ALBERT

Description: Neurologic complications are a major cause of morbidity and mortality in sickle cell disease (SCD). In children with sickle cell anemia, routine use of transcranial Doppler screening, coupled with regular blood transfusion therapy, has decreased the prevalence of overt stroke from ∼11% to 1%. Limited evidence is available to guide acute and chronic management of individuals with SCD and strokes. Current management strategies are based primarily on single arm clinical trials and observational studies, coupled with principles of neurology and hematology. Initial management of a focal neurologic deficit includes evaluation by a multidisciplinary team (a hematologist, neurologist, neuroradiologist, and transfusion medicine specialist); prompt neuro-imaging and an initial blood transfusion (simple followed immediately by an exchange transfusion or only exchange transfusion) is recommended if the hemoglobin is 〉4 gm/dL and

Description: Abstract 2647 Rationale: Among children with sickle cell disease (SCD), a physician diagnosis of asthma has been associated with increased rates of acute chest syndrome (ACS), pain and mortality. Respiratory symptoms, including wheezing, occur in individuals with SCD independent of an asthma diagnosis. Few studies have evaluated the significance of asthma or respiratory symptoms in adults with SCD. Objective: The primary objective of this study was to determine whether adults with SCD and a physician-diagnosis of asthma have more ACS and pain episodes compared to adults with SCD but without asthma. A secondary objective was to evaluate the relationship between asthma-like symptoms and ACS and pain among adults with SCD. Methods: This was an observational cohort study of adults (≥ 19 years) with SCD who received care exclusively in the Washington University/Barnes Jewish Hospital system and completed baseline questionnaires including the ATS-DLD respiratory symptom survey. The questionnaires documented the frequency, severity and precipitants of symptoms such as wheezing, cough and shortness of breath. Enrollment into the study began August 2006. Hospitalizations for ACS and pain were determined from retrospective and prospective review of electronic medical records from January 1, 2004 to March 1, 2010 and analyzed using adjusted negative binomial regression models. Cox proportional hazards models were used to determine survival rates from date of consent through March 1, 2010. Spirometry was obtained from 69% of the study cohort. Results: Of 114 adults with SCD, those with a physician diagnosis of asthma (n=34) were more likely to have classic features of asthma including cough and wheeze, history of eczema, parental history of asthma, and an IgE level 〉150 kU/L (all p

Description: Sickle cell disease is a common hemolytic disorder with a broad range of complications, including vaso-occlusive episodes, acute chest syndrome (ACS), pain, and stroke. Heme oxygenase-1 (gene HMOX1; protein HO-1) is the inducible, rate-limiting enzyme in the catabolism of heme and might attenuate the severity of outcomes from vaso-occlusive and hemolytic crises. A (GT)n dinucleotide repeat located in the promoter region of the HMOX1 gene is highly polymorphic, with long repeat lengths linked to decreased activity and inducibility. We examined this polymorphism to test the hypothesis that short alleles are associated with a decreased risk of adverse outcomes (hospitalization for pain or ACS) among a cohort of 942 children with sickle cell disease. Allele lengths varied from 13 to 45 repeats and showed a trimodal distribution. Compared with children with longer allele lengths, children with 2 shorter alleles (4%; ≤ 25 repeats) had lower rates of hospitalization for ACS (incidence rate ratio 0.28, 95% confidence interval, 0.10-0.81), after adjusting for sex, age, asthma, percentage of fetal hemoglobin, and α-globin gene deletion. No relationship was identified between allele lengths and pain rate. We provide evidence that genetic variation in HMOX1 is associated with decreased rates of hospitalization for ACS, but not pain. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Description: Introduction: Neurological injury is a common complication of sickle cell anemia (SCA). SCA is the most common cause of stroke in children between 1-14 years of age, while silent cerebral infarct is the most common neurologic injury in this population. Young children are particularly vulnerable to the adverse impact of strokes, and are at risk of cognitive and developmental deficits; thus, we sought to examine brain volume changes in children with SCA. The Silent Cerebral Infarct Transfusion (SIT) Trial was a multicenter trial designed to determine the efficacy of blood transfusion therapy for prevention of recurrent silent cerebral infarcts in participants with SCA. This intervention trial followed 196 children with SCA aged 5-14 years randomized to receive blood transfusion therapy or observation for 36 months (DeBaun et al. N Engl J Med. 2014;371(8):699-710). As a planned secondary analysis, we used the SIT Trial brain imaging archive to determine longitudinal brain volume change in children with SCA. We performed a multivariable analysis using demographic and clinical variables to identify predictors of brain volume change. Methods SIT participants: The current study used a subset of the registered participants (n=169) in the SIT Trial with brain MRIs at study entry and exit, demographic and clinical information. Estimation of brain volume and percent brain volume change: Baseline brain volume and longitudinal percent brain volume change (PBVC) were derived from T1-weighted structural MRIs using the automated image analysis programs SIENAX and SIENA, respectively, from the FMRIB Software Library (FSL) (www.fmrib.ox.ac.uk/fsl). For each participant, PBVC was calculated between entry and exit brain MR scans, a mean time of 41 ± 6 months. A negative PBVC indicates a decrease in brain volume and a positive PBVC indicates an increase in brain volume. All analyses were performed blinded to the participant's identity. Statistical Analysis: A multivariable linear regression analysis was used to determine predictors of PBVC. The model included the following potential covariates : demographic variables (age, gender), laboratory measures (baseline oxygen saturation, steady state hemoglobin, steady state WBC, systolic blood pressure, % Hemoglobin F, steady state reticulocytes), clinical measures (acute chest syndrome and painful crisis rates), and regular transfusions provided as part of the trial. Results: Of the 169 SIT participants, 96 were male and 73 were female, including 80 participants in the observation group and 89 in the transfusion group. Median normalized brain volume was 1,237.6 cm3 at the study entry and 1,194.7 cm3 at exit. Baseline brain volume in males was different from females (1,290.6 cm3 vs. 1,166.6 cm3; p

