Meningo-Encephalitis Associated with HHV-6 Related Exanthem Subitum

ABSTRACT. 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.     

Acute disseminated demyelination due to primary human herpesvirus-6 infection

A previously healthy 19-month-old boy developed acute encephalopathy, thrombocytopenia and hepatic dysfunction. Human herpesvirus-6 (HHV-6) DNA was found in his CSF during the acute stage of the disease by means of the polymerase chain reaction. T2-weighted MRI revealed high signal intensity in the left thalamus and left parieto-occipital deep white matter. The myelin basic protein concentration in the CSF was elevated suggesting acute demyelination. The patient is now 2.5 years old and has no sequelae. Conclusion Since clinical course and neuroimaging after HHV-6 infection are similar to those in acute disseminated encephalomyelitis, clinicians must pay attention to primary HHV-6 infection in patients under 2 years old with white matter lesions. Received: 17 December 1996 / Accepted: 25 February 1997     

Human herpesvirus-6 (HHV-6)-associated hemophagocytic syndrome

Virus-associated hemophagocytic syndrome (VAHS) is characterized by histiocytic proliferation and phagocytosis triggered by virus infections. Viruses in the herpes group, especially the Epstein-Barr virus (EBV), are well known to cause VAHS; however, the relationship between this syndrome and human herpesvirus-6 (HHV-6) infection has rarely been reported. In this study, we describe a 23-month-old girl who exhibited typical manifestations of VAHS associated with HHV-6 infection. To the best of our knowledge, this case is the fifth reported case in the English literature.     

Primary infections of human herpesvirus-7 and herpesvirus-6: a comparative, longitudinal study up to 6 years of age

In order to understand the infection status of human herpesvirus 7 (HHV-7) in Taiwan and clarify the serological cross-reactivity between HHV-7 and HHV-6, a longitudinal study was carried out in 52 infants from whom 9 sera were available from birth to 6 years of age. All sera were tested for antibodies against HHV-6 and HHV-7 by indirect immunofluorescence assay. HHV-7 infection was not seen before 6 months of age and gradually emerged thereafter, reaching a cumulative rate of 28.8%, 67.3%, 73.1 %, 78.8%, 82.7%, and 86.5% by the ages of 1. 2, 3, 4, 5 and 6 years, respectively. Primary HHV-6 infection induced a reactive HHV-7 antibody in 10/28 (35.7%) cases with a titre of no more than 10. Twenty-eight children (53.8%) were infected by HHV-6 earlier than HHV-7. while eight (15.4%) were infected by HHV-7 earlier than HHV-6. In summary, HHV-7 infected children later than HHV-6. A one-way cross-reaction of HHV-7 serology by HHV-6 was revealed and a titre of 20 is appropriate for defining HHV-7 infection.     

Distribution of human herpesvirus 6 and varicella-zoster virus in organs of a fatal case with exanthem subitum and varicella

The distribution of human herpesvirus 6 (HHV-6) and varicella-zoster virus (VZV) was examined in autopsy samples from a fatal case with both virus infections. A 9-month-old boy developed convulsive seizures followed by macular skin rashes, rapidly progressed to brain death, and died 15 days after the onset, when signs of varicella were noted. An isolation of HHV-6 from blood and evaluation of antibody activities to various viral agents including HHV-6 were performed before his death. Postmortem examinations included: (i) isolation of HHV-6 and VZV from tissues or organs; (ii) detection of both virus antigens in tissues or organs by an indirect immunofluorescent assay using monoclonal antibodies to both viruses; (iii) amplification of both viruses and human herpesvirus 7 DNA sequences by a nested polymerase chain reaction assay; and (iv) endonuclease digestion of amplified products of HHV-6 DNA for differentation of variants A and B. Human herpesvirus 6 DNA was detected in peripheral blood mononuclear cells (PBMC) and plasma obtained at the eruptive stage but present only in PBMC 15 days after, indicating the primary infection with HHV-6, although the virus was not isolated from the same blood sample and a significant rise in the antibody titers to HHV-6 was not observed. Both virus antigens and DNA were detected in various tissues or organs obtained at autopsy, but only VZV was isolated from these samples, suggesting disseminated infection with both viruses in an infant. All the amplified products of HHV-6 DNA were variant B. Among the findings for the distribution of virus antigens, it was noteworthy that HHV-6 antigen was demonstrated in the endothelial cells of small vessels in the frontal lobe of the brain. There was no evidence of HHV-7 infection. These data indicate that the primary HHV-6 infection closely followed by the primary VZV infection had the potential hazard of an unexpected and apparently life-threatening event, in which disseminated infections with both viruses were noted in multiple tissues or organs including the brain.     

