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Importance: Acute chest syndrome (ACS) is a common, serious complication of sickle cell disease (SCD) and a leading cause of hospitalization and death in both children and adults with SCD. Little is known about the effectiveness of guideline-recommended antibiotic regimens for the care of children hospitalized with ACS., Objectives: To use a large, national database to describe patterns of antibiotic use for children with SCD hospitalized for ACS and to determine whether receipt of guideline-adherent antibiotics was associated with lower readmission rates., Design, Setting, and Participants: Retrospective cohort study including 14 480 hospitalizations in 7178 children (age 0-22 years) with a discharge diagnosis of SCD and either ACS or pneumonia. Information was obtained from 41 children's hospitals submitting data to the Pediatric Health Information System from January 1, 2010, to December 31, 2016., Exposures: National Heart, Lung, and Blood Institute guideline-adherent (macrolide with parenteral cephalosporin) vs non-guideline-adherent antibiotic regimens., Main Outcomes and Measures: Acute chest syndrome-related and all-cause 7- and 30-day readmissions., Results: Of the 14 480 hospitalizations, 6562 (45.3%) were in girls; median (interquartile range) age was 9 (4-14) years. Guideline-adherent antibiotics were provided in 10 654 of 14 480 hospitalizations for ACS (73.6%). Hospitalizations were most likely to include guideline-adherent antibiotics for children aged 5 to 9 years (3230 of 4047 [79.8%]) and declined to the lowest level for children 19 to 22 years (697 of 1088 [64.1%]). Between-hospital variation in antibiotic regimens was wide, with use of guideline-adherent antibiotics ranging from 24% to 90%. Children treated with guideline-adherent antibiotics had lower 30-day ACS-related (odds ratio [OR], 0.71; 95% CI, 0.50-1.00) and all-cause (OR, 0.50; 95% CI, 0.39-0.64) readmission rates vs children who received other regimens (cephalosporin and macrolide vs neither drug class)., Conclusions and Relevance: Current approaches to antibiotic treatment in children with ACS vary widely, but guideline-adherent therapy appears to result in fewer readmissions compared with non-guideline-adherent therapy. Efforts to increase the dissemination and implementation of SCD treatment guidelines are warranted as is comparative effectiveness research to strengthen the underlying evidence base.

Objective: To assess the relationship between hospital volume and intensive care unit (ICU) transfer among hospitalized children with sickle cell disease (SCD)., Study Design: We conducted a retrospective cohort study of 83,477 SCD-related hospitalizations at children's hospitals (2009-2012) using the Pediatric Health Information System database. Hospital-level all-cause and SCD-specific volumes were dichotomized (low vs high). Outcomes were within-hospital ICU transfer (primary) and length of stay (LOS) total (secondary). Multivariable logistic/linear regressions assessed the association of hospital volumes with ICU transfer and LOS., Results: Of 83,477 eligible hospitalizations, 1741 (2.1%) involving 1432 unique children were complicated by ICU transfer. High SCD-specific volume (OR 0.77, 95% CI 0.64-0.91) was associated with lower odds of ICU transfer while high all-cause hospital volume was not (OR 0.87, 95% CI 0.73-1.04). A statistically significant interaction was found between all-cause and SCD-specific volumes. When results were stratified according to all-cause volume, high SCD-specific volume was associated with lower odds of ICU transfer at low all-cause volume (OR 0.46, 95% CI 0.38-0.55). High hospital volumes, both all-cause (OR 0.94, 95% CI 0.92-0.97) and SCD-specific (OR 0.86, 95% CI 0.84-0.88), were associated with shorter LOS., Conclusions: Children's hospitals vary substantially in their transfer of children with SCD to the ICU according to hospital volumes. Understanding the practices used by different institutions may help explain the variability in ICU transfer among hospitals caring for children with SCD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Pulmonary diseases form major sources of morbidity and mortality in children with sickle cell disease (SCD). The objective of the study was to determine the prevalence of lung function abnormalities and asthma and their association with acute chest syndrome (ACS) in children with SCD. This was a cross-sectional retrospective study of 127 children with SCD; we collected information regarding ACS and asthma and pulmonary function test (PFT) data. Based on PFT results, the patients were assigned to one pattern of lung function [normal, obstructive lung disease (OLD), restrictive lung disease (RLD)]. Statistical analyses included Pearson correlation, prevalence odds ratio (POR), cross-tabulation, and multiple binary logistic regression. OLD was noted in 35% and RLD in 23% of the patients, with the remainder exhibiting a normal PFT pattern. Forty-six percent of patients had asthma, 64% of whom had a history of ACS. OLD (r = .244, P = .008, POR = 2.8) and asthma (r = .395, P < .001, POR = 5.4) were significantly associated with a history of ACS. There was a negative correlation between having normal PFT data and a history of ACS (r = -.289, P = .002, POR = .3). Asthma and pulmonary function abnormalities are prevalent in children with SCD, with OLD being more common than RLD. There is an association between asthma, OLD, and ACS, however causality cannot be proven due to the study design. We stress the importance of actively investigating for a clinical diagnosis of asthma in all patients with SCD and suggest that PFT data may help detect patients at lower risk for ACS.

