HHV-6 DNA Research Articles

No Evidence for Long-Term Persistence of HHV-6 Viremia after Cord Blood Transplantation

HHV-6 reactivation is common after cord blood transplantation (CBT). However, the ability of the new immune system to clear HHV-6 viremias is unknown. A previous study of 23 CBT recipients suggested that ∼50% of patients had detectable HHV-6 by whole blood PCR over a year after transplant (Illiaquer et al. J Infect Dis 2014; 567-570). We studied HHV-6 persistence in a larger cohort using serum. We reviewed CBT recipients at the University of Minnesota (2011-2017) who reactivated HHV-6 (whole blood quantitative PCR > 500 copies/mL on at least 1 occasion) by 1 year post-transplant. A subset (n = 59) had an available research serum sample at 1 year (+/- 4 weeks) on an IRB-approved biorepository protocol; we tested these samples by quantitative PCR for HHV-6A and B (Rotor-Gene, Qiagen) in a CLIA-certified laboratory. Median (range) age was 44 (1-72) years; 40 (68%) were male. The most common underlying diseases were acute leukemia (n = 29), lymphomas (n = 10), and non-malignant disorders (n = 9). 33 patients were CMV seropositive. ATG or alemtuzumab were used in 16 patients. Conditioning was reduced-intensity in 31 patients. GVHD prophylaxis was cyclosporine/MMF in 41 and sirolimus/MMF in 18. Grade II-IV acute GVHD occurred in 25 patients and chronic GVHD by 1 year in 12. Twelve (20%) patients cleared viremia (based on whole blood PCR) before the research sample was collected. This clearance occurred at median (range) of 64 (13-244) days after HCT. One (2%) patient cleared HHV-6 at 538 days after HCT. 46 (78%) patients continued to have detectable whole blood PCR until a median (range) of 127 (15-1441) days after HCT with no subsequent negative sample. Among research serum samples collected at 1 year, only 1 had HHV-6A (14,556 copies/mL) and 1 had HHV-6B (below the lower limit of quantification). The patient with detectable HHV-6A had chromosomal integration. The patient with detectable HHV-6B had previous whole blood levels ranging 9,900-164,800 copies/mL. Late persisting HHV-6 viremia was rare in our 59 CBT recipients. Using serum in our study permitted exclusive detection of cell-free HHV-6 DNA, which is a more specific test for HHV-6 reactivation. We suggest no defect in cord blood allograft's ability to clear HHV-6 viremia.

Human herpesvirus-6B encephalitis following allogeneic hematopoietic stem cell transplantation: how should it be managed?

Human herpesvirus (HHV)-6B encephalitis has been increasingly recognized as an important central nervous system (CNS) complication after allogeneic hematopoietic stem cell transplantation. In this review, the best way to diagnose and treat this devastating complication is described. Diagnostic pitfalls: HHV-6B encephalitis should be diagnosed based on the presence of CNS symptoms, positive results for HHV-6 DNA in the cerebrospinal fluid (CSF), and exclusion of other causes of CNS symptoms. There are potential pitfalls when diagnosing HHV-6B encephalitis. Moreover, false-positive detection of HHV-6 DNA in the CSF can occur. Pleocytosis is observed in few patients, and CSF protein levels are often normal. Limbic encephalitis findings are not commonly detected through a brain MRI at the time of development. Prevention: Neither routine monitoring nor routine prophylactic antiviral therapy is recommended to prevent the development of HHV-6B encephalitis. Treatment: Empiric therapy should be started immediately after HHV-6B encephalitis is suspected. The Guideline Committee of the JSHCT recommends full-dose foscarnet (180 mg/kg/day) for the treatment of HHV-6B encephalitis. Therapeutic effect of anti-HHV6 therapy is assessed based on CNS symptoms and HHV-6 DNA in the CSF, which should be evaluated 1-2 weeks after initiating treatment. Even in patients exhibiting good therapeutic effects, antiviral treatment should be continued for at least 3 weeks.

