latently infected individuals, but was limited by the number of lymphocytes subjected to PCR. It is supposed that the presence of latent HHV-6 DNA in lymphocytes is common, but that infected lymphocytes are rare (less than or equal to 1 infected cell in 10(5) lymphocytes).(ABSTRACT TRUNCATED AT 250 WORDS)

Eight cases of acute human herpesvirus type 6 (HHV6) infection in infants were diagnosed serologically by the demonstration of IgM anti-HHV6 (8/8) and a significant change in total anti-HHV6 antibody titre (6/8). Four infants were sufficiently ill to require admission to hospital and further investigations: one with encephalitis and three with gross hepatosplenomegaly, two of whom had evidence of simultaneous infection with another herpes-virus. The remaining four infants had an illness compatible with roseola infantum, although this diagnosis had not been made clinically. Sera from two of those infants with rash had been sent for analysis to exclude rubella because the infants' mothers were pregnant. The other two had received antibiotics when febrile, and the subsequent appearance of the roseola rash had raised the possibility of antibiotic allergy. The data suggest that there are clinical syndromes in addition to roseola infantum associated with the presence of IgM anti-HHV6, in which serological screening for evidence of acute HHV6 infection may be useful.

The detection of human herpesvirus 6 (HHV-6) DNA was carried out in throat swabs of adults and children by the polymerase chain reaction, and isolation of virus was also attempted from peripheral mononuclear cells. Although virus was isolated only from peripheral blood mononuclear cells of infants with exanthem subitum, HHV-6 DNA was detected in one of 30 healthy adults (3%), two of nine adults (22%) with common cold, two of 10 infants (20%) with exanthem subitum, four of 39 febrile children (10%) with antibody to HHV-6 (including three of 10 infants aged under 1 year old, and one of 29 children aged over 1 year old). However, HHV-6 DNA was not detected in samples from healthy neonates.

We report a 10-month-old boy with acute meningo-encephalitis associated with exanthem subitum. It has recently been reported that human herpesvirus-6 is the causative agent of exanthem subitum, and to our knowledge our case is the first report of meningo-encephalitis associated with HHV-6 infection.

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 than that of measles. 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 measles with unique immunologic responses.

The polymerase chain reaction was used to detect human herpesvirus 6 (HHV-6) DNA in peripheral blood mononuclear cells from patients with exanthem subitum. Amplified products were detected by agarose gel electrophoresis and dot blot hybridization with a cloned DNA probe. No cross-hybridization with DNAs of five other human herpesviruses was observed in this system, and all HHV-6 strains gave positive reactions when the primer pairs were used. Immunoglobulin M antibody appeared about 5 days after the onset of disease, reaching a maximum after about 2 to 3 weeks and then decreasing to less than 1:10 1 month after the onset of disease in almost all patients. Mononuclear cells from seven patients with exanthem subitum all gave positive reactions in this system, and viral DNA was found in samples even during the convalescent phase of the disease. We conclude that this test, using polymerase chain reaction amplification, which takes only 1 to 2 days, is useful for the diagnosis of HHV-6 infection.

Peripheral blood cultures from children showing symptoms of generic infectious disease have been examined for human herpesvirus-6 (HHV-6). Two HHV-6-related isolates have been obtained: one from a child for whom a clinical diagnosis of exanthema subitum has been made when a typical rash appeared, and one from a child in whom the infectious symptomatology has maintained the characters of nonspecific syndrome. All the syndrome diagnosed as exanthema subitum resulted as being associated with fresh infection by HHV-6-related virus.