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Human herpesvirus-6B (HHV-6B) reactivation has been associated with non-relapse mortality (NRM) and overall mortality (OM) following allogeneic hematopoietic stem cell transplant (HCT). We performed a systematic review and meta-analysis to better quantify the association. Studies were included if they systematically tested a cohort of HCT recipients for HHV-6 infection or reactivation and described mortality for patients with and without HHV-6B. Random effects models were used to assess the pooled effect of HHV-6B positivity on each outcome of interest. Bayesian aggregation was additionally performed if models included 10 or fewer studies. Eight studies were included in the NRM analysis, which demonstrated a significant association between HHV-6 detection and NRM (pooled effect: 1.84; 95% CI: 1.29–2.62) without significant heterogeneity (I 2  = 0.0%, p  = 0.55). A Bayesian aggregation of the raw data used to construct the NRM random effects model supported these findings (95% credible interval: 0.15–1.13). Twenty-five studies were included in OM analysis, which showed a significant positive association (pooled effect: 1.37; 95% CI: 1.07–1.76), though considerable heterogeneity was observed (I 2  = 36.7%, p  < 0.05). HHV-6 detection is associated with NRM and OM following HCT. Randomized trials are warranted to evaluate if preventing or treating HHV-6B reactivation improves outcomes.

Bacteraemia is an important cause of morbidity and mortality in critically ill children. Our objective was to assess whether daily bathing in chlorhexidine gluconate (CHG) compared with standard bathing practices would reduce bacteraemia in critically ill children. In an unmasked, cluster-randomised, two-period crossover trial, ten paediatric intensive-care units at five hospitals in the USA were randomly assigned a daily bathing routine for admitted patients older than 2 months, either standard bathing practices or using a cloth impregnated with 2% CHG, for a 6-month period. Units switched to the alternative bathing method for a second 6-month period. 6482 admissions were screened for eligibility. The primary outcome was an episode of bacteraemia. We did intention-to-treat (ITT) and per-protocol (PP) analyses. This study is registered with ClinicalTrials.gov (identifier NCT00549393). 1521 admitted patients were excluded because their length of stay was less than 2 days, and 14 refused to participate. 4947 admissions were eligible for analysis. In the ITT population, a non-significant reduction in incidence of bacteraemia was noted with CHG bathing (3·52 per 1000 days, 95% CI 2·64–4·61) compared with standard practices (4·93 per 1000 days, 3·91–6·15; adjusted incidence rate ratio [aIRR] 0·71, 95% CI 0·42–1·20). In the PP population, incidence of bacteraemia was lower in patients receiving CHG bathing (3·28 per 1000 days, 2·27–4·58) compared with standard practices (4·93 per 1000 days, 3·91–6·15; aIRR 0·64, 0·42–0·98). No serious study-related adverse events were recorded, and the incidence of CHG-associated skin reactions was 1·2 per 1000 days (95% CI 0·60–2·02). Critically ill children receiving daily CHG bathing had a lower incidence of bacteraemia compared with those receiving a standard bathing routine. Furthermore, the treatment was well tolerated. Sage Products, US National Institutes of Health.

Improved understanding of double-stranded DNA (dsDNA) virus kinetics after hematopoietic cell transplantation (HCT) would facilitate development of therapeutic strategies. We tested weekly plasma samples from 404 patients through day 100 after allogeneic HCT for cytomegalovirus (CMV), human herpesvirus (HHV) 6A and 6B, BK polyomavirus (BKV), adenovirus (AdV), and Epstein-Barr virus (EBV) using quantitative polymerase chain reaction. Episodes lasting ≤1 week were defined as blips and >1 week as persistent. We described virus-specific kinetics, analyzed the association of virus area under the curve (AUC) with overall mortality, and identified risk factors for persistent episodes. We identified 428 episodes of CMV, 292 of BKV, 224 of HHV-6B, 46 of AdV, and 53 of EBV. CMV and BKV had the highest proportions of persistent episodes (68% and 80%, respectively). Detection and kinetics varied by virus. HHV-6B episodes reached maximum levels fastest and had the shortest intervals between detection and end-organ disease. End-organ disease occurred within 14 days of viremia in 68% of cases, generally during persistent episodes. For all viruses, higher viral load AUC increased risk for overall mortality through day 365, persistent episodes had higher viral load than blips, and higher first positive viral load significantly increased risk for persistent episodes. First viral load >2 log10 copies/mL (range, 2.04-3.06 per virus) had high specificity for persistent episodes. Persistent high viral load dsDNA viremia episodes after allogeneic HCT predict mortality. Virus-specific kinetics can guide timing and thresholds for early intervention in studies of novel agents.