ИНФЕКЦИЯ, ВЫЗВАННАЯ ВИРУСОМ ГЕРПЕСА ЧЕЛОВЕКА 6 ТИПА, У ДЕТЕЙ ПОСЛЕ АЛЛОГЕННОЙ ТРАНСПЛАНТАЦИИ ГЕМОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК В РЕСПУБЛИКЕ БЕЛАРУСЬ

Objective: To evaluate the frequency of reactivation of HHV-6 infection in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT); determine viral load in serum/plasma and associated clinical manifestations; to determine the criteria for initiating anti-viral prophylaxis and etiotropic therapy in patients with this infection in the Republic of Belarus. Methods: Monitoring of polymerase chain reaction (PCR) of blood serum in 42 patients after allo-HSCT. Results: In 31% of patients, HHV-6 DNA was detected in serum/plasma on 14-28 days after allo-HSCT. The concentration of HHV-6 DNA in blood serum was up to 2.3-6.5×103 copies/ml, in 3 patients (18.8%) with the concentration of DNA≥2.3×103 copies/ml, developed clinical manifestations in the form of hepatitis. Regular monitoring of HHV-6 infection revealed reactivation of the infection and, with a viral load of≥100 copies/ml, initiate timely preventive treatment with ganciclovir. Conclusions: HHV-6 DNA is detected in one-third of patients after allo-HSCT and in the form of hepatitis. Timely prevention and therapy with ganciclovir reduce the risk of severe complications and fatal outcomes. Keywords: Children, HHV-6, hematology, stem cells transplantation, hepatitis.

Pretransplant Risk Factors for Calcineurin Inhibitor-Induced Encephalopathy and Limbic Encephalitis Following Allogeneic Hematopoietic Cell Transplantation

Pretransplant Risk Factors for Calcineurin Inhibitor-Induced Encephalopathy and Limbic Encephalitis Following Allogeneic Hematopoietic Cell Transplantation

Combination of a Cyclophosphamide-Total Body Irradiation Conditioning Regimen and Tacrolimus Plus Mycophenolate Mofetil for Gvhd Prophylaxis Is Associated with Higher HHV-6 Encephalitis Incidence after Cord Blood Transplantation

Background Human herpesvirus-6 (HHV-6) encephalitis occurs frequently through cord blood transplantation (CBT), and leads to a high risk of mortality and morbidity. Although CBT is a known risk factor for HHV-6 encephalitis, a thorough analysis of risk factors for HHV-6 encephalitis in patients receiving CBT has not been performed, and several risk factors remain unidentified. In our center, generally, either tacrolimus (Tac) plus methotrexate (MTX) (Tac/MTX) or mycophenolate mofetil (MMF) (Tac/MMF) was selected for graft-versus-host disease (GVHD) prophylaxis after CBT, at the physician's discretion. However, in recent years, Tac/MMF became the standard choice. We observed that the incidence of HHV-6 encephalitis tended to be markedly higher among patients receiving treatment with a cyclophosphamide (Cy) and total body irradiation (TBI) (Cy/TBI)-based regimen and Tac/MMF after CBT. Therefore, we aimed to ascertain whether certain conditioning regimens and GVHD prophylaxis regimens are associated with the occurrence of HHV-6 encephalitis after CBT. Methods In this retrospective study, we examined 103 patients undergoing CBT for hematological diseases at our center between 2011 and 2019. To analyze the effect of GVHD prophylaxis on the occurrence of HHV-6 encephalitis, we divided patients into two groups based on the GVHD prophylaxis regimen used: the Tac/MTX group and the Tac/MMF group. We excluded one patient who received Tac alone and one who received cyclosporine plus MTX. Finally, 101 patients were enrolled. Routine peripheral blood examinations for HHV-6 were performed once or twice a week. HHV-6 encephalitis was defined as the presence of a central nervous system dysfunction, along with a positive polymerase chain reaction result for HHV-6 DNA in the cerebrospinal fluid. HHV-6 viremia was defined as the presence of HHV-6 in the peripheral blood. Results The median age of patients was 47 years, and the median follow-up duration for surviving patients was 432 days. Conditioning regimens included myeloablative conditioning (MAC, n=64) and reduced-intensity conditioning (RIC, n=37). MAC included Cy/TBI-based regimens in 42 patients and fludarabine (Flu) plus busulfan (Bu) (Flu/Bu)-based regimens in 23, and RIC included Flu plus melphalan-based regimens in 34 patients and other regimens in 2. Sixty-four patients received Tac/MMF as GVHD prophylaxis, whereas 37 received Tac/MTX. Six patients received HLA-matched (6/6) cord blood (CB), 27 received HLA one-antigen mismatched CB, and 68 received HLA two-antigen mismatched CB. The median total nucleated cell number and CD34-positive cell number at cryopreservation were 2.2 × 107/kg and 0.7 × 105/kg, respectively. Thirteen patients (12.8%) experienced primary graft failure. Overall, the cumulative incidence of HHV-6 viremia on day 40 was 68%, and the median time from CBT to HHV-6 viremia was 23 days. The cumulative incidence of HHV-6 viremia was significantly higher in the Tac/MMF group than in the Tac/MTX group (Tac/MMF group, 75%; Tac/MTX group, 56%; p=0.03). Ten patients developed HHV-6 encephalitis. Overall, the cumulative incidence of HHV-6 encephalitis on day 60 was 10.1%. The cumulative incidence of HHV-6 encephalitis tended to be higher in the Tac/MMF group than in the Tac/MTX group (14.1% vs. 2.7%, respectively; p=0.08). Therefore, the administration of Tac/MMF as GVHD prophylaxis after CBT was identified as a probable risk factor for HHV-6 encephalitis, and we sought to identify more such risk factors, specifically among patients receiving Tac/MMF. In the analysis of Tac/MMF group, the cumulative incidence of HHV-6 encephalitis was significantly higher among patients receiving Cy/TBI-based regimens than among those receiving other regimens (35.7% vs. 8.1%, respectively; p<0.01) (Fig. 1a). In addition, among the entire group of patients receiving Cy/TBI-based regimens, the cumulative incidence of HHV-6 encephalitis was significantly higher in the Tac/MMF than in the Tac/MTX group (35.7% vs. 0%, respectively; p<0.01) (Fig. 1b). Conclusion Our analysis showed that patients receiving Tac/MMF as GVHD prophylaxis after CBT with a Cy/TBI-based regimen have a significantly higher risk of developing HHV-6 encephalitis. Further studies using a large cohort are required to elucidate the association between the occurrence of HHV-6 encephalitis and the use of Tac/MMF in patients undergoing CBT with a Cy/TBI-based regimen. Disclosures No relevant conflicts of interest to declare.

