Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1.

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.

Congenital dyserythropoietic anemia type I: First report from the Congenital Dyserythropoietic Anemia Registry of North America (CDAR).

Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and distinctive erythroblast abnormalities; the diagnosis is often missed or delayed due to significant phenotypic heterogeneity. We established the CDA Registry of North America (CDAR) to study the natural history of CDA and create a biorepository to investigate the pathobiology of this heterogeneous disease. Seven of 47 patients enrolled so far in CDAR have CDA-I due to biallelic CDAN1 mutations. They all presented with perinatal anemia and required transfusions during infancy. Anemia spontaneously improved during infancy in three patients; two became transfusion-independent rapidly after starting interferon-α2; and two remain transfusion-dependent at last follow-up at ages 5 and 30 y.o. One of the transfusion-dependent patients underwent splenectomy at 11 y.o due to misdiagnosis and returned to medical attention at 27 y.o with severe hemolytic anemia and pulmonary hypertension. All patients developed iron overload even without transfusions; four were treated with chelation. Genetic testing allowed for more rapid and accurate diagnosis; the median age of confirmed diagnosis in our cohort was 3 y.o compared to 17.3 y.o historically. In conclusion, CDAR provides an organized research network for multidisciplinary clinical and research collaboration to conduct natural history and biologic studies in CDA.

Effect of Low-Dose Ferrous Sulfate vs Iron Polysaccharide Complex on Hemoglobin Concentration in Young Children With Nutritional Iron-Deficiency Anemia: A Randomized Clinical Trial.

Importance: 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. Objective: To compare the effect of ferrous sulfate with iron polysaccharide complex on hemoglobin concentration in infants and children with nutritional IDA. Design, Setting, and Participants: 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. Interventions: Three mg/kg of elemental iron once daily as either ferrous sulfate drops or iron polysaccharide complex drops for 12 weeks. Main Outcomes and Measures: Primary outcome was change in hemoglobin over 12 weeks. Secondary outcomes included complete resolution of IDA (defined as hemoglobin concentration >11 g/dL, mean corpuscular volume >70 fL, reticulocyte hemoglobin equivalent >25 pg, serum ferritin level >15 ng/mL, and total iron-binding capacity <425 µg/dL at the 12-week visit), changes in serum ferritin level and total iron-binding capacity, adverse effects. Results: 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). Conclusions and Relevance: 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. Trial Registration: clinicaltrials.gov Identifier: NCT01904864.

Iron Deficiency Anemia in Adolescents Who Present with Heavy Menstrual Bleeding.

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.

Intravenous Ferric Carboxymaltose in Children with Iron Deficiency Anemia Who Respond Poorly to Oral Iron.

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.

Deficiencies in the Management of Iron Deficiency Anemia During Childhood.

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.

Management of iron deficiency anemia: a survey of pediatric hematology/oncology specialists.

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.

Chemotherapy for Generalized Infantile Myofibromatosis With Visceral Involvement.

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.

Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease.

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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

PedsQL™ Multidimensional Fatigue Scale in sickle cell disease: feasibility, reliability, and validity.

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. PROCEDURE: 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. RESULTS: 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. CONCLUSIONS: 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.

Intravenous low molecular weight iron dextran in children with iron deficiency anemia unresponsive to oral iron.

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.

Prompt administration of antibiotics is associated with improved outcomes in febrile neutropenia in children with cancer.

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 associated 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 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. 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 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). CONCLUSIONS: TTA and presentation to the ED are independently associated with poor outcomes of FN.

PedsQL™ sickle cell disease module: feasibility, reliability, and validity.

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.

National trends in incidence rates of hospitalization for stroke in children with sickle cell disease.

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. PROCEDURE: 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. RESULTS: 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. CONCLUSIONS: 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.

Prophylactic penicillin after 5 years of age in patients with sickle cell disease: a survey of sickle cell disease experts.

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 ß(+) thalassemia, P = <0.001), and with increasing use of other preventive evaluations (e.g., MRI for silent stroke) in childhood (P = 0.05). CONCLUSION: Most pediatric hematologists with an SCD expertise recommend cessation of prophylactic penicillin after 5 years of age.

Time-to-antibiotic administration as a quality of care measure in children with febrile neutropenia: a survey of pediatric oncology centers.

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 min 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.

Hospitalization for invasive pneumococcal disease in a national sample of children with sickle cell disease before and after PCV7 licensure.

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 < 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. CONCLUSION: In a national sample, PCV7 licensure is temporally associated with a nearly threefold reduction in IPD hospitalizations in children with SCD.

Bordetella holmesii bacteremia in sickle cell disease.

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.