Description: Introduction: Silent cerebral infarcts (SCI) are the major cause of neurological injury occurring in almost 40% of the population in children with sickle cell anemia (SCA); and are associated with a Full-Scale IQ decrease of approximately 5 points. Acute anemic events, defined as hemoglobin〈 6.0 g/dl, is associated with an increase odds ratio (OR) of SCI (OR 2.72; 95% CI, 1.13-6.54; P = .025; Bernaudin et al. Blood. 2015 Mar 5; 125(10):1653-61). Infection with parvovirus B19 (B19V) causes a transient reticulocytopenia and an acute drop in hemoglobin levels in children with SCA. We tested the hypothesis that a history of B19V infection was associated with increased odds ratio of SCIs. Methods: In this retrospective cross-sectional study design, we performed a secondary analysis on the Silent Cerebral Infarct Multi-Center Clinical Trial (SIT Trial). Children with SCA between 5 and 15 years of age, with no history of overt strokes or seizures, were screened for SCIs with MRIs of the brain. Research personnel reviewed medical records to determine a history of B19V infection. Based on prior evidence from the SIT Trial cohort demonstrating that lower hemoglobin levels divided into tertiles are associated with an increase odds of SCI (DeBaun et al. Blood. 2012 Apr 19;119(16):3684-90), three analyses were performed. We stratified by hemoglobin levels into tertiles (8.4 g/dL), to determine an association between SCI status and history of B19V infection. Chi squared statistic was used as the measure of association. As a secondary analysis of the original SIT trial cohort, the level of strong significance associated with an increased odds ratio of SCI was determined to be

Description: Introduction In this study, we sought to validate the previous findings that asthma increases the incidence of acute chest syndrome (ACS) and pain in children with sickle cell anemia (SCA). Methods A retrospective cohort was comprised of children with SCA evaluated for at least six months from a single medical center. Asthma was defined as being present when the first wheezing episode was heard by a physician after the age of 2 years or after 3 episodes of bronchiolitis before the age of 2 years. ACS was defined as a recent abnormal X-ray of the lungs associated with fever, respiratory signs or thoracic pain. A painful episode was defined as pain that resulted in hospitalization. Therapeutic intervention (hydroxyurea, blood transfusion therapy or transplant) was uniformly applied to all children with three or more episodes of pain that required hospitalization within a 12 month period. Patient years were accumulated from birth until death, lost to follow up, last visit to the center or a therapeutic intervention, whichever came first. Results A total of 297 children with SCA were evaluable for a doctor diagnosis of asthma for a total of 1,805 patient-years. The mean length of follow-up was 6.1 patient-years. A doctor diagnosis of asthma was present in 8.4% (25 of 297). Among the children with asthma 75% (19 of 25) were consistently prescribed a beta 2 agonist or inhaled corticosteroids. After adjustment for the effect of age, asthma was significantly associated with ACS event (p = 0.03) but pain was not (〉0.05). Conclusion Among children with SCA, asthma is associated with an increased incidence of ACS, but not pain that required hositalization. The absence of an association between asthma and pain may be related to uniform therapeutic intervention for children with repetitive painful episodes that require hospitalizations coupled with active treatment for asthma in most of the children.

