Jane S. Hankins

R2* magnetic resonance imaging of the liver in patients with iron overload

R2* magnetic resonance imaging (R2*-MRI) can quantify hepatic iron content (HIC) by noninvasive means but is not fully investigated. Patients with iron overload completed 1.5T R2*-MRI examination and liver biopsy within 30 days. Forty-three patients (sickle cell anemia, n = 32; beta-thalassemia major, n = 6; and bone marrow failure, n = 5) were analyzed: median age, 14 years, median transfusion duration, 15 months, average (+/-SD) serum ferritin 2718 plus or minus 1994 ng/mL, and average HIC 10.9 plus or minus 6.8 mg Fe/g dry weight liver. Regions of interest were drawn and analyzed by 3 independent reviewers with excellent agreement of their measurements (intraclass correlation coefficient = 0.98). Ferritin and R2*-MRI were weakly but significantly associated (range of correlation coefficients among the 3 reviewers, 0.41-0.48; all P < .01). R2*-MRI was strongly associated with HIC for all 3 reviewers (correlation coefficients, 0.96-0.98; all P < .001). This high correlation confirms prior reports, calibrates R2*-MRI measurements, and suggests its clinical utility for predicting HIC using R2*-MRI. This study was registered at www.clinicaltrials.gov as #NCT00675038.

The effect of hydroxcarbamide therapy on survival of children with sickle cell disease.

Although evidence is accumulating that hydroxycarbamide decreases mortality among adults with sickle cell disease (SCD), there are no published data regarding the effect of hydroxycarbamide on mortality among children. The Paediatric Hydroxycarbamide Program was established to treat children with SCD aged 3–18 years if they met disease severity criteria. Mortality data and clinical/laboratorial effects of hydroxycarbamide were retrospectively collected for the first 9 years of the Program. Mortality among those who received hydroxycarbamide was compared to that of untreated children. Among 1760 subjects, 267 received hydroxycarbamide at a median dose of 20·8 mg/kg/d (range 10–32) for a median of 2 years (range 0·1–6·5). Survival among hydroxycarbamide‐treated children was significantly greater than that among untreated ones (99·5% vs. 94·5%, P = 0·01), due primarily to fewer deaths from acute chest syndrome and infection. Hydroxycarbamide therapy was significantly associated with increases in haemoglobin concentration, fetal haemoglobin, mean corpuscular volume, and reduction in platelet counts, reticulocytes and neutrophils. Toxicity was minimal and predominantly mild reversible neutropenia. Significantly fewer hospitalizations and emergency room visits, and shorter admissions were observed among hydroxycarbamide‐treated subjects, when compared to the 12‐month period prior to treatment initiation. Hydroxycarbamide therapy reduces disease severity and is probably associated with decreased mortality among children with SCD.

Preservation of spleen and brain function in children with sickle cell anemia treated with hydroxyurea

Chronic organ damage is an insidious process in patients with sickle cell anemia (SCA). Although hydroxyurea prevents acute vaso‐occlusive events, its effects on the preservation of organ function remain undefined.

The natural history of conditional transcranial Doppler flow velocities in children with sickle cell anaemia.

Children with sickle cell anaemia (SCA) and conditional transcranial Doppler (TCD) [time‐averaged mean velocity (TAMV) 170–199 cm/s] have increased risk of primary stroke, but receive no specific therapy. Some will convert to abnormal velocities (TAMV ≥200 cm/s) with further increase in stroke risk. In 2003, our centre initiated universal TCD screening, targeting all children (aged 2–16 years) with SCA. TCD examinations were repeated at intervals based on initial results. To determine rates and risk factors for TCD conversion, we reviewed all examinations since 2003, excluding patients receiving hydroxycarbamide (hydroxyurea) or transfusions. Of the eligible population, 274 children (98%) were screened at a median age of 7·1 years (range 1·7–18·2). Fifty‐four patients (20%) had conditional TAMV either on initial screening or a subsequent examination. The 18‐month cumulative incidence of conversion from conditional to abnormal TAMV was 23%. Age, initial TAMV, laboratory values, blood pressure and oxygen saturation were not significantly associated with conversion. Our cohort provides systematic longitudinal evaluation of an unselected paediatric population universally screened and retested at regular intervals. Our data document a high conversion rate to abnormal velocities among untreated children with SCA. Therapy should be considered for the prevention of conversion to abnormal TCD velocities.