Quantitation of human herpesvirus 6 DNA in infant with exanthem subitum by microplate PCR-hybridization assay

BACKGROUND: Quantitative analysis of human herpesvirus 6 (HHV-6) genome is important for monitoring active virus infection. The purpose of our study is to evaluate the reliability of a hybridization-based microtiter plate assay (polymerase chain reaction enzyme-linked immunosorbent assay (PCR ELISA)) for quantifying the virus genome. METHODS: Semiquantitative analysis of the virus genome was carried out in 31 (18 male and 13 female) infants with primary HHV-6 infection. If the HHV-6 virus could be isolated from the peripheral blood mononuclear cells (PBMC), the infants were defined as being infected with HHV-6. The PCR ELISA method was used to determine the virus load. A titration of the virus was also carried out in the samples obtained during the acute phase of exanthem subitum. RESULTS: Specificity of the method was demonstrated by a lack of amplification of human herpesvirus 7 and cytomegalovirus DNA. The upper and lower detection limits of the method were 58 and 5800 copies of the virus genome, respectively. The quantity of HHV-6 DNA in the PBMC during the acute phase (879 +/- 975 copies/10(4) PBMC) was significantly higher than during the convalescent phase (54 +/- 76 copies/10(4) PBMC). Furthermore, the virus load in acute phase plasma (53 +/- 75 copies/microL) was also significantly higher than in the convalescent phase samples (2 +/- 9 copies/microL). Virus load in both PBMC and plasma gradually increased after the onset of exanthem subitum until about day 3 to 4 of the illness, but then decreased quickly. However, there was no significant association between virus load and the numbers of infected cells. Conclusion: Virus load in both PBMC and plasma gradually increased after the onset of exanthem subitum until about day 3 and day 4 of the illness, respectively, then it decreased quickly. These results indicate that our PCR ELISA system is reliable for monitoring active HHV-6 infection in vivo.     

Prevalence and clinical significance of human herpesviruses 6 and 7 active infection in pediatric liver transplant patients

Recent studies in adult liver transplant patients have suggested that both human herpesvirus (HHV)-6 and HHV-7 infection are important causes of morbidity following liver transplantation. However, the impact of HHV-6 and -7 infection in pediatric liver transplant patients remains largely unknown. The aims were to determine the prevalence of HHV-6 and -7 infection in pediatric liver transplant patients and to determine whether there is an association between HHV-6 and -7 infection with episodes of graft rejection and cytomegalovirus (CMV) infection. A total of 46 pediatric liver transplant patients transplanted at Mayo Clinic between January 1994 and January 2000 were evaluated. Quantitative polymerase chain reaction (PCR) assays for CMV, HHV-6 and HHV-7 were performed on stored sera obtained prior to transplant, weekly for 8 wk and at 4 months and 1 yr post-transplant. Pretransplant sera were tested for HHV-6 antibodies by indirect immunofluorescence assay. A total of 215 blood samples were tested (mean 6.5 +/- 3.1, range 3-18). CMV infection occurred in 11 of 33 (33.3%) patients, while CMV disease occurred in 4 of 33 (12%) patients. Infection with HHV-6 (variant B) was detected in three of 33 (9.1%) patients. HHV-7 infection was not detected. Case 1 and 2 were infants (10- and 11-month old, respectively). Both were seronegative for HHV-6 pretransplant. In both cases, HHV-6 infection was associated with concurrent episodes of moderate to severe acute graft rejection. Case 3 was a 16-yr-old girl who was seropositive for HHV-6 pretransplant. No clinical events were recorded and a liver biopsy performed per protocol showed no evidence of rejection. None of the three patients had concomitant CMV infection or disease. In this study, HHV-6 infection occurred in 9% of pediatric liver transplant patients while HHV-7 was not detected. A potential association between primary HHV-6 infection and allograft rejection warrants further investigation.     

Outcomes of infants whose mothers are positive for human herpesvirus-6 DNA within the genital tract in early gestation

It has been reported that HHV-6 (human herpesvirus-6) DNA has been identified within the female genital tract. However, the clinical significance of this finding has been unclear. The clinical outcome of the presence of HHV-6 DNA in the genital tract of pregnant women on their infants was evaluated in the present study. One hundred and ten pregnant women were enrolled. Vaginal swabs were collected between 4 and 8 weeks of gestation and the presence or absence of HHV-6 DNA was evaluated by nested polymerase chain reaction (nPCR). The swabs were cultured to isolate the virus. The women were divided into two groups: HHV-6 DNA-positive, and negative. The outcome variables of the infants of these two groups were statistically estimated at birth and at 1 month of age. Saliva and blood cells were collected from the infants at birth and at 1 month of age and were also evaluated by nPCR. HHV-6 DNA was detected in the vaginal swabs of 28 pregnant women (25.5%), but was not detected in any other samples, including saliva and blood cells from their infants. Virus could not be isolated from any vaginal samples. Any outcome variables were not significantly different between the two groups. The presence of HHV-6 DNA within the genital tract of pregnant women did not affect the health of their infants. It is suggested that HHV-6 transmission to infants through the genital tract of their mothers during pregnancy does not occur, or only very rarely.     

