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Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood. Here, we describe a form of congenital hemolytic anemia caused by missense mutations in an intrinsically disordered region of GATA1, with a poorly understood role in transcriptional regulation. Through integrative functional approaches, we demonstrate that these mutations perturb GATA1 transcriptional activity by partially impairing nuclear localization and selectively altering precise chromatin occupancy by GATA1. These alterations in chromatin occupancy and concordant chromatin accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective terminal red cell production. We demonstrate how disease-causing mutations can reveal regulatory mechanisms that enable the faithful genomic targeting of master TFs during cellular differentiation.

We describe Hb Alcorn County, a heterozygous hemoglobin (Hb) variant, in a 6-month-old Hispanic male and his mother. DNA sequencing demonstrated a mutation on the HBB gene [β40(C6)Arg→Thr; HBB: c.122G>C (p.Arg41Thr)], predictive of a substitution of arginine to threonine at position 40 of the β-globin protein. This amino acid substitution involves the α1β2 contact and occurs at the same position as Hb Austin [β40(C6)Arg→Ser; HBB: c.[123G>C or 123G>T] (p.Arg41Ser)] and Hb Athens-GA [β40(C6)Arg→Lys; HBB: c.122G>A (p.Arg41Lys)], both of which show increased oxygen affinity.

Study Objective To assess the clinical severity and initial treatment of iron deficiency anemia (IDA) in female adolescents with heavy menstrual bleeding (HMB) in our center. Design Retrospective cohort study of electronic medical records via search of administrative records using International Classification of Diseases Ninth Revision codes for IDA or unspecified anemia and disorders of menstruation. Setting Children's Medical Center in Dallas, Texas. Participants One hundred seven patients with HMB and concomitant IDA (median age, 14.4 years) who presented to the outpatient, emergency department, and/or inpatient settings. Results The median initial hemoglobin concentration for all patients (n = 107) was 7.4 g/dL, and most (74%, n = 79) presented to the emergency department or via inpatient transfer. Symptomatic IDA was treated with blood transfusion in 46 (43%, n = 46). Ferrous sulfate was the most commonly prescribed oral iron therapy. Seven patients received intravenous iron therapy either initially or after oral iron treatment failure. Combined oral contraceptives were commonly prescribed for abnormal uterine bleeding, yet 10% of patients (n = 11) received no hormonal therapy during their initial management. Evaluation for underlying bleeding disorders was inconsistent. Conclusion Severe anemia because of IDA and HMB resulting in urgent medical care, including hospitalization and blood transfusion, is a common but underemphasized problem in adolescent girls. In addition to prevention and early diagnosis, meaningful efforts to improve initial management of adolescents with severe HMB and IDA are necessary.

We describe Hb Alcorn County, a heterozygous hemoglobin (Hb) variant, in a 6-month-old Hispanic male and his mother. DNA sequencing demonstrated a mutation on the

Infantile myofibromatosis (IM) is most commonly limited to cutaneous lesions that resolve spontaneously. However, generalized IM with visceral involvement, which has a reported mortality rate as high as 73%, has been successfully treated with a combination of methotrexate and vinblastine. Here we report the further efficacy of low-dose methotrexate and vinblastine in 2 pediatric patients with IM and visceral involvement and review the literature describing chemotherapy for these patients.

BACKGROUND AND OBJECTIVE: Time to opioid administration (TTO) has been suggested as a quality of care measure for sickle cell disease patients with vaso-occlusive crisis (VOC). We sought to determine whether TTO was associated with outcomes of emergency department (ED) visits for VOC. METHODS: We conducted a single-center retrospective cohort study of ED visits for VOC. The primary outcome was hospital admission, with secondary outcomes of change between the first 2 pain scores, area under the curve (AUC) for pain scores at 4 hours (pain score AUC), total ED length of stay, and total intravenous opioids. In both univariate and multivariate analyses, mixed regression (logistic for admission, linear for secondary outcome variables) was used to evaluate association of TTO with outcome. RESULTS: In 177 subjects, 414 ED visits for VOC were identified. Inpatient admission occurred in 53% of visits. The median TTO for admitted patients was 86 minutes vs 87 minutes for those not admitted. TTO was not associated with inpatient admission in either univariate or multivariate analyses. In multivariate analyses with secondary outcomes, decreased TTO was associated with greater improvement between the first 2 pain scores, decreased pain score AUC, decreased total ED length of stay, and increased total opioids. CONCLUSIONS: Although TTO was not associated with admission, it was independently associated with 4 important secondary outcomes: change in initial pain scores, pain score AUC, total ED length of stay, and total intravenous opioids. The association of a process measure, TTO, with these outcomes encourages the institution of TTO reduction efforts in the ED.

Background Iron deficiency anemia (IDA) is the most common hematologic condition in children and adolescents in the United States (US). No prior reports have described the management of IDA by a large cohort of pediatric hematology/oncology specialists. Procedure A 20-question electronic survey that solicited responses to two hypothetical cases of IDA was sent to active members of the American Society of Pediatric Hematology/Oncology (ASPHO) in the US. Results Of 1,217 recipients, 398 (32.7%) reported regularly treating IDA and completed the survey. In a toddler with nutritional IDA, 15% (N = 61) of respondents reported ordering no diagnostic test beyond a complete blood count. Otherwise, wide variability in laboratory testing was reported. For treatment, most respondents would prescribe ferrous sulfate (N = 335, 84%) dosed at 6 mg/kg/day (N = 248, 62%) divided twice daily (N = 272, 68%). The recommended duration of iron treatment after resolution of anemia and normalized serum ferritin varied widely from 0 to 3 months. For an adolescent with heavy menstrual bleeding and IDA, most respondents recommended ferrous sulfate (N = 327, 83%), with dosing based on the number of tablets daily. For IDA refractory to oral treatment, intravenous iron therapy was recommended most frequently, 48% (N = 188) using iron sucrose, 17% (N = 68) ferric gluconate, and 15% (N = 60) low molecular weight iron dextran. Conclusion The approach to diagnosis and treatment of IDA in childhood was widely variable among responding ASPHO members. Given the lack of an evidence base to guide clinical decision making, further research investigating IDA management is needed. Pediatr Blood Cancer 2015;62:842–846. © 2015 Wiley Periodicals, Inc.

Limited high-quality evidence supports the management of iron deficiency anemia (IDA). To assess our institutional performance in this area, we retrospectively reviewed IDA treatment practices in 195 consecutive children referred to our center from 2006 to mid-2010. The majority of children were ≤4 years old (64%) and had nutritional IDA (74%). In 11- to 18-year-old patients (31%), the primary etiology was menorrhagia (42%). Many were referred directly to the emergency department and/or prescribed iron doses outside the recommended range. Poor medication adherence and being lost-to-follow-up were common. Substantial improvements are required in the management of IDA.

Iron-deficiency anemia (IDA) affects millions of persons worldwide, and is associated with impaired neurodevelopment in infants and children. Ferrous sulfate is the most commonly prescribed oral iron despite iron polysaccharide complex possibly being better tolerated.To compare the effect of ferrous sulfate with iron polysaccharide complex on hemoglobin concentration in infants and children with nutritional IDA.Double-blind, superiority randomized clinical trial of infants and children aged 9 to 48 months with nutritional IDA (assessed by history and laboratory criteria) that was conducted in an outpatient hematology clinic at a US tertiary care hospital from September 2013 through November 2015; 12-week follow-up ended in January 2016.Three mg/kg of elemental iron once daily as either ferrous sulfate drops or iron polysaccharide complex drops for 12 weeks.Primary outcome was change in hemoglobin over 12 weeks. Secondary outcomes included complete resolution of IDA (defined as hemoglobin concentration11 g/dL, mean corpuscular volume70 fL, reticulocyte hemoglobin equivalent25 pg, serum ferritin level15 ng/mL, and total iron-binding capacity425 μg/dL at the 12-week visit), changes in serum ferritin level and total iron-binding capacity, adverse effects.Of 80 randomized infants and children (median age, 22 months; 55% male; 61% Hispanic white; 40 per group), 59 completed the trial (28 [70%] in ferrous sulfate group; 31 [78%] in iron polysaccharide complex group). From baseline to 12 weeks, mean hemoglobin increased from 7.9 to 11.9 g/dL (ferrous sulfate group) vs 7.7 to 11.1 g/dL (iron complex group), a greater difference of 1.0 g/dL (95% CI, 0.4 to 1.6 g/dL; P .001) with ferrous sulfate (based on a linear mixed model). Proportion with a complete resolution of IDA was higher in the ferrous sulfate group (29% vs 6%; P = .04). Median serum ferritin level increased from 3.0 to 15.6 ng/mL (ferrous sulfate) vs 2.0 to 7.5 ng/mL (iron complex) over 12 weeks, a greater difference of 10.2 ng/mL (95% CI, 6.2 to 14.1 ng/mL; P .001) with ferrous sulfate. Mean total iron-binding capacity decreased from 501 to 389 μg/dL (ferrous sulfate) vs 506 to 417 μg/dL (iron complex) (a greater difference of -50 μg/dL [95% CI, -86 to -14 μg/dL] with ferrous sulfate; P .001). There were more reports of diarrhea in the iron complex group than in the ferrous sulfate group (58% vs 35%, respectively; P = .04).Among infants and children aged 9 to 48 months with nutritional iron-deficiency anemia, ferrous sulfate compared with iron polysaccharide complex resulted in a greater increase in hemoglobin concentration at 12 weeks. Once daily, low-dose ferrous sulfate should be considered for children with nutritional iron-deficiency anemia.clinicaltrials.gov Identifier: NCT01904864.

Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care.In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04).Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Congenital dyserythropoietic anemias (CDA) are rare hereditary diseases of abnormal erythropoiesis. The CDA Registry of North America (CDAR) (NCT02964494) was opened in 2016 to investigate the natural history and molecular biology of CDA. CDA type I (CDA-I) is a recessive form of CDA characterized by macrocytic anemia, hemolysis with inadequate reticulocytosis, and iron overload. The bone marrow shows binucleated erythroblasts with chromatin bridges by light microscopy and spongy heterochromatin in erythroblasts by electron microscopy. The phenotypic heterogeneity in presentation and course of CDA-I is remarkable. Most CDA-I cases are caused by biallelic mutations in CDAN1or C15orf41, and 10-20% do not have an identifiable mutation. Non-hematological features, especially skeletal features, were historically reported in 10-20% of patients (Wickramasinghe, 1998). Due to the rarity of CDA-I and its clinical overlap with several disorders, the diagnosis is often missed or delayed by up to 17 yrs (median) (Roy, 2019). We describe in this study the characteristics and clinical course of CDA-I patients due to CDAN1 mutations enrolled in CDAR. Patients with a phenotypic diagnosis of CDA and their family members were enrolled in CDAR. Clinical and demographic data were gathered from participants at study entry and updated periodically thereafter. Participants elect to give blood, bone marrow, and DNA samples to the biorepository associated with CDAR. Participants with a phenotypic diagnosis of CDA-I and confirmed mutations in CDAN1 were included in this study. Six participants had a diagnosis of CDA-I due to biallelic CDAN1 mutations, comprising 18% (6/33) of affected CDAR participants. CDAN1 mutations were found in 75% of cases diagnosed phenotypically as CDA-I. All six participants presented early in life with a variable degree of non-immune hemolysis, and the diagnosis was confirmed within a median of 2 years from presentation. The characteristics of participants are summarized in table 1. Two had family history of stillbirth or fetal demise in older siblings due to hydrops fetalis. One participant presented prenatally with fetal anemia and started intrauterine transfusions at 24 weeks of gestation; 2 presented with severe anemia and signs of hydrops, pulmonary hypertension, transaminitis, severe hyperbilirubinemia, and thrombocytopenia at birth; and 3 presented with neonatal jaundice and moderate anemia. All participants required blood transfusions in the neonatal period. Three had spontaneous improvement and did not require transfusions after the first year of life. One remained transfusion-dependent at last follow up at the age of 4 yrs. One became transfusion-independent after starting interferon-alpha at 1 yr of age and did not need further transfusions even after discontinuation at 3 yrs of age. One had splenectomy at 11 y.o because he was misdiagnosed to have a membrane disorder but presented in adulthood with hemolytic anemia and pulmonary hypertension and was diagnosed at that time with CDA-I by genetic sequencing. All participants had one or more non-hematological manifestations, including hypertrophic skin folds, onychocryptosis, curved toenails, syndactyly, café-au-lait spots, macrocephaly, spinal fusion, scoliosis, and short stature. One participant suffered a thalamic stroke in the postnatal period, 2 had transient neonatal pulmonary hypertension in the setting of severe anemia, and one had pulmonary hypertension post-splenectomy in adulthood. Ferritin was high in all participants at last follow up, and 4 received chelation therapy. In summary, mutations in CDAN1 are the most common identified mutations in CDAR. CDA-I causes early-onset macrocytic anemia, which may present prenatally, with variable severity of hemolysis ranging from hydrops to mild neonatal jaundice and anemia. Non-hematological manifestations, mainly skeletal, nail and skin abnormalities are more common in CDA-I than previously reported, and their presence in infants with unexplained anemia should raise suspicion for the diagnosis. The availability of molecular testing has significantly accelerated the diagnosis. Management of patients with CDA-I requires multidisciplinary approach from an early age to improve outcome. Collaboration between clinicians, scientists, patients, and families is needed to advance the understanding and treatment of this rare disease. Disclosures Chonat: Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kalfa:Agios: Other: local PI of clinical research trial; FORMA: Other: sponsored research agreement.

Introduction: A serious complication in hemophilia A is the formation of inhibitors to clotting factors. The primary means for eradicating inhibitors is immune tolerance induction (ITI) therapy. Antihemophilic factor (human) (Koate®-DVI) is a purified dried concentrate indicated for the treatment of hemophilia A with insufficient activity of Factor VIII (FVIII). Although other plasma-derived concentrates containing von Willebrand factor have been utilized successfully for ITI, studies evaluating this product for ITI therapy have not been published. An evaluation of patient- and treatment-related factors associated with outcomes following primary or rescue ITI with antihemophilic factor (human) in patients with hemophilia A and inhibitors was conducted in this retrospective multicenter chart review project. Methods: An evaluation of medical records of 13 inhibitor patients treated with antihemophilic factor (human) for primary or rescue ITI therapy between January 1, 2012, and July 31, 2017, was conducted in five US hemophilia treatment centers. To be eligible for inclusion, patients were required to have a diagnosis of hemophilia A of any severity level, inhibitor to FVIII at the time of treatment initiation with antihemophilic factor (human), and ongoing treatment with antihemophilic factor (human) for primary or rescue ITI. Data were de-identified and analyzed descriptively. Outcome measures were defined, per the International Immune Tolerance consensus recommendations, as "complete success" (inhibitor titer 5 BU mL), or "failure" (neither complete nor partial success). Results: All (N=13) patients who met the inclusion criteria were males with severe hemophilia, with the exception of one with moderate hemophilia. Six patients were African American, four were Hispanic, two Caucasian, and one was Asian. They were diagnosed with inhibitors between the ages of 8 months and 39 years and were 5 to 53 years old upon ITI with antihemophilic factor (human). Ten of 13 patients (76.9%) had successful ITI; seven with complete success and three with partial success (Table). Three patients failed ITI. As primary therapy, complete success was obtained with all but one of the six patients treated with antihemophilic factor (human). These six patients were all older than 7 at the initiation of ITI, a risk factor for poor ITI. Seven of the 13 total patients had a combined previous 12 attempts at ITI with other products (plasma derived and/or recombinant). Of these seven rescue patients, ITI with antihemophilic factor (human) was completely successful in two and partially successful in three. Adverse events reported once in separate patients during treatment with antihemophilic factor (human) included catheter infection, portal infection, bacteremia, peritonitis due to a ruptured appendix, and complications in treatment. One patient had several adverse events, including cellulitis at the port site, abdominal wall hematoma, right thumb fracture and hematoma, and left shoulder hemarthrosis. Conclusions: While retrospective data has limitations, real-world evidence demonstrates that ITI with antihemophilic factor (human) concentrate can be successful or partially successful in diverse populations of moderately complex patients with hemophilia A and inhibitors. The data suggest that antihemophilic factor (human) may be most appropriate for patients when used as primary ITI, as even patients older than 7 years achieved complete success. Additional patients need to be evaluated to make a definitive conclusion regarding the impact of age on success of ITI therapy in addition to other risk factors. Disclosures Escobar: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rajan:Bayer, Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Amega:Kedrion Biopharma: Employment. OffLabel Disclosure: Koate is not approved to treat vWD, nor, cTTP however, based on some published reports using kotae for these indications, we are anticipating those type of off label inquiries. I will clearly disclose to the participants that these are off label indications.

Background Existing therapies for recurrent or refractory histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Rosai-Dorfman disease (RDD), have limited effectiveness. We report our experience with using clofarabine as therapy in children with recurrent or refractory histiocytic disorders, including LCH (11 patients), systemic JXG (4 patients), and RDD (3 patients).

Background Sickle cell disease (SCD) is an inherited blood disorder characterized by a chronic hemolytic anemia that can contribute to fatigue and global cognitive impairment in patients. The study objective was to report on the feasibility, reliability, and validity of the PedsQL™ Multidimensional Fatigue Scale in SCD for pediatric patient self-report ages 5–18 years and parent proxy-report for ages 2–18 years.

Background Iron deficiency anemia (IDA) in children is usually treated with oral iron, yet many respond poorly. Intravenous low molecular weight iron dextran (LMWID) offers the opportunity of employing a single outpatient infusion to correct the anemia and reduce the overall burden of treatment, but its use in children has been limited due to concerns of serious adverse effects. In this study we report our initial experience using LMWID in children with iron deficiency in whom oral iron was ineffective. Methods We performed a case series of LMWID treatment of children with IDA of diverse etiologies who were poorly responsive to oral iron therapy with the aim of measuring its efficacy and adverse effects. LMWID was administered as a total dose infusion over 60 minutes in the outpatient setting. Results Thirty-one patients age 11 months to 18 years received intravenous LMWID, and 24 were evaluable for hematologic response. Median hemoglobin increments were respectively 3.5, 1.9, and 1.8 g/dl in patients with IDA due to poor nutrition (n = 11), chronic blood loss (n = 13), and miscellaneous causes (n = 7). Two thirds of evaluable patients had a complete hematologic response. Nine of the patients (29%) had mild non-specific adverse effects upon initiation of the LMWID infusion. Conclusions LMWID as a total dose infusion was well tolerated and effective in a heterogeneous group of children and adolescents with IDA who were refractory to oral iron therapy. Transient reactions were common but not serious. Pediatr Blood Cancer 2013;60:1747–1752. © 2013 Wiley Periodicals, Inc.

Background Many academic hospitals have incorporated family-centered rounds, yet little is known about pediatrics residents' perspectives on the educational impact of these rounds. Objective To identify pediatrics residents' knowledge, attitudes, and beliefs about family-centered rounds, including perceived benefits and barriers. Methods We conducted focus groups of residents exposed to family-centered rounds at 2 university-affiliated, freestanding children's hospitals. Focus group data were analyzed using grounded theory. Results A total of 24 residents participated in 4 focus groups. Residents reported that family-centered rounds enhance education by increasing patient encounters and improving physical exam skills, direct observation, real-time feedback, and attending role modeling; improve parent satisfaction, interpersonal and communication skills, and safety; and reduce length of stay. Physical constraints (large teams and small rooms), lack of uniform approaches to family-centered rounds, variable attending teaching styles, and specific conditions (child abuse, patients on isolation) were cited barriers. Conclusions Pediatrics residents report that well-conducted family-centered rounds improve their education and the quality of patient care, including parent satisfaction, communication with families, and patients' length of stay. Standardizing family-centered rounds and reducing attending variability in teaching style might further enhance residents' educational experiences.