HYDROXYUREA TREATMENT DECREASES GLOMERULAR HYPERFILTRATION IN CHILDREN WITH SICKLE CELL ANEMIA

Glomerular hyperfiltration and microalbuminuria/proteinuria are early manifestations of sickle nephropathy. The effects of hydroxyurea therapy on these renal manifestations of sickle cell anemia (SCA) are not well defined. Our objective was to investigate the effects of hydroxyurea on glomerular filtration rate (GFR) measured by 99mTc‐DTPA clearance, and on microalbuminuria/proteinuria in children with SCA. Hydroxyurea study of long‐term effects (HUSTLE) is a prospective study (NCT00305175) with the goal of describing the long‐term cellular, molecular, and clinical effects of hydroxyurea therapy in SCA. Glomerular filtration rate, urine microalbumin, and serum cystatin C were measured before initiating hydroxyurea therapy and then repeated after 3 years. Baseline and Year 3 values for HUSTLE subjects were compared using the Wilcoxon Signed Rank test. Associations between continuous variables were evaluated using Spearman correlation coefficient. Twenty‐three children with SCA (median age 7.5 years, range, 2.5–14.0 years) received hydroxyurea at maximum tolerated dose (MTD, 24.4 ± 4.5 mg/kg/day, range, 15.3–30.6 mg/kg/day). After 3 years of treatment, GFR measured by 99mTc‐DTPA decreased significantly from 167 ± 46 mL/min/1.73 m2 to 145 ± 27 mL/min/1.73 m2 (P = 0.016). This decrease in GFR was significantly associated with increase in fetal hemoglobin (P = 0.042) and decrease in lactate dehydrogenase levels (P = 0.035). Urine microalbumin and cystatin C levels did not change significantly. Hydroxyurea at MTD is associated with a decrease in hyperfiltration in young children with SCA. Am. J. Hematol., 88:116–119, 2013.

Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin

Compound heterozygotes for sickle haemoglobin (HbS) and hereditary persistence of fetal haemoglobin (HPFH) have high fetal haemoglobin (HbF) levels but few, if any, sickle cell disease‐related complications. We studied 30 cases of HbS‐HPFH (types 1 and 2), confirmed by molecular analysis, and report the haematological features and change in HbF levels over time. These results were compared to those of patients with sickle cell anaemia or HbS‐β0 thalassaemia, including a subgroup of patients carrying the XmnI polymorphism, known to be associated with elevated HbF. Among the HbS‐HPFH patients, HbF level was 50–90% during infancy and declined steeply within the first few years of life, stabilizing between ages 3 and 5 years, at approximately 30%. Mean HbF of individuals age 5 or older was 31 ± 3%, average haemoglobin concentration was 130 ± 10 g/l and average mean corpuscular volume (MCV) was 75 ± 4 fl. Univariate and multivariate regression analyses significantly associated HbF with age, haemoglobin concentration, and MCV (P < 0·001). There was a strong inverse association between HbF and age (r = −0·9, P < 0·001). Despite having a much higher HbF level, patients with HbS‐HPFH have a similar age‐related pattern of HbF decline and associations as patients with sickle cell anaemia or HbS‐β0 thalassaemia.

Therapy preference and decision-making among patients with severe sickle cell anemia and their families&

Patients with severe sickle cell anemia (SCA) may benefit from therapeutic intervention with hydroxyurea (HU), chronic red cell transfusion (CT), or stem cell transplantation (SCT). Determination of best treatment is complicated by the tradeoff between each treatments risks and benefits and the lack of data comparing them to determine efficacy. We explored factors that influenced making decisions regarding interventions and examined the relations between treatment preference and health‐related quality of life (HRQOL).