COMPARATIVE ANALYSIS OF EFFECTIVENESS OF ANTIVIRAL THERAPY IN CHRONIC HUMAN HERPESVIRUS 6 TYPE INFECTION

Introduction. In recent years human-6 herpes virus (HHV-6) has become the most commonly detected virus in peripheral blood, saliva and cerebrospinal fluid, both in asymptomatic infections and in diseases potentially associated with HHV-6. Today, no antiviral drug has been officially approved for the treatment of HHV-6. Materials and methods. 57 patients with chronic HHV-6 infection were examined (mean age 33.34 ± 1.86 years). Patients were divided into three groups for different treatment regimens: 1 group (12 patients) received therapy with Famvir; Group 2 (16 patients) received Valcite; Group 3 (29 patients) - Ingaron. All patients were determined by the number of copies of HHV-6 DNA by PCR in saliva samples before and after the therapy. Results. None of the patient groups received negative PCR results after treatment. In groups of patients after valcyte therapy and therapy with Ingaron there is a significant decrease in the number of copies of HHV-6 DNA. The severity of complaints after therapy was also analyzed. Significant therapeutic effect a month after therapy showed Ingaron, to a slightly lesser extent - Valcite. The worst result was obtained in the group of patients receiving famvir.

COMPARATIVE ANALYSIS OF EFFECTIVENESS OF ANTIVIRAL THERAPY IN CHRONIC HUMAN HERPESVIRUS 6 TYPE INFECTION

Introduction. In recent years human-6 herpes virus (HHV-6) has become the most commonly detected virus in peripheral blood, saliva and cerebrospinal fluid, both in asymptomatic infections and in diseases potentially associated with HHV-6. Today, no antiviral drug has been officially approved for the treatment of HHV-6. Materials and methods. 57 patients with chronic HHV-6 infection were examined (mean age 33.34 ± 1.86 years). Patients were divided into three groups for different treatment regimens: 1 group (12 patients) received therapy with Famvir; Group 2 (16 patients) received Valcite; Group 3 (29 patients) - Ingaron. All patients were determined by the number of copies of HHV-6 DNA by PCR in saliva samples before and after the therapy. Results. None of the patient groups received negative PCR results after treatment. In groups of patients after valcyte therapy and therapy with Ingaron there is a significant decrease in the number of copies of HHV-6 DNA. The severity of complaints after therapy was also analyzed. Significant therapeutic effect a month after therapy showed Ingaron, to a slightly lesser extent - Valcite. The worst result was obtained in the group of patients receiving famvir.