Background Sickle cell disease (SCD) is an inherited chronic disease that is characterized by complications such as recurrent painful vaso-occlusive events that require frequent hospitalizations and contribute to early mortality. The objective of the study was to report on the initial measurement properties of the new PedsQL™ SCD Module for pediatric patient self-report ages 5–18 years and parent proxy-report for ages 2–18 years. Procedure The 43-item PedsQL™ SCD Module was completed in a multisite study by 243 pediatric patients with SCD and 313 parents. Participants also completed the PedsQL™ 4.0 Generic Core Scales and PedsQL™ Multidimensional Fatigue Scale. Results The PedsQL™ SCD Module Scales evidenced excellent feasibility, excellent reliability for the Total Scale Scores (patient self-report α = 0.95; parent proxy-report α = 0.97), and good reliability for the nine individual scales (patient self-report α = 0.69–0.90; parent proxy-report α = 0.83–0.97). Intercorrelations with the PedsQL™ Generic Core Scales and PedsQL™ Multidimensional Fatigue Scales were medium (0.30) to large (0.50) range, supporting construct validity. PedsQL™ SCD Module Scale Scores were generally worse for patients with severe versus mild disease. Confirmatory factor analysis demonstrated an acceptable to excellent model fit. Conclusions The PedsQL™ SCD Module demonstrated acceptable measurement properties. The PedsQL™ SCD Module may be utilized in the evaluation of SCD-specific health-related quality of life in clinical research and practice. In conjunction with the PedsQL™ Generic Core Scales and the PedsQL™ Multidimensional Fatigue Scale, the PedsQL™ SCD Module will facilitate the understanding of the health and well-being of children with SCD. Pediatr Blood Cancer 2013;60:1338–1344. © 2013 Wiley Periodicals, Inc.

published reports describe quality improvement initiatives designed to decrease TTA in pediatric patients with FN. Underly- ing these reports is the unstated assumption that decreased TTA is associated with improved outcomes of pediatric patients with FN (16-18). Therefore, we sought to test this assumption and deter- mine whether TTA is associated with outcomes of FN in the setting of pediatric cancer. We hypothesized that prolonged TTA would be associated with poor outcomes in FN. Background. Time-to-antibiotic (TTA) administration is a widely used quality-of-care measure for children with cancer and febrile neutropenia (FN). We sought to determine whether TTA is associat- ed with outcomes of FN. Procedure. A single-center, retrospective cohort study was conducted of 1,628 FN admissions from 653 patients from 2001 to 2009. Outcome variables included (1) an adverse event (AE) composite of in-hospital mortality, pediatric intensive care unit (PICU) admission within 24 hours of presenta- tion, and/or fluid resuscitation � 40 ml/kg within 24 hours of pre- sentation and (2) length of stay (LOS). TTA was measured as a continuous variable and in 60-minute intervals. Mixed regression models were constructed to evaluate associations of TTA with the outcome variables after adjusting for relevant covariates including cancer diagnosis, degree of myelosuppression, and presence of bacteremia. Results. The composite AE outcome occurred in 11.1% of admissions including 0.7% in-hospital mortality, 4.7% PICU admission, and 10.1% fluid resuscitation. In univariate analy- sis, TTA was associated with the composite AE outcome (Odds Ratio (OR) 1.29, 95% CI 1.02-1.64) but not LOS. In multivariate analysis, after adjustment for relevant covariates, 60-minute TTA intervals were associated with the composite AE outcome (61- 120 minutes vs. � 60 minutes, OR 1.81, 95% CI 1.01-3.26). Unex- pectedly, admission from the emergency department (ED) was also independently associated with the composite AE outcome (ED vs. clinic, OR 3.15, 95% CI 1.95-5.09). Conclusions. TTA and presen- tation to the ED are independently associated with poor outcomes of FN. Pediatr Blood Cancer 2013;60:1299-1306. 2013 Wiley Periodicals, Inc.

Objective To assess the benefits and risks of intravenous (IV) ferric carboxymaltose (FCM) in children with iron deficiency anemia (IDA). Study design In a retrospective cohort study of patients seen at our center, we identified all FCM infusions in children with IDA over a 12-month period through a query of pharmacy records. Clinical data, including hematologic response and adverse effects, were extracted from the electronic medical record. Results A total of 116 IV FCM infusions were administered to 72 patients with IDA refractory to oral iron treatment (median age, 13.7 years; range, 9 months to 18 years). Median preinfusion and postinfusion hemoglobin values were 9.1 g/dL and 12.3 g/dL, respectively (at 4-12 weeks after the initial infusion; n = 53). Sixty-five patients (84%) experienced no adverse effects. Minor transient complications were encountered during or immediately after 7 infusions. Conclusion FCM administered as a short IV infusion without a test dose proved to be safe and highly effective in a small yet diverse population of infants, children, and adolescents with IDA refractory to oral iron therapy.

Background The success of primary stroke prevention for children with sickle cell disease (SCD) throughout the United States is unknown. Therefore, we aimed to generate national incidence rates of hospitalization for stroke in children with sickle cell disease (SCD) before and after publication of the Stroke Prevention Trial in Sickle Cell Anemia (STOP trial) in 1998.

Objective To estimate national hospitalization rates for invasive pneumococcal disease (IPD) in children with sickle cell disease (SCD) before and after the 2000 licensure of the heptavalent pneumococcal conjugate vaccine (PCV7). Procedure We performed a retrospective trend analysis of the 1994–2007 Nationwide Inpatient Sample databases. Hospitalizations involving children with SCD and IPD were identified by ICD-9CM code. The primary outcomes, the annual hospitalization rate for IPD in children with SCD and the proportion of hospitalizations for IPD per 100 total SCD hospitalizations, were analyzed using multivariable linear regression and contingency analysis, respectively. Results A total of 1,242 hospitalizations for IPD in SCD patients were identified from 1994–2007, with a mortality rate of 2.4%. The national mean annual rate of IPD hospitalization decreased by 65%, from 131.8 cases/year from 1994 to 2000 to 45.5 cases/year from 2001 to 2007 (P = 0.001). The national proportion of hospitalizations for IPD per 100 total SCD hospitalizations decreased from 0.4 to 0.15 (P

Sickle cell disease (SCD) affects 70,000–100,000 people in the United States, accounting for nearly 100,000 hospitalizations annually [1]. In 2004, the average cost per SCD hospitalization was $6,223, with an estimated aggregate cost of $488 million [1]. Despite the large number and cost of hospitalizations in SCD patients, the quality of care (QOC) for these hospitalizations has not been studied sufficiently. In other medical conditions, frequently studied factors associated with QOC-related outcomes are hospital volume, hospital teaching status, patient socioeconomic status (SES), and patient insurance coverage. Most published reports have demonstrated that higher hospital volumes are associated with improved QOC, [2] an association first established in the surgical literature [3]. More recently, the association of hospital volume and outcomes has been reported for several medical conditions, including acute myocardial infarction (AMI) [4] and HIV/AIDS [5]. Similarly, lower SES and lack of health insurance have been consistently associated with poorer QOC [6–9]. The only published report investigating SES in SCD found no association between indirect SES markers and QOC-related outcomes in children [10]. The association between teaching status and QOC has been inconsistent [11]. To our knowledge, no prior study has investigated the effects of multiple potential determinants of QOC on QOC-related outcomes in SCD. We hypothesized that higher hospital volumes, specifically greater volume of SCD hospitalizations, are associated with improved QOC outcomes.

The survival of young children with sickle cell disease (SCD) has improved, but less is known about older children and adolescents. We studied the Dallas Newborn Cohort (DNC) to estimate contemporary 18-year survival for newborns with SCD and document changes in the causes and ages of death over time. We also explored whether improvements in the quality of medical care were temporally associated with survival. The DNC now includes 940 subjects with 8857 patient-years of follow-up. Most children with sickle cell anemia (93.9%) and nearly all children with milder forms of SCD (98.4%) now live to become adults. The incidence of death and the pattern of mortality changed over the duration of the cohort. Sepsis is no longer the leading cause of death. All the recent deaths in the cohort occurred in patients 18 years or older, most shortly after the transition to adult care. Quality of care in the DNC has improved over time, with significantly more timely initial visits and preventive interventions for young children. In summary, most children with SCD now survive the childhood years, but young adults who transition to adult medical care are at high risk for early death.

Limited high-quality evidence supports the management of iron deficiency anemia (IDA). To assess our institutional performance in this area, we retrospectively reviewed IDA treatment practices in 195 consecutive children referred to our center from 2006 to mid-2010. The majority of children were ≤4 years old (64%) and had nutritional IDA (74%). In 11- to 18-year-old patients (31%), the primary etiology was menorrhagia (42%). Many were referred directly to the emergency department and/or prescribed iron doses outside the recommended range. Poor medication adherence and being lost-to-follow-up were common. Substantial improvements are required in the management of IDA.

Time-to-antibiotic administration (TTA) has been suggested as a quality-of-care (QOC) measure for pediatric oncology patients with febrile neutropenia (FN). Unknown, however, is to what extent pediatric oncology centers utilize TTA. Therefore, we designed and administered an electronic survey (68% response rate) of programs in the Children's Oncology Group to assess TTA utilization. Nearly half of respondents track TTA. Most reported using a benchmark of less than 60 minutes from arrival. TTA is a commonly used QOC measure for pediatric FN despite an absence of studies establishing its validity and a lack of data supporting its impact on outcomes of FN.

Iron deficiency anemia (IDA) is the most common hematologic condition in children and adolescents in the United States (US). No prior reports have described the management of IDA by a large cohort of pediatric hematology/oncology specialists.A 20-question electronic survey that solicited responses to two hypothetical cases of IDA was sent to active members of the American Society of Pediatric Hematology/Oncology (ASPHO) in the US.Of 1,217 recipients, 398 (32.7%) reported regularly treating IDA and completed the survey. In a toddler with nutritional IDA, 15% (N = 61) of respondents reported ordering no diagnostic test beyond a complete blood count. Otherwise, wide variability in laboratory testing was reported. For treatment, most respondents would prescribe ferrous sulfate (N = 335, 84%) dosed at 6 mg/kg/day (N = 248, 62%) divided twice daily (N = 272, 68%). The recommended duration of iron treatment after resolution of anemia and normalized serum ferritin varied widely from 0 to 3 months. For an adolescent with heavy menstrual bleeding and IDA, most respondents recommended ferrous sulfate (N = 327, 83%), with dosing based on the number of tablets daily. For IDA refractory to oral treatment, intravenous iron therapy was recommended most frequently, 48% (N = 188) using iron sucrose, 17% (N = 68) ferric gluconate, and 15% (N = 60) low molecular weight iron dextran.The approach to diagnosis and treatment of IDA in childhood was widely variable among responding ASPHO members. Given the lack of an evidence base to guide clinical decision making, further research investigating IDA management is needed.

Treatment of vaso-occlusive crises (VOC) or events in sickle cell disease (SCD) remains limited to symptom relief with opioids. Animal models support the effectiveness of the pan-selectin inhibitor GMI-1070 in reducing selectin-mediated cell adhesion and abrogating VOC. We studied GMI-1070 in a prospective multicenter, randomized, placebo-controlled, double-blind, phase 2 study of 76 SCD patients with VOC. Study drug (GMI-1070 or placebo) was given every 12 hours for up to 15 doses. Other treatment was per institutional standard of care. All subjects reached the composite primary end point of resolution of VOC. Although time to reach the composite primary end point was not statistically different between the groups, clinically meaningful reductions in mean and median times to VOC resolution of 41 and 63 hours (28% and 48%, P = .19 for both) were observed in the active treatment group vs the placebo group. As a secondary end point, GMI-1070 appeared safe in acute vaso-occlusion, and adverse events were not different in the two arms. Also in secondary analyses, mean cumulative IV opioid analgesic use was reduced by 83% with GMI-1070 vs placebo (P = .010). These results support a phase 3 study of GMI-1070 (now rivipansel) for SCD VOC. This trial was registered at www.clinicaltrials.gov as #NCT01119833.