Chronic Transfusion Therapy for Children With Sickle Cell Disease and Recurrent Acute Chest Syndrome

The objective was to study the effects of chronic transfusion therapy (CTX) on the prevention of new episodes of acute chest syndrome (ACS) in children with sickle cell disease (SCD) and recurrent or unusually severe ACS. A retrospective chart review was performed of patients given CTX for recurrent or severe ACS. Frequency, median severity score, and median hospital stay for ACS episodes were determined. Differences in these values before and during CTX were analyzed. Twenty-seven patients were identified. Before treatment, the ACS incidence was 1.3 episodes per patient-year; during treatment, it decreased to 0.1 episodes per patient-year (P < 0.0001). The median severity score for ACS episodes was 0.8 (range 0-5) before CTX and 0.5 (0-3) during CTX (P = 0.84). The median hospital stay was 5 days (range 3-15 days) before CTX and 3 days (2-7 days) during CTX (P = 0.38). CTX significantly reduces the incidence of ACS events among patients with a history of recurrent or severe episodes but does not significantly decrease their severity. The effectiveness of CTX should be prospectively compared with that of hydroxyurea and stem cell transplantation.

International survey of T2* cardiovascular magnetic resonance in β-thalassemia major

Accumulation of myocardial iron is the cause of heart failure and early death in most transfused thalassemia major patients. T2* cardiovascular magnetic resonance provides calibrated, reproducible measurements of myocardial iron. However, there are few data regarding myocardial iron loading and its relation to outcome across the world. A survey is reported of 3,095 patients in 27 worldwide centers using T2* cardiovascular magnetic resonance. Data on baseline T2* and numbers of patients with symptoms of heart failure at first scan (defined as symptoms and signs of heart failure with objective evidence of left ventricular dysfunction) were requested together with more detailed information about patients who subsequently developed heart failure or died. At first scan, 20.6% had severe myocardial iron (T2*≤10ms), 22.8% had moderate myocardial iron (T2* 10–20ms) and 56.6% of patients had no iron loading (T2*>20ms). There was significant geographical variation in myocardial iron loading (24.8–52.6%; P<0.001). At first scan, 85 (2.9%) of 2,915 patients were reported to have heart failure (81.2% had T2* <10ms; 98.8% had T2* <20ms). During follow up, 108 (3.8%) of 2,830 patients developed new heart failure. Of these, T2* at first scan had been less than 10ms in 96.3% and less than 20ms in 100%. There were 35 (1.1%) cardiac deaths. Of these patients, myocardial T2* at first scan had been less than 10ms in 85.7% and less than 20ms in 97.1%. Therefore, in this worldwide cohort of thalassemia major patients, over 43% had moderate/severe myocardial iron loading with significant geographical differences, and myocardial T2* values less than 10ms were strongly associated with heart failure and death.

PARENTAL STRESS IN FAMILIES OF CHILDREN WITH A GENETIC DISORDER/DISABILITY AND THE RESILIENCY MODEL OF FAMILY STRESS, ADJUSTMENT, AND ADAPTATION

Background: Research suggests that parents of children with disabilities endure increased amounts of stress but also experience positive outcomes. Purpose: To further investigate findings from focus group interviews that explored parental stress in families of children with disabilities using a sequential mixed methods design. Method: This study sought to model parental stress using the McCubbin and McCubbin (1993) Resiliency Model of Stress, Adjustment, and Adaptation using qualitative and quantitative data collected sequentially. Twenty-five parents of children with autism spectrum disorder, cerebral palsy, Down syndrome, and sickle cell disease participated in a 2-step study that encompassed qualitative followed by quantitative data ascertainment. Results: Parents who quantitatively experienced high stress or low stress used different behavioral themes to describe their experience qualitatively. Positive appraisals, resources, and ability to engage in problem solving and coping were associated with family resiliency.