Enhanced Long-Term Brain Magnetic Resonance Imaging Evaluation of Children with Sickle Cell Disease after Hematopoietic Cell Transplantation.

Progressive neurovasculopathy in children with sickle cell disease (SCD) results in decreased cognitive function and quality of life (QoL). Hematopoietic cell transplantation (HCT) is believed to halt progression of neurovasculopathy. Quantitative analysis of T2-weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) for white matter hyperintensity (WMH) burden provides a meaningful estimate of small vessel cerebrovascular disease. We asked if quantitative analysis of WMH could complement standardized clinical assessment of MRI/magnetic resonance angiography (MRA) for assessing SCD central nervous system vasculopathy before and after HCT. Retrospective longitudinal clinical examination of scheduled annual MRI/MRA and quantitative analysis of WMH were performed before and 1 to 7 years after HCT at scheduled annual intervals, along with QoL measurements, in children who had engrafted after HCT. Of 18 patients alive and persistently engrafted (median age, 9.1 years), pretransplantation MRI demonstrated that 9 and 5 had sickle-related stroke and/or small infarcts, respectively. Patients were divided into WMH severity tertiles based on pretransplantation WMH volumes. MRI and WMH were assessed 1 to 7 years after HCT. MRI/MRA and WMH volume were stable or slightly better in 17 of 18 patients. By parent- and self-report, post-HCT QoL improved for children in the lowest WMH tertile significantly more than in the other groups. Based on this single-institution retrospective sample, we report that WMH appears to quantitatively support MRI-based findings that HCT stabilizes long-term small and large vessel cerebrovascular changes and is associated with the degree of improved QoL. While confirmation in larger prospective studies and evaluation by neurocognitive testing are needed, these findings suggest that WMH is a useful biomarker of neurovasculopathy after transplantation for SCD.

Decreased fetal hemoglobin over time among youth with sickle cell disease on hydroxyurea is associated with higher urgent hospital use.

BACKGROUND: Hydroxyurea (HU) induces dose-dependent increased fetal hemoglobin (HbF) for sickle cell disease (SCD). Large deviation from historical personal best (PBest) HbF, a clinic-based version of maximum dose, may identify a subset with suboptimal HU adherence over time. PROCEDURE: Retrospective clinical data from youth ages 10-18 years prescribed HU at two centers were extracted from medical records at three time points: pre-HU initiation, PBest and a recent assessment. Decrease from PBest HbF of 20% or more at recent assessment despite stable dosing was designated as high deviation from PBest. Acute hospital use was compared between 1-year periods, pre-HU and ±6 months for PBest and recent assessment. Groups were compared using descriptive and bivariate nonparametric statistics. RESULTS: Seventy-five youth, mean HU duration 5.9 years, met eligibility criteria. Mean ages of HU initiation, PBest and recent assessment were 8.0, 10.9 and 13.9 years, respectively. Despite stable dosing, average HbF of 19.5% at PBest overall declined by 31.8% at recent assessment. PBest HbF declined by 11.7 and 40.1% in two groups, the latter comprised 70.7% of the sample, had lower pre-HU and recent HbF and higher dosing. They experienced more urgent hospital use during the year framing recent assessment than during PBest; these findings were supported by sensitivity analysis. CONCLUSIONS: Decline from PBest HbF is a novel approach to assess HU effectiveness, is common among youth and may represent suboptimal adherence. Larger prospective studies using additional adherence measures are needed to confirm our approach of tracking HbF deviation over time and to define an appropriate cutoff.

Bacterial bloodstream infections in pediatric allogeneic hematopoietic stem cell recipients before and after implementation of a central line-associated bloodstream infection protocol: A single-center experience.