Patients with sickle cell disease (SCD) have an increased risk of invasive bacterial infection because of hyposplenism. Bordetella holmesii is a recently described Gram-negative coccobacillus with an apparent predilection for asplenic hosts. We report two patients with SCD and B. holmesii bacteremia. Fastidious growth in culture and a typically uncomplicated clinical course distinguish B. holmesii infection from other invasive bacterial infections in SCD. Providers for patients with SCD should be aware of this pathogen and ensure that their microbiology laboratories are capable of isolating and identifying this organism.

Existing therapies for recurrent or refractory histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Rosai-Dorfman disease (RDD), have limited effectiveness. We report our experience with using clofarabine as therapy in children with recurrent or refractory histiocytic disorders, including LCH (11 patients), systemic JXG (4 patients), and RDD (3 patients).Patients treated with clofarabine for LCH, JXG, or RDD by Texas Children's Hospital physicians or collaborators between May 2011 and January 2013 were reviewed for response and toxicity.Patients were treated with a median of three chemotherapeutic regimens prior to clofarabine. Clofarabine was typically administered at 25 mg/m(2) /day for 5 days. Cycles were administered every 28 days for a median of six cycles (range: 2-8 cycles). Seventeen of 18 patients are alive. All surviving patients showed demonstrable improvement after two to four cycles of therapy, with 11 (61%) complete responses, 4 (22%) partial responses, and 2 patients still receiving therapy. Five patients experienced disease recurrence, but three of these subsequently achieved complete remission. All patients with JXG and RDD had complete or partial response at conclusion of therapy. Side effects included neutropenia in all patients. Recurring but sporadic toxicities included prolonged neutropenia, severe vomiting, and bacterial infections.Clofarabine has activity against LCH, JXG, and RDD in heavily pretreated patients, but prospective multi-center trials are warranted to determine long-term efficacy, optimal dosing, and late toxicity of clofarabine in this population.

Iron deficiency anemia (IDA) in children is usually treated with oral iron, yet many respond poorly. Intravenous low molecular weight iron dextran (LMWID) offers the opportunity of employing a single outpatient infusion to correct the anemia and reduce the overall burden of treatment, but its use in children has been limited due to concerns of serious adverse effects. In this study we report our initial experience using LMWID in children with iron deficiency in whom oral iron was ineffective.We performed a case series of LMWID treatment of children with IDA of diverse etiologies who were poorly responsive to oral iron therapy with the aim of measuring its efficacy and adverse effects. LMWID was administered as a total dose infusion over 60 minutes in the outpatient setting.Thirty-one patients age 11 months to 18 years received intravenous LMWID, and 24 were evaluable for hematologic response. Median hemoglobin increments were respectively 3.5, 1.9, and 1.8 g/dl in patients with IDA due to poor nutrition (n = 11), chronic blood loss (n = 13), and miscellaneous causes (n = 7). Two thirds of evaluable patients had a complete hematologic response. Nine of the patients (29%) had mild non-specific adverse effects upon initiation of the LMWID infusion.LMWID as a total dose infusion was well tolerated and effective in a heterogeneous group of children and adolescents with IDA who were refractory to oral iron therapy. Transient reactions were common but not serious.

Sickle cell disease (SCD) is an inherited blood disorder characterized by a chronic hemolytic anemia that can contribute to fatigue and global cognitive impairment in patients. The study objective was to report on the feasibility, reliability, and validity of the PedsQL™ Multidimensional Fatigue Scale in SCD for pediatric patient self-report ages 5-18 years and parent proxy-report for ages 2-18 years.This was a cross-sectional multi-site study whereby 240 pediatric patients with SCD and 303 parents completed the 18-item PedsQL™ Multidimensional Fatigue Scale. Participants also completed the PedsQL™ 4.0 Generic Core Scales.The PedsQL™ Multidimensional Fatigue Scale evidenced excellent feasibility, excellent reliability for the Total Scale Scores (patient self-report α = 0.90; parent proxy-report α = 0.95), and acceptable reliability for the three individual scales (patient self-report α = 0.77-0.84; parent proxy-report α = 0.90-0.97). Intercorrelations of the PedsQL™ Multidimensional Fatigue Scale with the PedsQL™ Generic Core Scales were predominantly in the large (≥0.50) range, supporting construct validity. PedsQL™ Multidimensional Fatigue Scale Scores were significantly worse with large effects sizes (≥0.80) for patients with SCD than for a comparison sample of healthy children, supporting known-groups discriminant validity. Confirmatory factor analysis demonstrated an acceptable to excellent model fit in SCD.The PedsQL™ Multidimensional Fatigue Scale demonstrated acceptable to excellent measurement properties in SCD. The results demonstrate the relative severity of fatigue symptoms in pediatric patients with SCD, indicating the potential clinical utility of multidimensional assessment of fatigue in patients with SCD in clinical research and practice.

Time-to-antibiotic (TTA) administration is a widely used quality-of-care measure for children with cancer and febrile neutropenia (FN). We sought to determine whether TTA is associated with outcomes of FN.A single-center, retrospective cohort study was conducted of 1,628 FN admissions from 653 patients from 2001 to 2009. Outcome variables included (1) an adverse event (AE) composite of in-hospital mortality, pediatric intensive care unit (PICU) admission within 24 hours of presentation, and/or fluid resuscitation ≥ 40 ml/kg within 24 hours of presentation and (2) length of stay (LOS). TTA was measured as a continuous variable and in 60-minute intervals. Mixed regression models were constructed to evaluate associations of TTA with the outcome variables after adjusting for relevant covariates including cancer diagnosis, degree of myelosuppression, and presence of bacteremia.The composite AE outcome occurred in 11.1% of admissions including 0.7% in-hospital mortality, 4.7% PICU admission, and 10.1% fluid resuscitation. In univariate analysis, TTA was associated with the composite AE outcome (Odds Ratio [OR] 1.29, 95% CI 1.02-1.64) but not LOS. In multivariate analysis, after adjustment for relevant covariates, 60-minute TTA intervals were associated with the composite AE outcome (61-120 minutes vs. ≤ 60 minutes, OR 1.81, 95% CI 1.01-3.26). Unexpectedly, admission from the emergency department (ED) was also independently associated with the composite AE outcome (ED vs. clinic, OR 3.15, 95% CI 1.95-5.09).TTA and presentation to the ED are independently associated with poor outcomes of FN.

Background Since the publication of the Prophlyactic Penicillin Study II in 1995, the management of penicillin prophylaxis for children with sickle cell disease (SCD) after 5 years of age has been controversial. In this study, we sought to describe current practice patterns of pediatric hematologists related to cessation of penicillin prophylaxis for children with SCD after 5 years of age. Procedure We performed a cross-sectional, electronic survey of pediatric hematologists with expertise in SCD to examine practices regarding penicillin prophylaxis in children with SCD after 5 years of age. We also investigated factors potentially associated with continuation of penicillin prophylaxis using the Jonckheere–Terpstra test and Fisher's exact test. Results Of the 106 physicians surveyed from 76 centers, 84% completed the survey. Among respondents, 76% routinely recommended cessation of penicillin prophylaxis after 5 years of age. The practice of routinely continuing penicillin after 5 years of age was associated with decreased concern about antibiotic resistance in Streptococcus pneumoniae (P = 0.01), with the usage of prophylactic penicillin in mild SCD genotypes (sickle hemoglobin-C disease and sickle β+ thalassemia, P =

The success of primary stroke prevention for children with sickle cell disease (SCD) throughout the United States is unknown. Therefore, we aimed to generate national incidence rates of hospitalization for stroke in children with sickle cell disease (SCD) before and after publication of the Stroke Prevention Trial in Sickle Cell Anemia (STOP trial) in 1998.We performed a retrospective trend analysis of the 1993-2009 Nationwide Inpatient Sample and Kids' Inpatient Databases. Hospitalizations for SCD patients 0-18 years old with stroke were identified by ICD-9CM code. The primary outcome, the trend in annual incidence rate of hospitalization for stroke in children with SCD, was analyzed by linear regression. Incidence rates of hospitalization for stroke before and after 1998 were compared by the Wilcoxon rank-sum test.From 1993 to 2009, 2,024 hospitalizations were identified for stroke. Using the mean annual incidence rate of hospitalization for stroke from 1993 to 1998 as the baseline, the rate decreased from 1993 to 2009 (point estimate = -0.022/100 patient years [95% CI, -0.039, -0.005], P = 0.027). The mean annual incidence rate of hospitalization stroke decreased by 45% from 0.51 per 100 patient years in 1993-1998 to 0.28 per 100 patient years in 1999-2009 (P = 0.008). Total hospital days and charges attributed to stroke also decreased by 45% and 24%, respectively.After publication of the STOP trial and hydroxyurea licensure in 1998, the incidence of hospitalization for stroke in children with SCD decreased across the United States, suggesting that primary stroke prevention has been effective nationwide, but opportunity for improvement remains.