Human herpesvirus 6 infection after autologous stem cell transplantation: A multicenter prospective study in adult patients

to prospectively evaluate the incidence and the clinical relevance on hematopoietic reconstitution of HHV-6 infection in autologous hematopoietic stem cell transplantation (ASCT) recipients. HHV-6 DNA load was measured in whole blood specimens once during the 7 days before stem cell re-infusion and once a week after transplantation until hematopoietic recovery. Active HHV-6 infection was defined by 2 consecutive positive DNA loads. from July 2012 to February 2015, 196 adult patients undergoing ASCT were enrolled. Twenty-two (11.2%) patients developed active HHV-6 infection with a cumulative incidence of 19% at 40 days after transplantation. The onset of active HHV-6 infection occurred with a median of 13 days after stem cell re-infusion. HHV-6 infection was associated with an increased frequency of non-infectious complications (OR=5.05; 95%CI 1.78-14.32; P<0.001). Moreover, the severity of these non-infectious complications was higher in recipients exhibiting HHV-6 infection (OR=4.62; 95%CI 1.32-16.2; p<0.01). Delayed neutrophils 10 (IQR: 8-14) vs 8 (IQR: 6-11) days and platelets recoveries 15 (IQR: 11.8-18.5) vs 8 (IQR: 4-14) days were observed in patients with active HHV-6 infection compared to non-infected ones. in this study, 11.2% ASCT recipients presented active HHV-6 infection associated with significantly delayed hematologic reconstitution.

Human herpesvirus 6, 7, and 8 in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of HHV-6A, HHV-6B, HHV-7, and HHV-8 in the pre- and post-transplant period. The majority of HHV-6 (A and B) and HHV-7 infections in transplant recipients are asymptomatic; symptomatic disease is reported infrequently across organs. Routine screening for HHV-6 and 7 DNAemia is not recommended in asymptomatic patients, nor is prophylaxis or preemptive therapy. Detection of viral nucleic acid by quantitative PCR in blood or CSF is the preferred method for diagnosis of HHV-6 and HHV-7 infection. The possibility of chromosomally integrated HHV-6 DNA should be considered in individuals with persistently high viral loads. Antiviral therapy should be initiated for HHV-6 encephalitis and should be considered for other manifestations of disease. HHV-8 causes Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease and is also associated with hemophagocytic syndrome and bone marrow failure. HHV-8 screening and monitoring may be indicated to prevent disease. Treatment of HHV-8 related disease centers on reduction of immunosuppression and conversion to sirolimus, while chemotherapy may be needed for unresponsive disease. The role of antiviral therapy for HHV-8 infection has not yet been defined.

Human Herpes-8 virus copy to cell ratio: A diagnostic tool in primary effusion lymphoma

Primary effusion lymphoma (PEL) is a serious sequel to Human Herpes Virus 8 (HHV8) infection in the immunosuppressed host. Usually requiring a cytological diagnosis, body cavity effusions are often referred for investigation for possible PEL. Although absence of HHV8 effectively refutes this, the presence of HHV8 DNA, though indicative is not diagnostic. Referred effusion and plasma samples from 10 patients with HHV8-related pleural and pericardial effusions were submitted for quantitative investigations. HHV8 DNA and human DNA from unseparated effusion extracts have been quantified allowing estimation of virus-to-cell ratios in effusion fluid. These ratios varied widely between 0.003 and 700. Five fluids had in excess of 106 HHV-8 DNA genome equivalents per ML (GEq/ML), ranging between 18 and 300 million GEq/ML. Four of these five effusions were from patients with cytologically proven PEL and had virus to cell (V:C) ratios between 100 and 700 to 1. The remaining high load effusion exhibited a ratio of 1.6 to 1 and came from a patient with extensive thoracic Kaposi’s sarcoma. Five effusion fluids with low viral loads exhibited virus to cell ratios between 0.003 and 0.5. High effusion HHV8 load, though supportive of a diagnosis of PEL is less accurate than using virus to cell ratios.

Attenuation of human herpesvirus 6B reactivation by aging.