Human herpesvirus 6 (HHV-6) latently infects a majority of adults. In about 1% of the population HHV-6 exists in a chromosomally integrated form (ciHHV-6) that resides in every somatic and germ cell and can be transmitted through the germ line. Patients with ciHHV-6 have been misdiagnosed and unnecessarily treated for active HHV-6 infection, sometimes with important side effects, based on results from quantitative molecular HHV-6 tests. A droplet digital PCR (ddPCR) assay was developed to identify ciHHV-6 in cellular patient samples by precisely determining the ratio of HHV-6 to cellular DNA. We validated the assay on confirmed ciHHV-6 patient samples and a cell line derived from a ciHHV-6 patient, and we analyzed hematopoietic stem cell transplant patients suspected of having ciHHV-6. We additionally evaluated whether the assay could be applied to stored plasma samples from a study of clinical correlates of HHV-6. The ddPCR assay accurately identified ciHHV-6 in cellular samples (buffy coat, peripheral blood mononuclear cells), giving a ratio very close to 1 HHV-6/cell [mean (SD), 1.02 (0.03)] in fluorescence in situ hybridization-confirmed sample). In stored plasma samples, the assay performance was set by design to have 100% sensitivity, which resulted in 82% specificity for ciHHV-6. The possibility of ciHHV-6 is often overlooked in patients with detectable HHV-6 viral loads by quantitative PCR. Our ddPCR test provides rapid and accurate laboratory identification of ciHHV-6 from easily obtained cellular samples. In addition, the assay provides excellent sensitivity and specificity using stored plasma samples, facilitating retrospective analysis of the clinical significance of ciHHV-6.

Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplant (HCT). In this prospective multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT, we test blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and perform RNA-seq on paired blood. Among 116 participants, HHV-6B DNA is detected in 37% of BALs, 49% of which also have HHV-6B mRNA detection. We establish HHV-6B DNA viral load thresholds in BALF that are highly predictive of HHV-6B mRNA detection and associated with increased risk for overall mortality and death from respiratory failure. Participants with HHV-6B DNA in BALF exhibit distinct host gene expression signatures, notable for enriched interferon signaling pathways in participants clinically diagnosed with idiopathic pneumonia. These data implicate HHV-6B as a pulmonary pathogen after allogeneic HCT. Lower respiratory tract disease is a common complication after allogeneic hematopoietic cell transplant (HCT), but underlying reasons remain unclear. Here the authors show that HHV-6B detection in the lungs of allogeneic HCT recipients is associated with increased risk for death and distinct host gene expression profiles, implicating HHV-6B as a pulmonary pathogen in these patients.

•The Parent Attitudes about Childhood Vaccines survey identifies vaccine hesitancy.•54% with PACV scores <50 refused the vaccine compared to 90% with PACV scores ≥50.•The PACV can determine hesitancy toward the seasonal influenza vaccine in a PED. Providing influenza vaccine to patients in the pediatric emergency department (PED) is one strategy to increase childhood influenza vaccine uptake. The Parent Attitudes about Childhood Vaccines (PACV) survey is a new tool to identify vaccine-hesitant parents that may facilitate influenza vaccine uptake in the PED. To assess the feasibility of administering the PACV modified for influenza vaccination in the PED setting and to determine whether parental PACV scores are associated with patient receipt of influenza vaccine in the PED. We conducted a cross-sectional study in the PED of a tertiary pediatric hospital in Seattle, WA during the 2013–2014 influenza season. English-speaking parents of children aged 6 months to 7 years who were afebrile, medically stable to be discharged home from the PED, and had not already received an influenza vaccine this season were administered a modified version of the PACV. PACV scores (0–100, higher score=higher hesitancy) were dichotomized (<50 and ≥50) consistent with previous validation studies. Feasibility was assessed by determining time to complete the PACV. Our primary outcome was influenza vaccine refusal in the PED. We used multivariable logistic regression to estimate unadjusted and adjusted odds ratios for association between vaccine refusal and dichotomized PACV scores. 152 parent participants were included in the analysis. The median time for administering the PACV was 7min. The median PACV score was 28, with 74% scoring <50. Parents who scored ≥50 on the PACV had increased odds of refusing the influenza vaccine compared to parents who scored <50 (adjusted OR [95% CI]: 6.58 [2.03–21.38]). Administration of the PACV in the PED is feasible, and higher PACV scores in this setting are associated with increased influenza vaccine refusal.