Background The standard first line therapy for iron deficiency anemia (IDA) is oral iron. Yet, many patients fail to respond to oral iron due to poor adherence and/or adverse effects. Intravenous (IV) iron is an effective means of treating IDA in patients with malabsorption of iron or who are non-adherent and/or experience adverse effects with oral iron. Some IV iron preparations carry an FDA-mandated black box warning and/or require a test dose or prolonged infusion. Ferric carboxymaltose (FCM, Injectafer®) is a relatively new IV iron preparation with demonstrated safety and efficacy in adults with IDA. The manufacturer recommended dosing is 15 mg/kg/dose (maximum 750 mg) x2 doses administered at least 7 days apart, and each individual infusion can be administered over 10 to 15 minutes, without the need for a test dose. Limited data exist on its use in children. Our objective was to assess the hematologic response and adverse effects of IV FCM in a diverse population of infants, children and adolescents with IDA who failed oral iron therapy. Method All children with IDA who received FCM at Children's Health from June 1, 2014 through June 10, 2015 were included. Subjects were identified via search of pharmacy records. All patients received at least one dose of FCM 15 mg/kg (maximum 750 mg) administered as a 15-minute IV infusion (without test dose or pre-medications). Patient characteristics, adverse effects and hematologic response were retrospectively collected from the electronic medical record. Results During the study frame, one hundred twenty-five infusions of FCM were administered to 87 patients (71% female) with a median age of 14 years (range 9 months to 20.8 years). The most common racial/ethnic group was Caucasian/White (Latino) at 45% followed by African American/Black and Caucasian/White (Non-Latino), each at 22%. The primary etiologies were heavy menstrual bleeding (38%), nutritional (24%), and GI bleeding and/or malabsorption (20%) with the remaining 18% representing other/mixed causes of IDA (e.g., inflammatory). The median dose administered during a single infusion was 750 mg (range 132 to 750 mg). No adverse effects were noted during or following the infusion in 77 subjects. Two patients had transient tingling, nausea and/or mild abdominal pain. Five others developed generalized pruritis and/or urticaria and received diphenhydramine and/or hydrocortisone, with prompt resolution. Two adolescents had more clinically significant reactions, 1 with nausea/vomiting post-infusion (likely psychogenic) requiring admission, and 1 with dyspnea 2 minutes into the infusion, requiring its immediate termination and administration of diphenhydramine, hydrocortisone and normal saline with prompt symptom resolution. One patient experienced asymptomatic extravasation during the second infusion which resulted in localized iron-staining of the skin. Median pre-infusion hemoglobin concentration for all patients was 9.1 g/dL (range 3.9 to 13.3 g/dL) (Table). A follow-up measurement was available for 76 patients at a median time of 6 weeks (range 1 to 30 weeks) post-initial infusion with a median hemoglobin increase of 3.3 g/dL (range -1.5 to 9.5 g/dL). Conclusion Intravenous FCM, administered in an outpatient infusion setting as one or two short IV infusions and without need for a test dose, was safe and effective in most children and adolescents with IDA refractory to oral iron therapy. Further clinical data are necessary to more fully characterize the extent of adverse effects in young patients. Prospective studies of IV FCM in children are indicated to assess clinical efficacy, including outcomes such as health related quality of life and fatigue. Table. *Hematologic Response to FCM Pre-Infusion **Post-Infusion Hemoglobin concentration (g/dL) All Etiologies, Pre (n=87), Post (n=76) Heavy menstrual bleeding, Pre (n=33), Post (n=26) Nutritional, Pre (n=21), Post (n=20) - 9.1 (3.9 to 13.3) 9.3 (4.2 to 13.3) 8.8 (4.9 to 12.2) - 12.2 (7.1 to 16) 12.7 (8.8 to 16) 12.2 (10.5 to 13.7) Mean corpuscular volume (fl), Pre (n=87), Post (n=76) 71.6 (49.5 to 97.4) 80.9 (53.3 to 102) Serum ferritin (ng/mL), Pre (n=80), Post (n=60) 5.2 (0.6 to 288.6) 115.7 (2.3 to 679.3) *Median laboratory values are reported. **Follow-up laboratory testing occurred at median time of 6 weeks (range 1 to 30 weeks) post-infusion. Disclosures Powers: Gensavis Pharmaceuticals, LLC: Research Funding. McCavit:Pfizer: Research Funding; Gensavis LLC: Research Funding; Novartis: Speakers Bureau. Adix:Gensavis Pharmaceuticals, LLC: Research Funding. Buchanan:Gensavis Pharmaceuticals, LLC: Research Funding.

Background Administrative data are increasingly used in sickle cell disease (SCD) research to study large numbers of patients at low cost. However, the validity of research with these data depends on the accuracy of administrative coding, which has been understudied in SCD. In particular, the validity of ICD-9CM coding for SCD's clinical hallmark, vaso-occlusive crisis (VOC), has not been reported. Therefore, we aim to describe the accuracy of ICD-9CM coding for VOC, acute chest syndrome (ACS), and acute splenic sequestration crisis (ASSC) in addition to SCD genotypes. Methods Administrative coding for all acute care visits (emergency department [ED], inpatient observation, and inpatient hospitalization) in SCD patients was captured for the 2013 calendar year at Children's Medical Center Dallas (CMCD) by query of administrative records. SCD visits were identified using the ICD-9CM codes 282.4x and 282.6x in the primary or any of 14 secondary code positions. From the administrative data, VOC was defined by the use of the "in crisis" codes (282.42, 282.62, 282.64, or 282.69). ACS was defined by 517.3 and ASSC by 289.52. Genotypes were defined as HbSS - 282.61 or 282.62; HbSC - 282.63 or 282.64; and HbS-BetaThal - 282.41 or 282.42. For the chart review, all visits were independently evaluated by two reviewers with the senior author settling disagreements. Previously-published consensus definitions were used for the complications of interest: VOC was defined as new onset of pain lasting at last 4 hours for which there is no other explanation; ACS was defined by new pulmonary infiltrate on chest X-ray with associated fever or respiratory symptoms; and ASSC was defined as splenic enlargement leading to anemia (hemoglobin >2g/dL under baseline), typically with thrombocytopenia. The primary reviewers and senior author evaluated 10 cases for the purpose of consensus-building before beginning data abstraction. Data capture included demographics and cause of the visit. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) of ICD-9CM coding for VOC, ACS, ASSC, and the SCD genotype were calculated. The LR+ and LR- were prevalence-weighted. Results From 448 patients, 1107 acute care visits were identified at CMCD in 2013. Patients had a median age of 8.2 years (range 0.1 - 33.9 years). Females accounted for 53% of visits. Inpatient hospitalization accounted for 374 visits (34%) whereas ED-only visits accounted for 681(61%) and inpatient observation 52 (5%). The prevalence of SCD genotypes included 69% HbSS, 19% HbSC, and 7% HbS-BetaThal. VOC, ACS, and ASSC were the "true cause" for 36% (n=402), 6% (n=68), and 1% (n=13) of acute care visits, respectively. The results of the primary analyses are displayed in the table. Agreement between reviewers for VOC and ACS was 91% (kappa = 0.80) and 99% (kappa = 0.92), respectively. When VOC was falsely coded (n=176), the most common true diagnoses were ACS (26%), fever (24%), chronic pain exacerbation (14%), and abdominal pain (10%). When ACS was falsely coded (n=21), VOC was the most common true diagnosis (71%). Of 25 (2.2%) patients incorrectly coded for SCD, 14 had sickle trait. Conclusions ICD-9CM coding for VOC demonstrated poor accuracy; however, coding for ACS and ASSC was remarkably sensitive and specific. Genotype coding lacked sensitivity with otherwise variable results. Unfortunately, coding for SCD in ICD-10 differs minimally from ICD-9CM. Therefore, these data provide an impetus to restructure ICD coding for SCD. Table 1. Sensitivity (95% CI) Specificity (95% CI) PPV(95% CI) NPV(95% CI) Postive Likelihood Ratio(95% CI) Negative Likelihood Ratio(95% CI) VOC 91.8(88.6-94.2) 75.0(71.6-78.2) 67.7(63.6-71.6) 94.1(91.8-95.9) 2.1(1.8-2.4) 0.06(0.04-0.08) ACS 92.6(83.0-97.3) 98.0(96.9-98.7) 75.0(64.1-83.5) 99.5(98.8-99.8) 3.0(2.0-4.4) 0.004(0.002-0.01) ASSC 92.3(62.1-99.6) 99.8(99.3-100.0) 85.7(56.2-97.5) 99.9(99.4-100.0) 6.0(1.6-22.0) 0.0009(0.0001-0.006) HbSS genotype 74.2(70.9-77.2) 67.7(62.5-72.6) 83.8(80.7-86.4) 53.8(49.0-58.6) 5.1 (4.2-6.1) 0.9(0.8-1.0) HbSC genotype 31.0(24.9-37.7) 99.6(98.8-99.9) 94.3(85.3-98.2) 85.8(83.5-87.9) 16.5(6.4-42.8) 0.16(0.14-0.19) HbS-BetaThalgenotype 57.1(45.4-68.2) 99.6(98.9-99.9) 91.7(79.1-97.3) 96.9(95.6-97.8) 11(4.3-28.2) 0.03(0.02-0.05) Disclosures McCavit: Pfizer: Research Funding; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Gensavis LLC: Research Funding; Pfizer: Research Funding.

[Graphic][1] Background Iron deficiency anemia (IDA) is prevalent in young children whose diet includes prolonged breast feeding without iron supplementation and/or excessive cow milk consumption. Oral iron therapy is recommended to correct the anemia and reconstitute iron stores, but few data exist to guide clinical decision-making. The recommended dosing of elemental iron has been inconsistent in the literature, ranging from 2 to 6 mg/kg/day, given one to three times daily. To address the paucity of treatment data, the BESTIRON study (Clinicaltrials.gov [NCT01904864][2]) was initiated to compare two liquid oral iron agents (ferrous sulfate and NovaFerrum, an iron polysaccharide) using a once daily, low-dose regimen. Methods This study is a single center, double-blinded, randomized controlled superiority trial. Inclusion criteria include: age 9 months to 4 years with nutritional IDA by history and laboratory indices (Hgb 425 mg/dL). Exclusion criteria include: evidence of blood loss, malabsorption, other cause of anemia, prematurity (gestational age 11 g/dL, MCV >70 fl, Ret He >25 pg, serum ferritin >15 ng/mL, and TIBC

To estimate national hospitalization rates for invasive pneumococcal disease (IPD) in children with sickle cell disease (SCD) before and after the 2000 licensure of the heptavalent pneumococcal conjugate vaccine (PCV7).We performed a retrospective trend analysis of the 1994-2007 Nationwide Inpatient Sample databases. Hospitalizations involving children with SCD and IPD were identified by ICD-9CM code. The primary outcomes, the annual hospitalization rate for IPD in children with SCD and the proportion of hospitalizations for IPD per 100 total SCD hospitalizations, were analyzed using multivariable linear regression and contingency analysis, respectively.A total of 1,242 hospitalizations for IPD in SCD patients were identified from 1994-2007, with a mortality rate of 2.4%. The national mean annual rate of IPD hospitalization decreased by 65%, from 131.8 cases/year from 1994 to 2000 to 45.5 cases/year from 2001 to 2007 (P = 0.001). The national proportion of hospitalizations for IPD per 100 total SCD hospitalizations decreased from 0.4 to 0.15 (P 0.0001) over the same interval. Following PCV7 licensure, the mean annual cumulative hospital days and cumulative hospital charges decreased nationally by 53% and 36%, respectively.In a national sample, PCV7 licensure is temporally associated with a nearly threefold reduction in IPD hospitalizations in children with SCD.

