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Objectives: The quality of life (QoL) of children with sickle cell anaemia (SCA) in the United Kingdom has not been examined, and a discrepancy measure based on Gap theory has rarely been used. This study investigated whether (1) child self-reports of QoL using a discrepancy measure (the Generic Children's QoL Measure; GCQ) are lower than those from healthy children, (2) proxy reports from parents and health care professionals are lower than child self-reports, and (3) demographic and disease severity indicators are related to QoL., Design and Methods: An interdependent groups, cross-sectional design was implemented. Seventy-four children with SCA, their parent, and members of their health care team completed the GCQ. Demographic and disease severity indicators were recorded. GCQ data from healthy children were obtained from the UK Data Archive., Results: Contrary to past research, when examining generic discrepancy QoL, children with SCA did not report a lower QoL than healthy children, and parent- and health care professional-proxy reports were not lower than child self-reports. Few of the demographic and disease severity indicators were related to QoL., Conclusions: Proxy reports may be used to gain a more complete picture of QoL, but should not be a substitute for self-reports. The explanation for the relatively high levels of QoL reported is not clear, but children with SCA may have realistic expectations about their ideal-self, place greater emphasis on aspects other than health in shaping their QoL, and define achievements within the limits of their illness. Future research should focus on psychological factors in explaining QoL. Statement of contribution What is already known on this subject? Children with sickle cell disease (SCD) generally have a reduced QoL compared with healthy children, but there appears to be no research measuring QoL in paediatric SCD in the United Kingdom. Proxy QoL reports from parents are often lower than child self-reports, but there is less research examining proxy reports from health care professionals. Previous research has measured paediatric QoL using measures of current health-related QoL, but this is not in line with the WHO's definition of QoL as the discrepancy between current state and expectations. What does this study add? Children with Sickle cell anaemia do not have an impaired discrepancy QoL; they may have realistic expectations about their ideal-self and define achievements within the limits of their illness. Health care professionals are able to gauge a SCA child's discrepancy QoL better than parents. The GCQ (a generic discrepancy measure of QoL) takes into account expectations about ideal QoL and does not emphasize health; it may be of use to Psychologists working with SCA children., (© 2014 The British Psychological Society.)

Background: The majority of children with sickle cell disease (SCD), approximately 75%, are born in sub-Saharan Africa. For children with elevated transcranial Doppler (TCD) velocity, regular blood transfusion therapy for primary stroke prevention is standard care in high income countries, but is not feasible in sub-Saharan Africa., Procedure: In the first U.S. National Institute of Health (NIH) sponsored SCD clinical trial in sub-Saharan Africa, we describe the protocol and challenges unique to starting a clinical trial in this region. We are conducting a single arm pilot trial of hydroxyurea therapy in children with TCD velocity ≥200 cm/sec in the middle cerebral arteries. Eligible children will be placed on hydroxyurea (n = 40) and followed for 3 years at Aminu Kano Teaching Hospital, Nigeria. Adherence will be measured via the Morisky Scale and adverse events will be determined based on hospitalization., Results: Originally, a randomized placebo trial was planned; however, placebo was not approved by the local Ethics Committee. Hence a single arm trial of hydroxyurea will be conducted and five controls per patient with normal TCD measurements will be followed to compare the rate of adverse events to those with abnormal TCD measurements taking hydroxyurea. Using non-NIH funding, over 9 months, multiple face-to-face investigator meetings were conducted to facilitate training., Conclusion: A hydroxyurea trial (NCT01801423) for children with SCD is feasible in sub-Saharan Africa; however, extensive training and resources are needed to build a global patient oriented multi-disciplinary research team with a common purpose., (© 2014 Wiley Periodicals, Inc.)

