Acute Human Herpesvirus 6 Infection Research Articles

Inherited IRAK-4 Deficiency in Acute Human Herpesvirus-6 Encephalitis.

Human herpesvirus-6 (HHV-6) infection can rarely cause life-threatening conditions, such as encephalitis, in otherwise healthy children, with unclear pathogenesis. We studied a child who presented with acute HHV-6 encephalitis at the age of 10 months and who was homozygous for a novel missense mutation in IRAK4, encoding interleukin-1 receptor-associated kinase 4, identified by whole-exome sequencing. We tested the damaging impact of this mutation in silico by molecular dynamics simulations and in vitro by biochemical and functional experiments utilizing cell lines and patient’s cells. We found that the mutation is severely hypomorphic, impairing both the expression and function of IRAK-4. Patient’s leukocytes had barely detectable levels of IRAK-4 and diminished anti-viral immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors. Overall, these findings suggest that acute HHV-6 encephalitis can result from inborn errors of immunity to virus. This study represents the first report of isolated acute HHV-6 infection causing encephalitis in an inherited primary immunodeficiency, notably autosomal recessive (AR) partial IRAK-4 deficiency, and the first report of AR IRAK-4 deficiency presenting with a severe viral disease, notably HHV-6 encephalitis upon an acute infection, thereby expanding the clinical spectrum of IRAK-4 deficiency.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10875-022-01369-4.

Human Herpesvirus 6 Infection and Diagnostics

Human herpesvirus 6 (HHV-6) causes primary infection in early childhood and establishes lifelong latency in its host. Reactivation of HHV-6, especially in immunosuppressed patients, has been associated with a variety of clinical complications. Diagnosis of acute HHV-6 infection has been a major challenge due to high prevalence of the virus and the difficulty in distinguishing latent infections from acute. Chromosomal integration of HHV-6 also occurs further complicating the management and diagnostics of HHV-6 disease. PCR-based methods have become the mainstay of HHV-6 diagnostics, however, interpretation of results in the context of clinical disease is of utmost importance.

Clinical Significance of Cerebrospinal Fluid Herpesvirus 6 Positivity- A Case Series Study

Human herpesvirus 6 (HHV-6) is a common pathogen at childhood, remains in a latent form and can reactivate, causing encephalitis with the impairment of the immune system. The acute primary HHV-6 infection in adult immunocompetent hosts is being questioned. The cerebrospinal fluid (CSF) HHV-6 positivity can be detected in infection, in latency period, in asymptomatic reactivation or in viral chromosomic integration. To establish the clinical significance of CSF HHV-6 positivity, the authors reviewed the CSF HHV-6 positive cases in a tertiary hospital from 13 years. A total of 2111 tests were made with 0.9% of HHV-6 positivity. Only 2 cases were considered “likely” HHV-6 infected, reinforcing that most positive results do not indicate infection. Immune status and quantitative viral load studies on CSF and blood can be of great benefit, but clinical judgement is fundamental to determine the significance of HHV-6 positivity and need for treatment.

Human Herpesvirus 6, 7 and 8 in Solid Organ Transplantation

Human Herpesvirus 6, 7 and 8 in Solid Organ Transplantation

HHV‐6 infection in multiple sclerosis. A clinical and laboratory analysis

To elucidate the role of human herpesvirus-6 (HHV-6) in the development of multiple sclerosis (MS). Nine patients with MS and with acute or chronic HHV-6 infection were evaluated. Intrathecal antibody production to HHV-6 and oligoclonal IgG bands in the cerebrospinal fluid (CSF) was observed in two patients with a clinically definite MS and chronic HHV-6 infection (based on the presence of HHV-6 specific antibodies in the CSF). A temporal association between the symptoms of clinically possible MS and acute primary HHV-6A infection (based on avidity of HHV-6 specific antibodies) was observed in two patients. Human herpesvirus-6 infection may be an associated agent in some MS cases. Viral studies are needed to identify a possible viral etiology and give specific therapy.

Human herpesvirus 6 infection and transient acquired myelodysplasia in children

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. 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. 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. 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.

Bilateral optic neuropathy and unilateral tonic pupil associated with acute human herpesvirus 6 infection: a case report

Human herpesvirus 6 (HHV-6), a widespread virus and causative agent of exanthema subitum in children, has been associated with a number of neurologic disorders including cranial nerve palsies, seizures, encephalitis, meningitis, and multiple sclerosis. A 31-year-old man presented with bilateral optic neuropathy, disc edema, and unilateral tonic pupil, which were found to be associated with acute HHV-6 infection. The patient had been suffering from juvenile diabetes for 5 years. One week after onset of intravenous antiviral therapy with foscarnet, disc edema subsided, and tonic pupil reaction was no longer detectable. HHV-6 infection may play a role as a causative agent in patients with optic neuropathy and tonic pupil.