Invasive pneumococcal disease (IPD) in children with sickle cell disease has decreased with prophylactic penicillin, pneumococcal polysaccharide vaccine, and pneumococcal protein-conjugate vaccine usage. We report 10 IPD cases since pneumococcal protein-conjugate vaccine licensure, including a recent surge of non-vaccine serotypes. IPD continues to be a serious risk in sickle cell disease.

Background: The natural history of sickle cell disease (SCD) includes premature death. Advancements in care, such as penicillin prophylaxis, have made death during childhood uncommon. Prior survival estimates for adults with SCD have been limited by survival bias (subjects enrolled as adults) or the limitations of administrative data. No prior study has estimated survival for adults with SCD from a newborn cohort. Herein, we report an continued observation of subjects in the Dallas Newborn Cohort (DNC)1. Methods: The DNC is an inception cohort of patients with SCD defined by: (1) diagnosis by Texas newborn screening after October 31, 1983; (2) evaluation in the pediatric sickle cell program at UT Southwestern (UTSW) / Children’s Medical Center Dallas (CMCD); and (3) confirmation of SS, SC, Sβ0 or Sβ+ genotype. Patients followed at CMCD are transitioned to adult care before the 19th birthday. To identify transitioned patients or those lost to follow-up (LTFU), we reviewed the medical records at Parkland Memorial Hospital (PMH) and UTSW University Hospital (UH), the public and private hospitals affiliated with CMCD and the most common care-sites for transitioned patients. In addition, for patients no longer actively followed at CMCD, we queried the National Death Index (NDI). The NDI is a centralized database of death records obtained from all state vital statistic bureaus in the US and is maintained by the National Center for Health Statistics. As of our query in April 2014, deaths occurring from 1/1/79 - 12/31/11 were available in the NDI. Probabilistic matching is performed by the NDI to identify subjects using identifiers such as name, social security number, birthdate, gender, state of birth, and race. Patients who were LTFU or transitioned to adult care were censored at 12/31/11 or the date of their last clinical encounter, whichever occurred latest. Patients actively followed at CMCD, PMH, or UH were censored at 12/31/13. In addition to descriptive statistics, we constructed survival curves using the Kaplan-Meier method to evaluate overall survival and survival by genotype. Also, Cox Proportional Hazard modeling was used to assess genotype, baseline hemoglobin, baseline reticulocyte count (%), and baseline oxygen saturation as potential predictors of early mortality. To test the sensitivity of the NDI to identify deceased individuals, we submitted 36 known deaths from the cohort. Results: The DNC is now comprised of 1214 patients with 16,636 years of follow-up. The cohort is 49.2% female with a mean age, and duration of follow-up, of 13.2 years (Range 0.1 – 30.0 years). SCD genotypes included 60.5% HbSS, 30.6% HbSC, 6.8% HbSβ+, and 2.1% HbSβ0. Of the 1214 patients in the cohort, 511 were active in the pediatric program, 195 were in the pediatric age range but had moved or were LTFU, 238 were adults with 1 or more visits at PMH or UH, 234 were adults with no subsequent identifiable clinical encounters, and 36 were deceased. Of 36 known deaths submitted to the NDI, 34 were identified by their databases (94.4% sensitivity). Of the 606 patients who were LTFU or aged out of the pediatric program, only 10 were reported to have died by the NDI. One of them was confirmed to be erroneous because the patient had clinical encounters after the NDI-reported date of death. In addition to these 9 deaths in the NDI, 8 additional patients were known to have died as of 12/31/13, bringing the total number of deaths to 53 (4.3%). Of these, 21 (39.6%) have been identified since the last cohort update in 2007. Overall survival in the DNC to age 25 years was 91.4% (95% CI: 88.4%, 93.7%) for all members (Figure), 87.7% (95% CI: 83.3%, 91%) for those with HbSS or HbSβ0, and 98.6% (95% CI: 96.7%, 99.4%) for those with HbSC or HbSβ+. In univariate analysis, early mortality was associated with SS or Sβ0 genotypes (compared to HbSC or HbSβ+), lower baseline hemoglobin, and low baseline SpO2 but not gender or reticulocytes. In multivariate analysis, early mortality was associated with only lower baseline hemoglobin (Hazard Ratio 0.76 [95% CI 0.59, 0.98], P=0.037). Conclusions: These are the first modern estimates of survival into adulthood with an unbiased newborn cohort of SCD patients. Early mortality is associated with low baseline hemoglobin. Survival to age 20 remains excellent at 95% but the mortality rate appears to accelerate in early adulthood. Reference: 1. Quinn et al. Blood. 115(17):3447-52, 2010. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: The pan-selectin antagonist rivipansel (GMI-1070) reduced intravascular arrest of red/white blood cell aggregates and improved blood flow and survival in a mouse model of sickle cell disease vaso-occlusive crisis (SCD VOC). In a Phase 1 study of GMI-1070 infusion in SCD adults at steady state (not in VOC), GMI-1070 decreased markers of cellular activation including neutrophil integrins, platelet/neutrophil aggregates, soluble adhesion molecule concentration; and markers of hemostatic activation. Furthermore, in a randomized Phase 2 study of SCD patients, treatment of VOC with GMI-1070 improved clinical outcomes such as time to resolution of crisis, time to discharge, and IV opioid use. Herein we report on the effect of GMI-1070 on biomarkers of cellular and hemostatic cascade activation from this Phase 2 trial. Methods: Patients in VOC enrolled in a prospective, randomized multi-center double-blind Phase 2 trial, ages 12-60 with HbSS or HbSB0thalassemia were treated with GMI-1070 q12h or placebo, in addition to standard treatment per institutional practice, until resolution of VOC. Clinical outcomes and pharmacokinetics have been previously reported (ASH 2013 Abstracts 775, 776, and 2206). Biomarker blood samples were drawn prior to study drug, and on a sparse sampling basis at times starting 30 minutes after initial dose and continuing until 36 hours after the last dose. Analytes measured included: soluble adhesion molecules E-selectin (sEsel), P-selectin, L-selectin, intercellular adhesion molecules 1 and 3, vascular cell adhesion molecule-1; and tissue factor and thrombin-antithrombin complexes by ELISA. At some sites, surface expression of monocyte b2 integrins MAC-1 & LFA-1 and platelet-monocyte aggregates were also measured by flow cytometry. Comparisons were made between the GMI-1070 and placebo groups, and serial expression levels were compared over time. Subgroup analyses were performed by hydroxyurea (HU) use, age group, baseline WBC, and ‘responders' based on clinical outcomes. A mixed effect model was used to test the LS means difference at each time point and ANCOVA model was used to analyze the nadir, peak, and last dose values. Results: ELISA and flow cytometry samples were collected from 70 and 15 subjects, respectively. Soluble E-selectin levels were reduced for the group on GMI-1070 compared to placebo throughout hospitalization, and the differences were statistically significant at some time-points (Figure 1). Baseline sEsel levels were similar; but the peak, nadir, and level at last dose were all lower in the GMI-1070 group (Figure 2). Exploratory subgroup analysis by HU use, age group, response as measured by visual analog scale or opiate use, frequency of VOC in the past, and baseline white blood cell count revealed consistently lower sEsel levels in the GMI-1070 group. Many, but not all, of these differences reached statistical significance. Conclusion: GMI-1070 use during VOC resulted in consistent and significant reductions of sEsel, overall and in sub-groups as compared to placebo. These findings are consistent with the hypothesized effect of GMI-1070 on endothelial activation and/or apoptosis, mediated by inhibition of E-selectin, although an effect on sEsel clearance cannot be excluded. A Phase 3 study is planned to evaluate efficacy and safety of GMI-1070 as treatment for VOC. Soluble E-selectin concentrations may be useful as a biomarker of pharmacodynamic effect. Figure 1: sE-sel was reduced in the GMI-1070 group at all timepoints tested. Comparison to placebo for change from baseline over time is shown. *p Figure 2: Figure 2: sE-sel was similar at baseline between GMI-1070 and placebo groups; mean change was different for GMI-1070 compared to placebo at the nadir, peak, and last dose values. Change from baseline is shown. *p Disclosures Wun: GlycoMimetics: Research Funding; Pfizer: Steering Committee, Steering Committee Other; Emmaus Medical: Consultancy. Telen:GlycoMimetics: Research Funding; Pfizer: Consultancy; Dilaforette: Research Funding. Krishnamurti:GlycoMimetics: Research Funding. McCavit:GlycoMimetics: Research Funding; Pfizer: Consultancy. DeCastro:GlycoMimetics: Research Funding. Flanner:GlycoMimetics: Employment, Equity Ownership. Kuypers:GlycoMimetics: Research Funding. Larkin:GlycoMimetics: Research Funding. Rhee:GlycoMimetics: Consultancy. Magnani:GlycoMimetics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership.