The completion of the Multicenter Silent Infarct Transfusion Trial demonstrated that children with pre-existing silent cerebral infarct and sickle cell anemia (SCA) who received regular blood transfusion therapy had a 58% relative risk reduction of infarct recurrence when compared to observation. However, the total benefit of blood transfusion therapy, as assessed by the parents, was not measured against the burden of monthly blood transfusion therapy. In this planned ancillary study, we tested the hypothesis that a patient centered outcome, health-related quality of life (HRQL), would be greater in participants randomly assigned to the blood transfusion therapy group than the observation group. A total of 89% (175 of 196) of the randomly allocated participants had evaluable entry and exit HRQL evaluations. The increase in Change in Health, measured as the child's health being better, was significantly greater for the transfusion group than the observation group (difference estimate = -0.54, P ≤ 0.001). This study provides the first evidence that children with SCA who received regular blood transfusion therapy felt better and had better overall HRQL than those who did not receive transfusion therapy., (© 2014 Wiley Periodicals, Inc.)

While a doctor-diagnosis of asthma is associated with an increased risk of pain and acute chest syndrome (ACS) in children with sickle cell anemia (SCA), little is known about the relationship between specific asthma characteristics and clinical factors and future morbidity in children with SCA. We evaluated the relationship between (i) asthma risk factors at the time of a clinical visit (respiratory symptoms, maternal history of asthma, allergy skin tests, spirometry results) and (ii) the known risk factor of ACS early in life, on prospective pain and ACS episodes in a cohort of 159 children with SCA followed from birth to a median of 14.7 years. An ACS episode prior to 4 years of age, (incidence rate ratio [IRR] = 2.84; P < 0.001], female gender (IRR = 1.80; P = 0.009), and wheezing causing shortness of breath (IRR = 1.68; P = 0.042) were associated with future ACS rates. We subsequently added spirometry results (obstruction defined as FEV1 /FVC less than the lower limits of normal; and bronchodilator response, FEV1 ≥ 12%) and prick skin test responses to the model. Only ≥ 2 positive skin tests had a significant effect (IRR 1.87; P = 0.01). Thus, early in life ACS events, wheezing causing shortness of breath, and ≥ 2 positive skin tests predict future ACS events., (© 2014 Wiley Periodicals, Inc.)

Stroke in sickle cell anaemia (SCA) is either infarctive or haemorrhagic in nature. In childhood, over 75% of strokes in SCA are infarctive. We present an adolescent with SCA who developed hypertension at the age of 13, and was treated with lisinopril. Sixteen months later she was found in cardiorespiratory arrest and died on arrival in hospital. The last transcranial Doppler scan performed 6 months before her death and a brain MRI were reported normal. The autopsy discovered massive subarachnoid haemorrhage in association with vascular damage in the circle of Willis arteries. The case highlights a cause of haemorrhagic stroke, the first reported association between hypertension, SCA and a histopathologically proven cerebral vasculopathy. The difficulties in the management of haemorrhagic stroke and the poor outcome in SCA are discussed., (2014 BMJ Publishing Group Ltd.)

Children with sickle cell anemia have a higher-than-expected prevalence of poor educational attainment. We test two key hypotheses about educational attainment among students with sickle cell anemia, as measured by grade retention and use of special education services: (1) lower household per capita income is associated with lower educational attainment; (2) the presence of a silent cerebral infarct is associated with lower educational attainment. We conducted a multicenter, cross-sectional study of cases from 22 U.S. sites included in the Silent Infarct Transfusion Trial. During screening, parents completed a questionnaire that included sociodemographic information and details of their child's academic status. Of 835 students, 670 were evaluable; 536 had data on all covariates and were used for analysis. The students' mean age was 9.4 years (range: 5-15) with 52.2% male; 17.5% of students were retained one grade level and 18.3% received special education services. A multiple variable logistic regression model identified that lower household per capita income (odds ratio [OR] of quartile 1 = 6.36, OR of quartile 2 = 4.7, OR of quartile 3 = 3.87; P = 0.001 for linear trend), age (OR = 1.3; P < 0.001), and male gender (OR, 2.2; P = 0.001) were associated with grade retention; silent cerebral infarct (P = 0.31) and painful episodes (P = 0.60) were not. Among students with sickle cell anemia, household per capita income is associated with grade retention, whereas the presence of a silent cerebral infarct is not. Future educational interventions will need to address both the medical and socioeconomic issues that affect students with sickle cell anemia., (© 2014 Wiley Periodicals, Inc.)