There has been little research on human herpesvirus 6B (HHV-6B) in healthy adults and prevalences in different age groups have been unclear. Therefore, the major objective of this study was to evaluate seroprevalence to HHV-6 antibodies in ordinary working people and examine the effect of aging on seroprevalence. Also, as HHV-6B is reactivated in saliva, another objective was to investigate an association between age and HHV-6B reactivation based on measured salivary HHV-6 DNA levels. Our subjects were 77 ordinary office workers who underwent a health checkup. In this population, we measured anti-HHV-6 antibody titers using enzyme-linked immunosorbent assay and salivary HHV-6 DNA levels. In addition to examining an association with age, we examined associations with body mass index, smoking habit, and alcohol consumption as confounding factors. There was a significant decrease in the seropositivity of HHV-6 antibodies in subjects of 50 years and older, and age was significantly negatively correlated with anti-HHV-6 antibody titers. Age and salivary HHV-6 DNA levels were also significantly negatively correlated but there were no significant correlations with other factors. Our results suggest that HHV-6B reactivation is attenuated by aging. Thus, HHV-6 antibodies steadily decrease in the body with aging.

Age-Related Patterns of DNA Detection and Specific IgG Subclasses in Healthy HHV-6- and HHV-7-Infected Individuals

Human herpesvirus 6A (HHV-6A), Human herpesvirus 6B (HHV-6B), and Human herpesvirus 7 (HHV-7) can persist by establishing a lifelong infection which could have implications on the immunocompetent host. The aim of this work is to contribute with some knowledge about the HHV-6 A/B and HHV-7 infection in healthy individuals. We have carried out a longitudinal study in seropositive healthy individuals for the detection of viral DNA in saliva and plasma samples, and for determining a specific IgG isotype immune response, which enabled the performance of these viruses to be observed over time. Furthermore, an elderly population was transversely studied to provide data of the activity of these viruses in the older population. In the longitudinal study, HHV-6 DNA was occasionally detected and an isotype immune response with a specific IgG1 profile, while in the older group HHV-6 DNA was frequently detected and an isotype immune response with specific IgG1, IgG3, and IgG4. HHV-7 DNA was frequently detected in both groups and isotype patterns of specific IgG1, IgG3, and IgG4. The results of this study highlight that the long-lasting relationship in healthy HHV-6 A/B-infected individuals have the imprint of age groups.

Prevalence of human herpesvirus 8 infection in patients undergoing hemodialysis using nested-PCR

Objective: To study the prevalence of HHV-8 infection in patients undergoing hemodialysis. Methods: In this study, blood samples of 89 patients undergoing hemodialysis were collected. DNA was extracted from peripheral blood mononuclear cells and HHV-8 DNA was evaluated by nested-PCR. Results: Of total 89 patients, 51 (57.3%) were males and 38 (42.7%) were females. The patients’ age ranged from 24 to 90 years and the mean age was (57.5±1.4) years. HHV-8 DNA was found in 9 of 89 (10.1%) peripheral blood mononuclear cell samples, 8/51 (15.7%) in males and 1/38 (2.6%) in females (P=0.07). All patients who were positive for HHV8-DNA were more than 50 years old. Conclusions: This study shows high prevalence of HHV-8. Since hemodialysis patients are candidates for kidney transplantation and due to the possibility of HHV8-reactivation and its serious complications in immunocompromised patients, routine screening for detection of the virus should be implemented for all hemodialysis patients.

THE DETECTION OF IGG TO HUMAN HERPESVIRUS TYPE 7 IN CHILDREN

Background. There are no data on HHV-7 seroprevalence in Russia. Previously we detected HHV-7 DNA in plasma of 8-10% children with exanthem subitum and fever without rash. Aim. To perform the comparative study of the seroprevalence of HHV-7 and HHV-6 in children in Russia. Materials and methods. The pilot study included 116 children, aged from 10 days to 10 years. Serum samples were tested for IgG to HHV-7 and HHV-6 by indirect immunofluorescent assays and ELISA correspondingly. Results. The prevalence rate antibodies to HHV-7 was three times lower than for antibodies to HHV-6. There were only 18% of patients seropositive to HHV-7, whereas 50% of cases appeared to be seropositive to HHV-6. In infants younger 6 months the frequency of HHV-7 seropositivity amounted to 14.8%, which possibly was due to maternal antibodies. In babies aged from 7 months to 4 years, the HHV-7 seroprevalence was about 7-13%. In children older than 4 years the rate of seropositivity raised to 31%. Conclusion. We can conclude that in life the contact with HHV-7 occurs later than to HHV-6, predominantly after the age of four years. In children under 10 years, the seroprevalence to HHV-7 is lower than to HHV-6. The sample size of our study is too small to extrapolate on Russian population and other seroprevalence studies are needed.