Introduction Vaso-occlusive crisis (VOC) is the hallmark of sickle cell anemia (SCA), yet VOC treatment has not improved in decades. Recently the role of adhesive interactions between leukocytes, erythrocytes, and the vascular endothelium has been recognized in VOC. GMI 1070, a pan-selectin inhibitor, was designed to decrease the contribution of leukocyte adhesion to VOC. Herein, we report a sub-analysis of the pediatric patients enrolled in a study of GMI 1070 with the aims of determining the efficacy and toxicities in this subgroup and comparing pediatric to adult patients. Methods This multi-center, randomized, double-blind, placebo-controlled phase 2 trial enrolled afebrile patients ≥ 12 yrs with HbSS or HbSβ0 thalassemia presenting with VOC. Subjects had no organ dysfunction or other acute SCA complications. GMI 1070 was administered IV as a loading dose, then in up to 14 q12 h maintenance doses. Following a pre-specified interim PK analysis including 1 pediatric and 10 adult subjects, the loading and maintenance doses were doubled. Other management was at the discretion of the treating physician. Pain intensity was measured with a 10 cm visual analog scale. The primary outcome was time to resolution of VOC, defined as either a sustained 1.5 cm decrease in the pain score and cessation of IV analgesics; readiness for discharge; or hospital discharge. Secondary outcomes included time to discharge, time to transition from IV to oral analgesics, opioid usage, and safety profile. Median time-to-event was compared between arms using the Kaplan-Meier (KM) method. Analysis of covariance was used to compare the mean hourly opioid use, by hospital day. Results Seven sites enrolled 20 pediatric subjects: GMI 1070 - 13 vs placebo - 7. The median age was 14 years, and 40% were female. Time to 1st dose of study drug was a mean of 15 h from initial medical evaluation. Median length of stay was 105 h. The GMI 1070 arm had a 60.7 h reduction in the median time to resolution of VOC compared to placebo (Fig. 1a). Similarly, the median difference in time to transition to oral opioids and time to discharge were clinically significant between GMI 1070 and placebo at 87.8 h and 96 h, respectively (Fig. 1b & 1c). Mean hourly opioid use was lower with GMI 1070 than placebo in the first 24 h, but the trajectory thereafter did not differ (Fig. 1d). The effect of GMI 1070 on the primary and secondary outcomes was similar for pediatric and adult subjects (Table 1). Differences between pediatric and adult subjects included which opioid was used (pediatrics – 80% morphine vs adults – 80% hydromorphone). Also more pediatric subjects received IV antibiotics (Table 1), particularly in the first 24 hrs of study drug (pediatrics – 35% vs adults – 14%). The proportion of pediatric subjects experiencing a serious adverse event (SAE) was similar between arms (GMI 1070 – 31% vs placebo – 43%). Most SAE's were VOC recurrence; 1 SAE was an episode of acute chest syndrome (ACS) in the GMI 1070 arm (0 in the placebo arm). Of 4 total ACS events (1 SAE, 3 AE), 3 occurred within 24 h of 1st study drug, 1 required red blood cell transfusion and 0 required intensive care. No severe or unusual infections occurred in either arm. Conclusions GMI 1070 is a promising agent for reducing duration of VOC in SCA. Compared to adults, pediatric subjects demonstrated similar efficacy and safety. The ACS cases in the GMI 1070 arm are noteworthy but are not definitively associated with study drug. The strong efficacy signal in adolescents, along with minimal safety concerns, warrants inclusion of younger children in a subsequent phase 3 clinical trial of GMI 1070. Disclosures: McCavit: Pfizer, Inc.: Consultancy; GlycoMimetics, Inc.: Research Funding. Krishnamurti:GlycoMimetics, Inc.: Research Funding. Hsu:GlycoMimetics, Inc.: Research Funding. Quinn:Glycomimetics: Research Funding; Eli Lilly: Research Funding; MAST Therapeutics: Research Funding; American Society of Hematology: Advisory Committees, Advisory Committees Other, Honoraria. Odame:Glycomimetics: Research Funding. Alvarez:Glycomimetics: Research Funding. Driscoll:Glycomimetics: Research Funding. Smith-Whitley:GlycoMimetics, Inc: Research Funding. Rhee:Rho, Inc.: Employment; GlycoMimetics, Inc.: Research Funding. Wun:Emmaus, Inc.: Clinical Adjudication Committee Other; Pfizer, Inc.: Consultancy; GlycoMimetics: Research Funding. Telen:GlycoMimetics, Inc.: Research Funding; Dilaforette, NA: Research Funding; Pfizer, Inc.: Consultancy. Thackray:GlycoMimetics, Inc.: Employment, Equity Ownership.

Background Treatment for vaso-occlusive crisis (VOC) in sickle cell disease (SCD) remains supportive, focusing largely on symptom relief with opioids. Animal models have suggested a role for both red cell and leukocyte selectin-mediated adhesion in VOC, and the pan-selectin inhibitor GMI 1070 restored blood flow in a mouse model of VOC. We therefore explored safety and possible efficacy of GMI 1070 in patients with VOC. Methods This prospective, randomized multi-center double blind, adaptive Phase 2 study enrolled patients ages 12-60 yrs with HbSS or HbSβ0 thalassemia presenting with VOC. Patients were randomized 1:1, stratified by site. A loading dose of GMI 1070 to achieve steady state, followed by ≤14 subsequent doses, were given q 12 h. Other treatment was per institutional standard of care. The primary efficacy endpoint was resolution of VOC, defined as: 1.5 cm sustained decrease in visual analog scale (VAS) pain score from baseline and transition to oral analgesia; or documented readiness for discharge; or order for discharge. Pre-planned population PK was examined after 11 subjects, and dose was subsequently escalated, per protocol. Secondary endpoints included cumulative opioid use (morphine equivalent units [MEU]/kg) and adverse events. Differences by treatment were analyzed by ANCOVA (means, adjusted for age and sex) and Kaplan-Meier (KM, medians), stratified by age and dose. Results Seventy-six subjects were enrolled (ages 12-51; 45 F, 31 M). Drug dose was doubled to reach target nadir levels after interim PK analysis. All 76 patients reached the primary endpoint: 58 subjects continued study drug until criteria for resolution of VOC were met or the maximum number of doses were given; 18 discontinued drug for AEs, no improvement at day 5, or other reasons. In the primary efficacy analysis, reduction in mean time to VOC resolution was consistently observed in all treatment groups (pooled high and low dose GMI 1070, 103.6 h ± 20.9 (SE), n=43, vs placebo, 144.6 h ± 23.5, n=33, p=0.192). KM analysis showed median times to resolution of 69.6 h (CI 44.3, 115.5) for the GMI 1070 group vs 132.9 h (CI 67.0, 164.2) for the placebo group (p=0.187, Log-rank, Fig 1a). Thus, GMI 1070 resulted in differences in time to resolution of 41 h (mean) and 63 h (median). Similar differences were seen when analysis was stratified by age. Proportionally more subjects receiving GMI 1070 than placebo achieved resolution of VOC at 48, 72, 96 and 120 h. Analyses by how endpoint was reached were consistent with composite findings. The time to transition to oral pain medications was substantially decreased in all treatment groups: this reduction was 76 h in the GMI 1070 group (KM p=0.089) and reached statistical significance in the pediatric population (87.8 h, KM p=0.037). Time to discharge was reduced from a median of 156.1 h (CI 75.4, 185.8) for placebo to 72.2 h (CI 59.9, 121.0) for GMI 1070 (p=0.092). Stratified analysis by age and dose showed similar reductions in time to discharge. Although 24 subjects (31.6%) did not achieve a sustained reduction in VAS while hospitalized, active treatment was associated with a decrease in time to first sustained reduction in VAS. Median times to VAS reduction were: GMI 1070, 72.0 h (CI 34.5, 115.7); placebo, 125.3 h (CI 19.7, 180.2). Time to agreement about readiness for discharge was documented in 88% and 85% of the treatment and placebo groups, with medians of 72.5 h (CI 60.9, 139.1) and 137.4 h (CI 83.2, 165.7), respectively (p=0.151). An 83% reduction in mean cumulative IV opioid analgesic use (mg/kg MEU) was seen across all treatment groups (p=0.010, Fig 1b). The effect on opioid use was seen within 24 h. Total adverse event (AE) rates, serious AEs, and ‘treatment related’ AEs were comparable across all groups and ages (high dose, low dose, and pooled GMI 1070, or placebo; pediatric vs. adult). No subjects discontinued the study due to AEs. Conclusion Treatment with GMI 1070 was associated with substantial reductions in mean and median time to resolution of VOC, analyzed either as a composite or component endpoints, that were near statistical significance. The magnitude of reduction was clinically meaningful. GMI 1070 was also associated with reduction in both hourly and daily opioid use. There was no evidence for heterogeneity of effect among patient groups. These promising results support a role for selectins in the pathophysiology of VOC and justify a Phase 3 study of GMI 1070 for SCD patients with VOC. Disclosures: Telen: Dilaforette, NA: Research Funding; Pfizer, Inc.: Consultancy; GlycoMimetics, Inc.: Research Funding. Wun:Emmaus, Inc.: Clinical Adjudication Committee Other; Pfizer, Inc.: Consultancy; GlycoMimetics: Research Funding. McCavit:GlycoMimetics, Inc.: Research Funding; Pfizer, Inc.: Consultancy. De Castro:GlycoMimetics, Inc.: Research Funding; Novella Clinical: Consultancy. Krishnamurti:GlycoMimetics, Inc.: Research Funding. Lanzkron:GlycoMimetics, Inc.: Research Funding. Hsu:GlycoMimetics, Inc.: Research Funding. Smith:GlycoMimetics, Inc.: Research Funding. Rhee:Rho, Inc.: Employment; GlycoMimetics, Inc.: Research Funding. Magnani:GlycoMimetics, Inc.: Employment, Equity Ownership. Thackray:GlycoMimetics, Inc.: Employment, Equity Ownership.

Abstract 4753 Introduction For many patients with sickle cell anemia (SCA), jaundice, yellow discoloration of the skin and mucous membranes, may be the most visible manifestation of their disease. The degree to which jaundice impacts the daily lives of patients with SCA has not been previously described. This study aims to assess the effect of jaundice on the health-related quality of life (HRQOL) of adults living with SCA. Methods This study was a cross-sectional survey of patients with SCA. A convenience sample of patients age > 17 years with SCA were approached during routine clinic visits to Parkland Memorial Hospital or UT Southwestern University Hospitals. Consenting patients completed a 15 question survey instrument. The survey was divided into three subscales (personal, relational, and behavioral) where individual items were presented in a 5-point Likert scale. This instrument was reviewed by non-study hematologists, nurses and patients for face validity. No other assessment of reliability or validity was performed. Additional data collected included serum total bilirubin (TB), hemoglobin, reticulocyte count (%) and patient self-report of current treatment for SCA (hydroxyurea [HU], chronic blood transfusions, or other). We tested for associations between survey subscales and TB, reticulocyte count, or hemoglobin using Spearman correlation coefficients. We compared the Spearman correlations of the survey subscales and TB between treatment and non-treatment groups using the Fisher's z transformation. Gender and age adjustments were made using linear regression. TB was transformed by natural log for regression analysis. Results We surveyed 100 subjects (58% female) with SCA. The median age was 25 years (range: 18–63), and the median TB was 2.5 mg/dL (range: 0.4–13.8). Nearly half of patients reported receiving treatment with 28% on HU and 14% on chronic transfusions. The majority of patients reported a history of jaundice, with 79% listing responses of ‘sometimes’, ‘often’, or ‘always’. Summary results for the remainder of the survey are listed in the table. TB was positively correlated with the 3 subscales (personal, r=0.32, p=0.002; relational, r=0.38, p=0.0002; behavioral, r=0.31, p=0.003). We compared these correlations between ‘treatment’ and ‘no treatment’ groups and observed strong correlations in the ‘no treatment’ group (personal, r=0.55, p Conclusion Jaundice negatively impacts the lives of many adults with SCA. The personal and relational subscales suggest more impact on the self-image of respondents, but only a few reported behavioral changes. The impact of jaundice appears to be mitigated by disease-modifying therapy for SCA (HU or chronic transfusions); however, this study was not created to determine the effectiveness of these reported treatments. Despite the fact this instrument was not validated, our study results suggest jaundice should be well-represented in HRQOL assessment tools in adults with SCA. Moreover, prospective studies are needed to clarify potential benefits of disease-modifying therapies, particularly HU, on the burden of jaundice in SCA. Disclosures: Buchanan: HemaQuest Pharmacuetical, Inc.: Research Funding.