Objective: To ascertain the prevalence of and risk factors for obstructive sleep apnea syndrome (OSAS) in children with sickle cell anemia (SCA)., Methods: Cross-sectional baseline data were analyzed from the Sleep and Asthma Cohort Study, a multicenter prospective study designed to evaluate the contribution of sleep and breathing abnormalities to SCA-related morbidity in children ages 4 to 18 years, unselected for OSAS symptoms or asthma. Multivariable logistic regression assessed the relationships between OSAS status on the basis of overnight in-laboratory polysomnography and putative risk factors obtained from questionnaires and direct measurements., Results: Participants included 243 children with a median age of 10 years; 50% were boys, 99% were of African heritage, and 95% were homozygous for β(S) hemoglobin. OSAS, defined by obstructive apnea hypopnea indices, was present in 100 (41%) or 25 (10%) children at cutpoints of ≥1 or ≥5, respectively. In univariate analyses, OSAS was associated with higher levels of habitual snoring, lower waking pulse oxygen saturation (Spo2), reduced lung function, less caretaker education, and non-preterm birth. Lower sleep-related Spo2 metrics were also associated with higher obstructive apnea hypopnea indices. In multivariable analyses, habitual snoring and lower waking Spo2 remained risk factors for OSAS in children with SCA., Conclusions: The prevalence of OSAS in children with SCA is higher than in the general pediatric population. Habitual snoring and lower waking Spo2 values, data easily obtained in routine care, were the strongest OSAS risk factors. Because OSAS is a treatable condition with adverse health outcomes, greater efforts are needed to screen, diagnose, and treat OSAS in this high-risk, vulnerable population., (Copyright © 2014 by the American Academy of Pediatrics.)

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSβ° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Background: The Stroke Prevention Trial in Sickle Cell Anaemia (STOP) demonstrated the value of selective transfusion based on transcranial Doppler (TCD) US screening. This facilitated widespread surveillance, but due to reported differences with non-imaging TCD, imaging velocity thresholds have been reduced in some centres., Objective: (1) Retrospectively review velocity measurements obtained by non-imaging and imaging TCD, using a standardised protocol. (2) Determine the impact on STOP classification of different velocity thresholds., Materials and Methods: TCD data from 23 children (2-19 years of age) were reviewed. The TCD protocol focused on obtaining the velocity corresponding to the highest audible Doppler frequency. STOP velocity thresholds were the recommended for non-imaging TCD and values reduced by 5-15%., Results: Non-imaging and imaging TCD velocities were correlated closely with little overall bias. Reducing imaging TCD velocity thresholds increased the number of abnormal and conditional classifications. Abnormal TCD imaging classifications ranged from 1.9% to 37% depending on the degree of correction applied to the velocity data., Conclusion: The current approach for applying STOP thresholds to imaging TCD data may not be required. Centres need to validate their imaging TCD practice to avoid inappropriate selection of patients for transfusion therapy.

To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow-up (9·2%) and adverse events (AEs) (7·6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥ 4 years deferasirox exposure significantly decreased by -591 μg/l (95% confidence intervals, -1411, -280 μg/l; P = 0·027; n = 67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years., (© 2011 Blackwell Publishing Ltd.)

Children with sickle cell disease (SCD) and strokes receive blood transfusion therapy for secondary stroke prevention; despite this, approximately 20% experience second overt strokes. Given this rate of second overt strokes and the clinical significance of silent cerebral infarcts, we tested the hypothesis that silent cerebral infarcts occur among children with SCD being transfused for secondary stroke prevention. A prospective cohort enrolled children with SCD and overt strokes at 7 academic centers. Magnetic resonance imaging and magnetic resonance angiography of the brain were scheduled approximately every 1 to 2 years; studies were reviewed by a panel of neuroradiologists. Eligibility criteria included regularly scheduled blood transfusion therapy. Forty children were included; mean pretransfusion hemoglobin S concentration was 29%. Progressive cerebral infarcts occurred in 45% (18 of 40 children) while receiving chronic blood transfusion therapy; 7 had second overt strokes and 11 had new silent cerebral infarcts. Worsening cerebral vasculopathy was associated with new cerebral infarction (overt or silent; relative risk = 12.7; 95% confidence interval, 2.65-60.5, P = .001). Children with SCD and overt strokes receiving regular blood transfusion therapy experience silent cerebral infarcts at a higher rate than previously recognized. Additional therapies are needed for secondary stroke prevention in children with SCD.