Human herpesvirus-6 and -7 in pediatric stem cell transplantation

BACKGROUND: Human herpesvirus-6 (HHV-6) and -7 (HHV-7) may reactivate with immunosuppression and cause symptoms varying from subclinical to severe organ manifestations. The presence of HHV-6 and -7 and their possible association with clinical problems among pediatric recipients of stem cell grafts was studied in a single institution setting between November 1999 and December 2001. PROCEDURE: A total of 60 patients, mean age 8.5 years, were transplanted: 2/3 received allogeneic grafts and 1/3 autologous stem cell rescue. The presence of HHV-6 and -7 was studied in blood by polymerase chain reaction (PCR) (HHV-6) and antigenemia (HHV-6 and -7). RESULTS: Both HHV-6 and -7 were frequently present in the blood of stem cell graft recipients. No significant difference in the incidence of HHV-6 or -7 reactivations between the allogeneic and autologous patients nor recipients of sibling or unrelated donor (URD) grafts was observed. HHV-6 antigenemia was associated with fever, rash, and delayed engraftment. Among symptomatic patients two cases of encephalitis were encountered with both having HHV-6 detectable in their cerebrospinal fluid (CSF) by PCR. CONCLUSIONS: HHV-6 and -7 seem to be common in blood both pre- and post-transplant among pediatric recipients of stem cell grafts. Prolonged reactivations appear to correlate with clinical symptoms such as fever, rash, and bone marrow suppression in the post-stem cell transplant setting (SCT), but severe complications are rare. Transient reactivations appear to be of very limited clinical significance.     

Cytomegalovirus and Human Herpesvirus-6 in Sudden Infant Death Syndrome: An in situ Hybridization Study

Thirty lung, spleen, and thymus sections and four lymph node sections from 40 sudden infant death syndrome (SIDS) cases were probed with biotinylated DNA probes specific for human herpesvirus-6 (HHV-6) and cytomegalovirus (CMV). Control material gave a strong, distinct signal with little or no background staining and no cross-reactivity. No staining was found with the SIDS material. We find no evidence to implicate an overwhelming infection by either virus in SIDS.     

Human Herpesvirus 6 (HHV-6) Infection and Exanthem Subitum in Thailand

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.     

Human Herpesvirus 6 (HHV-6) Infection in the Central Nervous System

Human herpesvirus 6 (HHV-6) was isolated from patients with exanthem 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 exanthem 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.     

144例手足口病患儿细胞和体液免疫变化及意义

目的探讨轻症和重、危重症手足口病(HFMD)患儿细胞免疫及体液免疫改变与临床表现及预后的关系。方法将144例HFMD患儿分为轻症和重、危重症2组,于入院2 h内行血清体液免疫、细胞免疫检测,同期取10例择期手术儿童做正常对照,比较各组患儿体液免疫(血清免疫球蛋白IgA、IgG、IgM)及细胞免疫(T细胞亚群)水平的差异。结果轻症组和重、危重症组HFMD患儿体液免疫异常,两组HFMD患儿体液免疫与正常对照组比较,差异有统计学意义(P<0.05)。轻症组和重、危重症组HFMD患儿细胞免疫均存在异常,差异均有统计学意义(P<0.05)。结论 HFMD患儿有在细胞免疫和体液免疫变化,与临床轻症和重、危重症经过相关。     

Human herpesvirus-6 and -7 infections in transplantation

Human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7) are ubiquitous in the human population and cause exanthem subitum, a benign disease seen in infancy. The viruses remain latent in the body after primary infection, and reactivate in immunocompromised patients. HHV-6 infection occurs in nearly 50% of all bone marrow and in 20-30% of solid-organ transplant recipients, 2-3 weeks following the procedure. It has been suggested that the viral infection and activation result in clinical symptoms, including fever, skin rash, pneumonia, bone marrow suppression, encephalitis, and rejection. In order to understand the viral infection in greater detail, several studies investigating the route of viral transmission and diagnostic procedures have been carried out. In contrast to studies of HHV-6 infection in organ-transplant recipients, the number of studies examining HHV-7 infection in these patients is limited. According to several recent studies, HHV-7 may act as a cofactor for cytomegalovirus disease in organ-transplant recipients.     