Background: Neurocognitive impairment occurs in children and adults with sickle cell anemia, but little is known about neurodevelopment in very young children. We examined the neurodevelopmental status of infants participating in the Pediatric Hydroxyurea Phase III Clinical Trial (Baby Hug) to determine relationships with age, cerebral blood flow velocity, and hemoglobin concentration., Methods: Standardized measures of infant neurodevelopment were administered to 193 infants with hemoglobin SS or hemoglobin S-β(0) thalassemia between 7 and 18 months of age at the time of their baseline evaluation. Associations between neurodevelopmental scores and age, family income, parent education, hemoglobin concentration, and transcranial Doppler velocity were examined., Results: Mean functioning on the baseline neurodevelopment scales was in the average range. There were no mental development scores <70 (impaired); 22 children had scores in the clinically significant range, 11 with impaired psychomotor scores and 11 with problematic behavior rating scores. Significantly poorer performance was observed with older age at baseline. Behavior rating scores were an average of 2.82 percentile points lower per month of age, with similar patterns observed with parent report using adaptive behavior scales. Parent-reported functional abilities and hemoglobin were negatively associated with higher transcranial Doppler velocities., Conclusions: Whereas overall functioning was in the normal range, behavioral and adaptive function was poorer with older age, even in this very young group of children. Explanatory mechanisms for this association between poorer developmental function and older age need to be identified.

Background: Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects., Methods: This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sβ(0)thalassaemia, were aged 9-18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on (99)Tc spleen scan) and renal function (glomerular filtration rate by (99m)Tc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2-4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00006400., Findings: 96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m(2), p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p<0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia., Interpretation: On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia., Funding: The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Sickle cell disease (SCD) is associated with a large spectrum of renal abnormalities, one of which, microalbuminuria/proteinuria (MA/P), is a known predictor of end-stage renal disease. We studied 90 children with SCD (57% male; mean age 11.4 +/- 5.2 years) to determine the prevalence and examine clinical correlates of MA/P. The average of two spot urine microalbumin-to-creatinine samples obtained 6 months apart was recorded. Medical records were reviewed for demographic and biochemical data. Medication use, resting office blood pressures (BP), vaso-occlusive pain crises (VOC), and monthly transfusions were recorded. Fourteen children (15.5%) had MA/P. Hemoglobin (Hb) levels were significantly lower in the children with MA than in those without MA/P (8.8 +/- 1.1 vs. 9.8 +/- 1.4 g/dL, respectively) and were significantly correlated with MA (rho = 0.24, p = 0.03). Children with MA were more likely to have abnormal BP (p = 0.058), with 5/14 being hypertensive or pre-hypertensive. In a multivariate logistic regression model of MA, both Hb and BP classification remained in the final model. MA is a simple screening biomarker of early kidney injury in children with SCD. Larger studies to evaluate predictive factors of MA and the relationship to BP are needed.

Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso-occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might support widespread use of the drug at an early age. BABY HUG is a randomized, double-blind placebo-controlled trial to test whether treating young children ages 9-17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for 2 years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of 200. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially vulnerable subjects were allayed by inclusion of a research subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of an unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity (ClinicalTrials.gov number, NCT00006400)., ((c) 2009 Wiley-Liss, Inc.)