Background. Although human herpesvirus 6 (HHV-6) is known to reactivate during hematopoietic stem cell transplantation (HSCT), the clinical significance of this finding is controversial. Methods. We used a quantitative PCR test for HHV-6 to assay plasma samples prospectively collected from a cohort of 110 allogeneic HSCT recipients to evaluate the clinical effects of HHV-6 infection. A retrospective review of medical records was performed to determine clinical end points. Results. HHV-6 reactivation occurred in 52 (47%) of the 110 subjects. Factors that increased the risk of subsequent HHV-6 reactivation were hematologic malignancy that occurred at a time other than the first remission (adjusted P = .002), a mismatch in the sexes of donor and recipient (adjusted P = .05), younger age (adjusted P = .01), and the receipt of glucocorticoids (adjusted P = .06). HHV-6 reactivation was associated with subsequent all-cause mortality (adjusted hazard ration [HR], 2.9; 95% confidence interval [CI], 1.1–7.5), grade 3–4 graft-versus-host disease (GVHD) (adjusted HR, 4.9; 95% CI, 1.5–16), a lower probability of monocyte engraftment (adjusted HR, 0.42; 95% CI; 0.22–0.80), a lower probability of platelet engraftment (adjusted HR, 0.47; 95% CI, 0.21–1.1; P = .05) and a higher platelet transfusion requirement (adjusted P = .02). A higher level of HHV-6 DNA was associated with subsequent central nervous system (CNS) dysfunction (HR, 21; 95% CI, 1.8–249). Conclusions. HHV-6 reactivation is common after allogeneic HSCT and is associated with subsequent delayed monocyte and platelet engraftment, increased platelet transfusion requirements, all-cause mortality, grade 3–4 GVHD, and CNS dysfunction.

Background Human herpesvirus-6A and -6B (HHV-6) are betaherpesviruses that reach > 90% seroprevalence in the adult population. Unique among human herpesviruses, HHV-6 can integrate into the subtelomeric regions of human chromosomes; when this occurs in germ line cells it causes a condition called inherited chromosomally integrated HHV-6 (iciHHV-6). Only two complete genomes are available for replicating HHV-6B, leading to numerous conflicting annotations and little known about the global genomic diversity of this ubiquitous virus. Results Using a custom capture panel for HHV-6B, we report complete genomes from 61 isolates of HHV-6B from active infections (20 from Japan, 35 from New York state, and 6 from Uganda), and 64 strains of iciHHV-6B (mostly from North America). HHV-6B sequence clustered by geography and illustrated extensive recombination. Multiple iciHHV-6B sequences from unrelated individuals across the United States were found to be completely identical, consistent with a founder effect. Several iciHHV-6B strains clustered with strains from recent active pediatric infection. Combining our genomic analysis with the first RNA-Seq and shotgun proteomics studies of HHV-6B, we completely reannotated the HHV-6B genome, altering annotations for more than 10% of existing genes, with multiple instances of novel splicing and genes that hitherto had gone unannotated. Conclusion Our results are consistent with a model of intermittent de novo integration of HHV-6B into host germline cells during active infection with a large contribution of founder effect in iciHHV-6B. Our data provide a significant advance in the genomic annotation of HHV-6B, which will contribute to the detection, diversity, and control of this virus.

In this study of serial saliva specimens from 277 children, 40 percent were infected with human herpesvirus 6 (HHV-6) by 12 months of age and 77 percent were infected by 2 years of age. Nearly all primary infections were symptomatic, with almost 40 percent leading to clinic visits for symptoms such as fever, fussiness, and diarrhea. In this study of serial saliva specimens from 277 children, 40 percent were infected with human herpesvirus 6 by 12 months of age and 77 percent were infected by 2 years of age. Human herpesvirus 6 (HHV-6) infects over 90 percent of people within the first two years of life. 1 Studies of febrile children in the emergency department indicate that primary HHV-6 infection accounts for a large proportion of visits and febrile seizures. 2 Despite the interest in HHV-6 as an important pathogen, 3 – 5 no prospective, population-based study has evaluated the acquisition of HHV-6 outside the acute care setting. Thus, the full spectrum of illness and virologic aspects of primary HHV-6 infection remain unknown. We developed a noninvasive method of testing serially collected saliva specimens for HHV-6 6 and used it prospectively in children from . . .

The FilmArray respiratory virus panel detects 15 viral agents in respiratory specimens using polymerase chain reaction. We performed FilmArray respiratory viral testing in a core laboratory at a regional children's hospital that provides service 24 hours a day 7 days a week. The average and median turnaround time were 1.6 and 1.4 hours, respectively, in contrast to 7 and 6.5 hours documented 1 year previously at an on-site reference laboratory using a direct fluorescence assay (DFA) that detected 8 viral agents. During the study period, rhinovirus was detected in 20% and coronavirus in 6% of samples using FilmArray; these viruses would not have been detected with DFA. We followed 97 patients with influenza A or influenza B who received care at the emergency department (ED). Overall, 79 patients (81%) were given oseltamivir in a timely manner defined as receiving the drug in the ED, a prescription in the ED, or a prescription within 3 hours of ED discharge. Our results demonstrate that molecular technology can be successfully deployed in a nonspecialty, high-volume, multidisciplinary core laboratory.