Description: Objective While hemarthrosis contributes to morbidity in males with Hemophilia, less is known about joint destruction in females with FVIII deficiency. Our hypothesis was that females with FVIII deficiency enrolled in the Universal Data Collection (UDC) project had a reduced mean overall joint range of motion (ROM) compared to historic controls from the Normal Joint Study. Methods We employed a cross-sectional study design utilizing the UDC dataset. The overall joint ROM was the sum of the right and left ROM measurements of the five joints (hip, ankle, elbow, knee, shoulder) for the females with FVIII deficiency from the UDC and for healthy females without the deficiency 2-69 years of age from the Normal Joint Study. Females that were very obese (BMI 〉35) were excluded from the Normal Joint Study thus they were excluded from the UDC cohort. Mean overall joint ROM between affected and normal females was assessed for statistical difference using the non-parametric Wilcoxon-rank-sum test. Results were displayed as mean overall ROM with 95% confidence interval (CI) and p-value by age group and factor deficiency. Multivariate linear regression was performed using the General Linear Model (GLM) procedure with the overall joint ROM as the dependent variable and the clinical hemophilia severity as the independent variable adjusting for age, race, body mass index (BMI) and number of joint bleeds reported over the last six months. Summary A total of 522 females were identified with FVIII deficiency; 28% (144/522) of females were removed because of inability to assign factor deficiency type and 14% (75/522) of females were removed due to being very obese (BMI〉35) or outside the age range studied in the Normal Joint Study. Final analysis was performed on 303 females with FVIII deficiency between the ages of 2-69 years for comparison to the control group. As FVIII activity decreased, the mean overall joint range of motion became reduced and in most cases was significantly lower than that of the controls (see table 1). In FVIII deficient females there was a significant (p〈 0.0001) correlation between Hemophilia severity and mean overall joint ROM. Furthermore, using multivariate linear regression analysis, stratifying by age and clinical hemophilia severity and controlling for BMI and race, females with severe (5% and

Description: Background: As patient-centered care advances, measurement of health-related quality of life (HRQL) has become increasingly important when assessing the impact of a disease or therapy on a child. Red blood cell transfusions are an effective preventative therapy for some acute and chronic complications in children with sickle cell disease (SCD). This study aimed to determine the impact of transfusion therapy on health-related quality of life (HRQL) outcomes of children with SCD. Procedure: Children (n = 196) who participated in the Multicenter Silent Infarct Transfusion (SIT) Trial were grouped per protocol into either those who received 18 months or more of transfusion or less than 18 months of transfusion (observation). Parents/guardians of children ages 5 to 18 years completed assessments of HRQL using the Child Health Questionnaire at baseline and at the time of study exit or neurological event, if that occurred. Results: Children (43% female) had a mean age of 9.55 years (SD= 2.59) at study enrollment, and 92% were Black. There were no differences between study groups (effectively transfused vs. observation) in regards to gender, disease severity, rates of pain and acute chest syndrome, or baseline levels of HRQL. At study exit, independent samples t-tests revealed children in the effectively transfused group had significantly higher scores than the observation group for the following HRQL domains: Physical Function (M = 12.68, SE = 3.52), t (174) = 3.61, p ≤ 0.001; Bodily Pain (M = 13.16, SE = 3.74), t (174) = 3.51, p ≤ 0.001; and Change in Health (M = 0.39, SE = 0.14), t(166) = 2.71, p=0.01. Additionally, children in the effectively transfused group scored 4.98 (SE = 1.98) points higher on Physical Summary Scores than children in the observation group, t (170) = 2.52, p= 0.01. Thus, parents report that children who received at least 18 months of transfusions had better overall physical functioning, less bodily pain, and more improved overall health than children who had fewer than 18 months of transfusions. Both groups reported changes in HRQL over time. Compared to study entry, paired samples t-tests revealed children in the observation group indicated an increase of 0.42 (SE = 0.14) points for Change in Health scores [t (77) = 3.06, p ≤ 0.001], but had a decrease of 5.95 (SE = 2.07) points for Self-Esteem at study exit, t (85) = -2.87, p = 0.01. Children in the transfusion group improved by 7.22 (SE = 3.11) points in regards to pain over the course of the study, t (78) = 2.32, p = 0.02. Additionally, these children had better overall health as exhibited by their Change in Health scores (MD = 0.93, SE = 0.14), t (72) = 6.80, p = ≤ 0.001, and General Health scores (MD = 4.13, SE = 1.83), t (77) = 2.26, p = 0.03. Further improvements over time were noted for the effectively transfused group for Physical Functioning (MD = 6.58, SE = 3.09), t (78) = 2.13, p = 0.04, and Physical Summary Scores(MD = 4.89, SE = 1.82), t (73) = 2.69, p= 0.01. Although both study groups reported improvements in Change in Health scores over the course of the study (Effectively Transfused: MD = 0.93, SE = 0.14; Observation: MD = 0.42, SE = 0.14), an estimated Least Square Means analysis revealed children in the observation group did not improve as much as children in the effectively transfused group, Difference Estimate = -0.46, p= 0.02. Conclusions: This study provides the first evidence that blood transfusion improves HRQL in children with SCD. Children in the SIT trial who received at least 18 months of chronic blood transfusion therapy felt better and had better overall HRQL than those who had less than 18 months of transfusion therapy. Disclosures Casella: Mast Therapeutics, previously Adventrix, ImmunoArray: Consultancy, Honoraria, Other, Patents & Royalties, Research Funding.