Clinical Features of Childhood Multiple Sclerosis

Clinical Features of Childhood Multiple Sclerosis

Strong interaction between human herpesvirus 6 and peripheral blood monocytes/macrophages during acute infection.

Human herpesvirus 6 (HHV-6) encodes a viral chemokine and chemokine receptors that may modify the functions of monocytes/macrophages (MO/M phi) during productive HHV-6 infection. The interactions between HHV-6 and MO/M phi during acute infection, however, remain poorly understood. In this study, we investigated the tropism of HHV-6 in peripheral blood mononuclear cells (PBMCs) during acute infection. We detected 637 +/- 273 copies of viral DNA in 10(4) MO/M phi. in contrast, in 10(4) CD4+ T cells, which have been reported to be viral carriers during the acute infection of HHV-6, we found only 115 +/- 42 copies of viral DNA. Consistent with these data, virus was isolated from MO/M phi an order of magnitude more frequently than from CD4+ T cells. Viral mRNA U79/80, which indicates viral replication, was detectable in the MO/M phi. In addition, the mRNAs that encode viral chemokine receptors U12 and U51, which may modify the function of MO/M phi, were expressed in the cells. Therefore, productively infected MO/M phi may be the dominant cell population that is responsible for HHV-6 viremia during acute HHV-6 infection. The strong interaction of HHV-6 with MO/M phi may be partly responsible for the pathogenesis of this virus.

The rapid diagnosis and clinical features of human herpesvirus 6

Since human herpesvirus 6 (HHV6) was first linked with exanthem subitum in 1988 there has been increasing evidence that the morbidity associated with acute HHV6 infection may be more significant and variable. However, the clinical appreciation of HHV6 infection has been hampered by the lack of rapid and clinically useful diagnostic methods. In this prospective study of hospitalized febrile children under 3 years of age we compared three rapid viral diagnostic methods, (polymerase chain reaction assay (PCR), IgM serology and direct antigen detection), with conventional serology on paired serum samples. In addition, we documented the range of clinical features associated with acute HHV6 infection. Of 67 children recruited, 11 (16%) had evidence of acute HHV6 infection: six had detectable, specific, IgM; four were PCR positive; and one was PCR positive with IgM. Direct antigen testing on batched frozen samples detected no infections. Apart from high fever (median peak 38.5 degrees C), common features were non-specific. Two children had febrile convulsions and only one child had a non-specific rash. We conclude that rapid microbiological diagnosis at present requires two tests (IgM and PCR). HHV6 is a common cause of febrile illness in hospitalized infants with no rash and should be considered in their diagnosis.

Case-control study of primary human herpesvirus 6 infection in children with febrile seizures.

Human herpesvirus 6 (HHV-6) has been demonstrated to be the causative agent in roseola infantum. It has been suggested that HHV-6 may have neurotropic properties and be involved in the pathogenesis of febrile seizures in infants. We describe a case-control study to examine the hypothesis that acute HHV-6 infection occurs more commonly in children with febrile seizures than in controls. Patients presenting with a first or second febrile seizure between 6 months and 2 years of age were entered in the study. Control patients did not have a seizure but had similar inclusion and exclusion criteria. Specimens were obtained for HHV-6 viral serology and polymerase chain reaction in the acute stage and approximately 2 weeks later. A diagnosis of HHV-6 infection was based on HHV-6-specific IgM and IgG serology and HHV-6 polymerase chain reaction of peripheral blood mononuclear cells and saliva. Eighty-six patients (45 with febrile seizures; 41 controls) were enrolled. The HHV-6 infection status could be determined in only 68 patients (35 with febrile seizures; 33 controls). Acute HHV-6 infection was identified in 15 of 35 febrile seizure patients and in 15 of 33 controls. Evidence of past HHV-6 infection was demonstrated in 13 febrile seizure patients and in 8 controls. The incidence of primary HHV-6 infection is similar in patients with febrile seizures and age-matched controls. HHV-6 does not seem to be a major factor in the pathogenesis of first and second febrile seizures.

Human herpesvirus-6 infection in children with first febrile seizures

We evaluated febrile convulsions prospectively in 42 children to investigate the association between acute human herpesvirus-6 (HHV-6) infection and first-time febrile convulsions, using both virologic and serologic methods. Eight children had primary HHV-6 infection documented by viral culture and an additional three by acute- and convalescent-phase serologic studies. These findings indicate that acute HHV-6 infection is a frequent cause of febrile convulsions in young children. (J P EDIATR 1995;127:95-7)