Prevalence of human herpesviruses infections in nonmalignant tonsils: The SPLIT study.

To assess the prevalence of all known human herpesviruses (HHV) in tonsils of an age-stratified large sample of immunocompetent children and adults. Patients undergoing tonsillectomy for benign indications were recruited in 19 French hospitals. After resection, the entire outer surfaces of right and left half tonsils were extensively brushed. A highly sensitive species-specific multiplex assay was used to detect herpes simplex virus 1 (HSV1), HSV2, Epstein-Barr virus (EBV; types 1 and 2), and human cytomegalovirus (CMV) DNA in 688, as well as varicella zoster virus (VZV), HHV6A, HHV6B, HHV7, and Kaposi's sarcoma-associated herpesvirus (KSHV) DNA in a subset of 440 tonsil brushings. Overall 85% of tonsil brushing samples were infected with at least one HHV species. HHV7 and EBV were the most prevalent (≈70%), followed by HHV6B (≈50%), HSV1, CMV, VZV (≈2%), and KSHV and HSV2 (<1%), while HHV6A was not detected. EBV prevalence was significantly higher in adults than in children, whereas it was opposite for HHV6B and VZV. No difference in HHV prevalence was observed by sex. In multivariate analysis, EBV detection was associated with age greater than or equal to 15 years (prevalence ratio [PR] = 1.8; 95% confidence interval [CI]: 1.5-2.3) and marginally with tobacco smoking (PR = 1.2; 95% CI: 1.1-1.3). Differing patterns of HHV infection in tonsils in a large age-stratified population were described. This study is by far the largest available and shows that EBV, HHV6B, and HHV7 are commonly detected in the tonsils in both men and women, in contrast to other HHVs.

Journal Digest

Journal Digest

Chromosomally integrated human herpesvirus 6 in the Japanese population.

The objectives of the work are to elucidate the incidence and virological findings of chromosomally integrated human herpesvirus 6 (ciHHV-6) in Japanese population and to analyze an association between ciHHV-6 and the clinical manifestation of exanthema subitum (ES). Real-time polymerase chain reaction was performed to determine HHV-6 DNA loads in 2347 cord blood samples from healthy neonates (cohort A), febrile children less than 5 years old (cohort B), and hematopoietic cell transplant recipients (cohort C). CiHHV-6 was confirmed by detection of high copy numbers of viral DNA in somatic cells. The integration site was determined by fluorescent in situ hybridization analysis. In the ciHHV-6 subjects of cohorts A and B, HHV-6 antibody titers were measured, the history of ES was obtained, and the incidence of ES was compared with non-ciHHV-6 children without primary HHV-6B infection in the cohort B. CiHHV-6 was detected in 14 (0.60%) of the 2347 samples: A (6/1006, 0.60%), B (6/790, 0.76%), and C (2/551, 0.36%). The integration sites were on chromosome 22q in seven cases, Yp in two cases, and 17q and Xp in one case. No past history of ES was observed in 11 of the 12 subjects. Nine children with ciHHV-6 underwent serological analysis and were found to be positive for HHV-6 IgG antibodies. Incidence of ES was statistically higher in the control subjects than the ciHHV-6 subjects (P = 0.0039). In Japan, the frequency of ciHHV-6 was 0.60%. A high incidence of ciHHV-6A, specifically in chromosome 22, is a characteristic finding among the Japanese. CiHHV-6 may interfere with the clinical symptoms of primary HHV-6B infection.

Long-term prognosis of human herpesvirus 6 reactivation following allogeneic hematopoietic stem cell transplantation.