Abstract 2111 Background: The acute painful crisis is the clinical hallmark of sickle cell disease (SCD). Recently, time-to-opioid administration (TTO) has been suggested as quality-of-care (QOC) measure for SCD patients with an acute painful crisis (Wang,Pediatrics,128:484,2011). We sought to determine whether TTO was associated with outcomes of emergency department (ED) visits for acute painful crisis. Methods: We conducted a retrospective cohort study of ED visits for acute painful crisis to Children's Medical Center Dallas between 1/1/2008 and 12/31/2010. Potential subjects were identified by query of hospital administrative records using all ICD-9CM codes for SCD (282.41, 282.42, and 282.6x) as either the primary or a secondary diagnosis. We included patients with any SCD genotype between 5 and 18 years of age. Records of all potential subjects were reviewed to determine whether the episode represented an acute painful crisis, defined as the recent onset of acute pain not explained by other mechanisms. We excluded patients with confounding sources of pain (e.g., headache and gallstones), patients transferred from other medical centers, and patients who had a surgical procedure within 2 weeks of presentation. We also excluded patients who received a simple transfusion in the preceding 30 days or were part of a chronic transfusion program in the preceding 6 months. The primary predictor variable was TTO in minutes, analyzed continuously and in quartiles. The primary outcome variable was hospital admission with secondary outcomes of change in pain scores 1 & 2, area under the curve (AUC) for pain scores at 4 hours (pain score AUC), and length of stay in the ED (ED LOS) in minutes. Univariate mixed regression (logistic for admission, linear for other outcome variables), including patient random effects, was used to test for association between TTO and other relevant covariates with the outcome variables. Variables with P-values Results: From 2,866 ED visits in 2008–2010, 177 subjects were identified with 416 presentations for acute painful crisis treated with IV opioids. 47% of subjects were female and 65% had HbSS/HbSβ0. The primary outcome, inpatient admission, occurred in 53% of ED visits. The median TTO was 86 minutes (intraquartile range (IQR) 54 – 130 minutes) and was not different between those admitted and not admitted to the hospital (not admitted - 86.5 minutes, (IQR 56.5, 126.5); admitted - 85.5 minutes, (IQR 50.5, 130)). TTO (both as a continuous and categorical variable) was not associated with inpatient admission in either univariate or multivariate analyses. In multivariate analyses with secondary outcomes, TTO was associated with change in pain scores 1 & 2, pain score AUC at 4 hours, and ED LOS. After adjusting for age and initial pain score, decreased TTO was independently associated with a decrease in pain scores 1 & 2 (referent - TTO Quartile 4 (>131 minutes) vs Quartile1 ( Conclusions: For acute painful crisis, TTO in the ED setting has been suggested as a QOC measure. While TTO is not associated with our primary outcome, inpatient admission, it is independently associated three other important outcomes: change in pain scores 1 & 2, pain score AUC, and ED LOS. The association of the process measure, TTO, with these outcomes increases the appeal for its use in broader sickle cell populations and should lead to necessary steps to reduce TTO in the ED setting. Subsequent studies should investigate TTO in other SCD populations including adults, examine determinants of prolonged TTO, and study interventions designed to reduce TTO in various ED settings. Disclosures: No relevant conflicts of interest to declare.

Abstract 476 Background: Sickle cell disease (SCD) is an inherited chronic disease characterized by complications such as recurrent painful vaso-occlusive events that can require hospitalizations and contribute to early and increased mortality. Prior work using generic health-related quality of life (HRQL) instruments has demonstrated that patients with SCD experience significantly impaired HRQL in their baseline state of health that worsens during acute complications of the disease. To better understand differences in health status in children with SCD, we developed the PedsQL™ SCD Module to measure SCD-specific HRQL. The goal of this study was to determine the measurement properties for the child self- and parent-proxy reports for the newly developed PedsQL™ SCD Module. We hypothesized that the PedsQL™ SCD Module would be feasible and reliable and that children with more severe SCD would have worse HRQL than those with mild disease as measured by the PedsQL™ SCD Module. Methodology: This was a cross-sectional study conducted at 5 sites across the United States. Study participants were children with SCD ages 2–18 years who presented to clinic for a routine visit. HRQL was the main outcome measured with the newly developed 43-item PedsQL™ SCD Module which includes nine scales: Pain/Hurt (PH, 9 items), Pain Impact (PI, 10 items), Pain Management/Control (PMC, 2 items), Worry I (WO1, 5 items), Worry II (WO2, 2 items), Emotions (EM, 2 items), Treatment (TR, 7 items), Communication I (CO1, 3 items), Communication II (CO2, 3 items). Higher scores indicate better HRQL and lower SCD symptoms. Missing items were used to determine feasibility and Cronbach's alpha was used to determine reliability. HRQL of children with mild and severe disease were compared using an independent t-test to determine construct validity. Severe disease was defined as patients with 3 or more hospitalizations for pain in the 3 years prior, history of stroke and/or prior acute chest syndrome. Results: A total of 321 families (313 parents, 243 children ages 5–18 years) completed questionnaires. The average age of the children (46.7% boys) was 9.62 years (SD = 4.88). Feasibility was established, with 3% or less missing data for the module. The PedsQL™ SCD Module was reliable and distinguished between children with mild and severe SCD (Table 1). Conclusions: The PedsQL™ SCD Module performed well and demonstrated strong measurement properties in patients with SCD. Overall, both the parent-proxy report and child self-report differentiated between patients with severe and mild SCD supporting construct validity of the module. Although these are the first results using the PedsQL™ SCD Module, it has shown great potential as being a strong measure of HRQL for patients with SCD. Future studies incorporating the PedsQL™ SCD Module will benefit from the measure's disease-specific scales and overall ability to distinguish between mild and severe symptoms. Continually, these studies will help further define its' measurement properties and advance our knowledge of the HRQL in patients with SCD. Disclosures: Off Label Use: Hydroxyurea is approved for use in sickle cell disease in adults but not children. Varni:Mapi Research Trust: Dr. Varni holds the copyright and the trademark for the PedsQL™ and receives financial compensation from the Mapi Research Trust, which is a nonprofit research institute that charges distribution fees to for-profit companies that use the Pediatric Quality Other, PedsQL™, PedsQL™ Patents & Royalties.

Sickle cell disease (SCD) affects about 100,000 Americans and is responsible for approximately 100,000 hospitalizations annually at a cost of $500 million. Quality of care in patients hospitalized for SCD has been insufficiently studied. Therefore, we aimed to examine whether three potential determinants of quality care, hospital volume, hospital teaching status, and patient socioeconomic status (SES) are associated with three quality indicators: length of stay (LOS), cost of hospitalization, and mortality for hospitalized patients with SCD. The data source was the National Inpatient Sample (NIS) from 2003–2005, which includes data on nearly 8 million hospitalizations annually from 1000 hospitals in 37 states. The NIS comprises a 20% stratified sample of US community hospitals that includes all payers. In the NIS, hospital volumes are categorized as small, medium, or large depending on geography and population. SCD-specific hospital volumes were determined by ascertaining the total number of SCD discharges at each hospital. No patient-specific SES data is available in the NIS, so we utilized an indirect marker of SES, the median household income for the patient’s ZIP code. Cases were identified using all ICD-9CM codes for SCD as either the primary or a secondary diagnosis. Patients of all ages were included. Four severity of illness markers, were included as covariates to control for referral bias. Other independent variables we examined were age, gender, year of admission, insurance type, and weekend admission. Multivariable analyses included multiple logistic regression to examine adjusted odds of mortality and mixed linear models to examine adjusted length of stay and costs. 70,748 SCD discharges occurred from 2003–2005. 425 deaths occurred yielding a mortality rate of 6 deaths per 1000 hospitalizations. The median length of stay was 4 days (5th–95th %ile range – 1–15 days), and the median cost per hospitalization was $4,100 (5th–95th %ile range – $1,200–20,500). Bivariate analyses revealed an inverse relationship between SCDspecific hospital volume and mortality with odds ratios of 3.1, 2.1, and 1.8 for quartiles 1, 2, and 3, respectively, relative to quartile 4 (highest volume.) Multivariable analyses (table), controlling for severity of illness and several other factors, confirmed that a lower SCD-specific hospital volume was associated with significantly increased adjusted odds of mortality and a decreased length of stay. Additionally, self-pay status for insurance type was associated with increased adjusted odds of mortality and a decreased length of stay. Teaching hospitals had higher adjusted costs of care for all patients but decreased LOS in adults only. There was no significant association with mortality and hospital teaching status. SES was not associated with LOS or cost, but lower SES trended toward higher mortality in adults (not shown). In conclusion, these are the first national data that demonstrate that hospitals with low volumes of SCD hospitalizations have significantly higher adjusted mortality rates for SCD patients than those with high volumes. These findings suggest that identification of the specific factors associated with reduced mortality in high-volume hospitals, such as greater adherence to accepted standards of care and clinical practice guidelines, might have the potential to reduce mortality at low-volume hospitals. We also demonstrate that a lack of health insurance coverage is associated with higher adjusted mortality rates and decreased LOS in SCD, a finding which should prompt greater efforts to provide coverage for this frequently underinsured population. Table Multivariable Analyses – All Patients Mortality Length of Stay Cost Risk Factors Odds Ratio (95% C.I.) Fixed Effect Estimate (95% C.I.) Fixed Effect Estimate (95% C.I.) 1NS – non-significant Sickle cell volume 1.47 (1.11, 1.95) −0.21 (−0.28, −0.13) Quartile 1 1.21 (0.98, 1.48) −0.12 (−0.17, −0.06) 2 1.31 (1.15, 1.49) −0.02 (−0.07, 0.03) NS1 3 -- -- 4 (Comparator) Hospital teaching status −2.94 (−4.9, −0.98) Non-teaching NS NS -- Teaching (Comparator) Patient’s Primary Payer 1.76 (1.36,2.29) −0.05 (−0.08, −0.01) −1.16 (−2.55,0.23) Self-pay 1.02 (0.89, 1.18) 0.08 (0.07, 0.1) 0.49 (−0.16, 1.14) Medicaid 1.05 (0.91, 1.21) 0.13 (0.11, 0.15) 1.35 (0.54, 2.17) Medicare 0.81 (0.57, 1.16) 0.04 (−0.003, 0.08) 0.43 (−1.06, 1.91) Other -- -- -- HMO/Private (Comparator)