Cord blood G-6-PD activity by quantitative enzyme assay and fluorescent spot test in Chinese neonates

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is a common X-linked recessive disorder among the Chinese population. Neonatal screening for this condition is important and with necessary precaution, enzyme deficient infants are less likely to develop severe haemolysis and subsequent kernicterus. Screening of G-6-PD deficiency by fluorescent spot test on cord blood samples of 1228 Chinese neonates revealed an incidence of 4.4% in males and 0.35% in females. Simultaneous direct enzyme assay confirmed the sensitivity and specificity of the spot test in the identification of male hemizygotes and female homozygotes. However, the spot test was unsatisfactory in detecting heterozygotes. Even quantitative enzyme assay could detect only 70% of the partially deficient subjects.     

Human herpesvirus 6 infection and transient acquired myelodysplasia in children

BACKGROUND: To demonstrate that primary human herpesvirus 6 (HHV-6) infection in childhood can cause hematopoietic dysplasia that mimics a myelodysplastic syndrome (MDS) in severe cases. PROCEDURE: Seven immunocompetent children, who presented at admission with concomitant cytopenias in blood and morphologic features of dysplasia in bone marrow, were evaluated. Diagnosis of acute HHV-6 infection was secondary made by detection of HHV-6 DNA in plasma, bone marrow, or cerebrospinal fluid and measurement of plasma antibody titers. Peripheral blood and bone marrow aspirate smears were examined at diagnosis and during follow-up. Morphologic recognition of myelodysplasia was made according to the recommendations of the Third MIC Cooperative Group. RESULTS: Anemia was the most frequent cytopenia (five of seven cases). Bi- or tri-lineage dysplasia was observed in the marrow samples. Granulocytic and erythroid cells were always affected with dysgranulopoiesis and dyserythropoiesis scores equal to or higher than 3. Myelodysplasia was not due to a clonal disorder and disappeared gradually within 1 or 2 months. CONCLUSIONS: Our results indicate that severe HHV-6 infection may induce reversible myelodysplastic changes. These findings contribute to elucidate the pathogenicity of HHV-6 and furthermore suggest that HHV-6 infection must also be considered as a cause of dysplasia in the differential diagnosis of MDS.     

Human herpes virus 6 infection in pediatric organ transplant patients

Transplant patients need lifelong immunosuppressive medication, but this reduces their defense mechanisms, making them prone to viral infections and reactivations. We aimed to clarify the prevalence and clinical manifestations of the human herpes virus 6 (HHV‐6) infection in children after pediatric solid organ transplants. Clinical findings and viral loads were compared between primary HHV‐6 infections and reactivations. The study comprised 47 kidney, 25 liver, and 12 heart transplant patients who underwent surgery from 2009 to 2014. HHV‐6 antibodies were analyzed before surgery, and HHV‐6 DNAemia tests were regularly carried out after the transplant using a real‐time quantitative polymerase chain reaction method. We found the primary HHV‐6 infection in 19 of 22 (86%) seronegative patients, and it was more common in patients under 3 years of age (79%) than over 3 (38%, P=.0002). Post‐transplant HHV‐6 DNAemia affected 48 of 84 (57%) patients and was significantly higher in primary infections than reactivations (P=.001), and 17 of 48 (35%) patients had symptoms when it was detected at a median of 2 weeks post‐transplant. The HHV‐6 infection was common after solid organ transplants, especially under 3 years of age, and it typically started 2 weeks after surgery. Testing for HHV‐6 DNAemia is recommended shortly after transplantation, especially in patients with fever, diarrhea, rash, seizures, or abnormal liver enzyme tests.     

Three mutations analysis of glucose-6-phosphate dehydrogenase deficiency in neonates in South-west China

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human enzymatic defects, is characterized by extreme molecular and biochemical heterogeneity. The underlying DNA changes associated with G6PD deficiency in Asian subjects have not been extensively investigated. METHODS: Three gene mutations (G1388A, G1376T, A95G, corresponding amino acid change: Arg463His, Arg459Leu, His32Arg, respectively) were examined in 240 G6PD-deficient subjects originating from South-west China using specific polymerase chain reaction. RESULTS: Of the 240 patients with G6PD deficiency, 190 were found to have the G1388A mutation, 48 had G1376T and two had A95G. There were no significant differences between the clinical manifestations caused by the former two gene mutations, which both cause acute hemolytic anemia and jaundice. Therefore the most common gene mutations of G6PD deficiency in neonates in South-west China are G1388A and G1376T mutations. CONCLUSION: It is suggested that G6PD deficiency screening be done in higher risk neonates with jaundice in qualified hospitals as soon as possible.