INTRODUCTION: There are only few reports describing the influence of central line-associated bloodstream infection (CLABSI) prevention strategies on the incidence of bacterial bloodstream infections (BBSIs). METHODS: We performed a retrospective cohort study among pediatric recipients of allogeneic hematopoietic stem cell transplantation (allo-HCT) to assess potential changes in BBSI rates during 3 time periods: pre-CLABSI prevention era (era 1, 2004-2005), CLABSI prevention implementation era (era 2, 2006-2009), and maintenance of CLABSI prevention era (era 3, 2010-2012). BBSI from day 0-365 following allo-HCT were studied. The comparison of person-years incidence rates among different periods was carried out by Poisson regression analysis. RESULTS: The mean age of patients was 10.0 years. During the study period, 126 (65%) of 190 patients had at least a single BBSI. From day 0-30, day 31-100, day 101-180, and day 181-365, 20%, 28%, 30%, and 17% of patients, respectively, experienced BBSIs. The rate of Staphylococcus epidermidis and gram-negative pathogens significantly declined from 3.16-0.93 and 6.32-2.21 per 100 person-months during era 1 and era 3, respectively (P = .001). CONCLUSIONS: Patients undergoing allo-HCT during era 3 were associated with decreased risk of BBSI (P = .012). Maintenance of CLABSI protocols by nursing staff and appropriate education of other care providers is essential to lower incidence of BBSI in this high-risk population, and further strategies to decrease infection burden should be studied.

Survival Impact of Early Post-Transplant Toxicities in Pediatric and Adolescent Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Malignant and Nonmalignant Diseases: Recognizing Risks and Optimizing Outcomes.

In pediatric and adolescent patients undergoing allogeneic hematopoietic cell transplantation, treatment-related toxicities remain a clinical challenge. A paucity of data investigates the risks for and survival impact of treatment-related toxicities in this population. Here the authors assess the relative toxicity of myeloablative, reduced-toxicity, and reduced-intensity conditioning regimens; identify patient-related predictors of post-transplant toxicities; and investigate the impact of early post-transplant toxicities on transplant-related mortality (TRM). In this retrospective study, 164 patients (aged 1 to 22 years) underwent allogeneic stem cell transplantation after busulfan-based conditioning for malignant and nonmalignant diseases between 2000 and 2014. The number of grades III to IV toxicities between days 0 and +30 was calculated for each patient. TRM was calculated to 2 years. Median patient age was 9 years, and median number of toxicities was 3 (range, 0 to 17). The 100-person day incidence of post-transplant toxicities in myeloablative conditioning was not different from the incidence in reduced-toxicity conditioning (13.88 versus 13.59, P = .812). Reduced intensity was less toxic than both myeloablative and reduced toxicity (13.75 versus 8.41, P < .001). Age ≥ 12 years (.276 with SE = .138, P = .045) and unrelated donor transplant (.318 with SE = 0.113, P = .005) were risk factors for ≥3 toxicities. Having ≥3 toxicities or a performance score < 90 conferred higher risk of TRM (P = .021). In pediatric and adolescent patients undergoing hematopoietic cell transplantation, reduced-toxicity conditioning was not significantly less toxic than myeloablative conditioning. Additionally, the number of post-transplant toxicities correlated with the risk of mortality. Further investigations to confirm our findings are warranted.

Analysis of DNA methylation acquisition at the imprinted Dlk1 locus reveals asymmetry at CpG dyads.

BACKGROUND: Differential distribution of DNA methylation on the parental alleles of imprinted genes distinguishes the alleles from each other and dictates their parent of origin-specific expression patterns. While differential DNA methylation at primary imprinting control regions is inherited via the gametes, additional allele-specific DNA methylation is acquired at secondary sites during embryonic development and plays a role in the maintenance of genomic imprinting. The precise mechanisms by which this somatic DNA methylation is established at secondary sites are not well defined and may vary as methylation acquisition at these sites occurs at different times for genes in different imprinting clusters. RESULTS: In this study, we show that there is also variability in the timing of somatic DNA methylation acquisition at multiple sites within a single imprinting cluster. Paternal allele-specific DNA methylation is initially acquired at similar stages of post-implantation development at the linked Dlk1 and Gtl2 differentially methylated regions (DMRs). In contrast, unlike the Gtl2-DMR, the maternal Dlk1-DMR acquires DNA methylation in adult tissues. CONCLUSIONS: These data suggest that the acquisition of DNA methylation across the Dlk1/Gtl2 imprinting cluster is variable. We further found that the Dlk1 differentially methylated region displays low DNA methylation fidelity, as evidenced by the presence of hemimethylation at approximately one-third of the methylated CpG dyads. We hypothesize that the maintenance of DNA methylation may be less efficient at secondary differentially methylated sites than at primary imprinting control regions.