Patients undergoing hematopoietic stem cell transplantation (HSCT) frequently have HHV-6 reactivation typically during the early phase following HSCT. The long-term clinical complications and prognosis, however, remain unclear. Between September 2010 and October 2012, whole blood samples from 105 patients collected weekly from prior to 6weeks after HSCT underwent multiplex polymerase chain reaction (PCR) to screen for viral DNA, followed by real-time PCR for quantitative estimation. In 48 patients, only HHV-6 was detected in at least one sample. In 30 patients, no viral DNA was detected. Long-term clinical records were reviewed in March 2016. All 48 HHV-6-positive patients, and 24 patients in whom no viral DNA detected, were followed up. Median maximum HHV-6 DNA load in the blood of the HHV-6 reactivation group (n=48) was 11800copies/μg peripheral blood leukocyte DNA (range, 52-310000000). Hemophagocytic syndrome (HPS) was diagnosed in two subjects with HHV-6 reactivation. Acute graft-versus-host disease (GVHD) developed more frequently in patients with HHV-6 reactivation than in patients without viral reactivation (P=0.002), but there was no difference in incidence of chronic GVHD. There was no difference in engraftment of neutrophils and platelets between groups. There was also no difference in overall survival between groups. Onset of HPS, however, was associated with lower overall survival (P=0.009). Human herpesvirus 6 reactivation was associated with acute GVHD, but not with chronic GVHD, engraftment or overall survival. Onset of HPS, however, predicts lower overall survival.

Human Herpes Virus 8 in HIV-1 infected individuals receiving cancer chemotherapy and stem cell transplantation.

BackgroundHuman Herpes Virus 8 (HHV8) can cause Kaposi’s Sarcoma (KS) in immunosuppressed individuals. However, little is known about the association between chemotherapy or hematopoietic stem cell transplantation (HSCT), circulating HHV8 DNA levels, and clinical KS in HIV-1-infected individuals with various malignancies. Therefore, we examined the associations between various malignancies, systemic cancer chemotherapy, T cell phenotypes, and circulating HHV8 DNA in 29 HIV-1-infected participants with concomitant KS or other cancer diagnoses.MethodsWe quantified HHV8 plasma viral loads and cell-associated HHV8 DNA and determined the relationship between circulating HHV8 DNA and lymphocyte counts, and markers of early and late lymphocyte activation, proliferation and exhaustion.ResultsThere were no significant differences in plasma HHV8 DNA levels between baseline and post-chemotherapy time points or with the presence or absence of clinical KS. However, in two participants circulating HHV8 DNA increased following treatment for KS or HSCT for lymphoma,. We observed an approximately 2-log10 reduction in plasma HHV8 DNA in an individual with KS and multicentric Castleman disease following rituximab monotherapy. Although individuals with clinical KS had lower mean CD4+ T cell counts and percentages as expected, there were no significant associations with these factors and plasma HHV8 levels. We identified increased proportions of CD8+ and CD4+ T cells expressing CD69 (P = 0.01 & P = 0.04 respectively), and increased CD57 expression on CD4+ T cells (P = 0.003) in participants with detectable HHV8.ConclusionThese results suggest there is a complex relationship between circulating HHV8 DNA and tissue-based disease in HIV-1 and HHV8 co-infected individuals with various malignancies.

Laboratory Diagnosis of Pediatric Herpesvirus Infections of the Central Nervous System by a Multiplex Polymerase Chain Reaction Assay and Intrathecal Antibodies

Abstract Introduction Central nervous system (CNS) viral infections are a serious problem requiring accurate diagnosis and treatment. Human herpesviruses (HHVs) are an important cause of these infections. Recent research has focused on new diagnostic methods allowing accurate and rapid identification of viral infections because there are still diagnostic difficulties for these infections. This study was done to determine the etiologic role of human herpes viruses and to obtain information that will contribute to the diagnostic algorithm in suspected cases of viral encephalitis or aseptic meningitis. Materials and Methods In our study, herpes simplex virus (HSV)-1, HSV-2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), and HHV-6 DNA was detected in the cerebrospinal fluid (CSF) by multiplex polymerase chain reaction (PCR) and virus-specific immunoglobulin G (IgG) antibodies in CSF and serum by EIA in pediatric encephalitis/meningitis cases. Results HSV-1 and VZV were detected in 5 and 3.3% of aseptic meningitis cases, respectively, but no encephalitis cases. Other viruses were not identified as etiologic agents. The seroprevalences were determined as 72.4, 34.3, 81.9, 93.3, 88.6, and 80.9%, respectively for HSV-1, HSV-2, VZV, CMV, EBV, and HHV-6. The performance of specific IgG CSF/serum antibody index (AI) was not satisfactory. Conclusion Our study indicates that the multiplex PCR method is the most suitable for the diagnosis of CNS infections caused by HHVs. However, due to the high cost of the PCR method, the positive results of the specific AI may be significant, but the negative results are unreliable, especially in limited health care facilities.