In patients who have inherited both the sickle cell gene and the β-thalassemia (β-thal) gene, the nature of the β-thal mutation will impact on the disease phenotype. The β-thal mutation caused by the 1393 bp deletion has previously been described as having a mild clinical phenotype when inherited with the sickle gene. We describe three members of a family with this deletion who present with a more severe phenotype. The severity cannot be explained by their Hb F levels, or the XmnI-HBG2 polymorphism. This deletion cannot be presumed to be associated with a mild disease phenotype and we recommend that patients with Hb S/β(0)-thal are screened for this deletion.

Infection is a significant contributor to morbidity and mortality in sickle cell disease (SCD). The sickle gene confers an increased susceptibility to infection, especially to certain bacterial pathogens, and at the same time infection provokes a cascade of SCD-specific pathophysiological changes. Historically, infection is a major cause of mortality in SCD, particularly in children, and it was implicated in 20-50% of deaths in prospective cohort studies over the last 20 years. Worldwide, it remains the leading cause of death, particularly in less developed nations. In developed countries, measures to prevent and effectively treat infection have made a substantial contribution to improvements in survival and quality of life, and are continually being developed and extended. However, progress continues to lag in less developed countries where the patterns of morbidity and mortality are less well defined and implementation of preventive care is poor. This review provides an overview of how SCD increases susceptibility to infections, the underlying mechanisms for susceptibility to specific pathogens, and how infection modifies the outcome of SCD. It also highlights the challenges in reducing the global burden of mortality in SCD., (Copyright 2009 International Society for Infectious Diseases. All rights reserved.)

Rickets is increasingly encountered in practice, even in the Western world. One recent publication reports an overall incidence of 7.5 per 100 000 children. Respiratory infections are well known to be associated with rickets. We present a case of rickets with severe respiratory complications. Tracheobronchomalacia was detected on bronchoscopy. We believe that tracheobronchomalacia may be a hitherto unrecognised finding in rickets and may need to be investigated further.

Sickle cell anemia results from the single amino acid substitution of valine for glutamic acid in the beta-chain owing to a nucleotide defect that causes the production of abnormal beta-chains in hemoglobin S. Abnormal hemoglobin chains form polymers in the deoxygenated state, leading to the characteristic sickle cells. The polymerization of deoxygenated hemoglobin S accounts for the pathologic changes in sickle cell disease. The main-stay of therapy in sickle cell disease aims to reduce the amount of sickled hemoglobin present through the prevention of polymerization and reversal of this process. One way of discouraging polymerization is to increase the level of fetal hemoglobin, which because of its high oxygen affinity, does not participate in the polymerization process. Fetal hemoglobin production may be induced pharmacologically or by the use of gene therapy and genetic engineering techniques.

Background: Rosai-Dorfman Disease is an uncommon benign systemic histio-proliferative disease. This is the first time the disease, although more common in people of African descent, is described in association with Sickle cell disease., Case Presentation: A Nigerian boy born started a complex medical history with post-natal anemia of unknown origin. Subsequently he was diagnosed with Sickle Cell Anemia (Hb SS). At age 3 during a routine review, he was noted to have generalised massive lymphadenopathy. He had further reoccurrences of this lymphadenopathy, but investigations did not reveal the cause until age five. At this point, because of the progressive lymph node enlargement, a biopsy was performed, and he was diagnosed with Rosai-Dorfman Disease. Since that time, the child has had further episodes of intermittent massive lymphadenopathy, particularly associated with Sickle Crisis. His medical history has been further complicated by development of complications from Sickle Cell Disease, cardiomyopathy and an autoimmune hemolytic anemia with multiple alloantibodies., Conclusion: This case for the first time presents the co-existence of two diseases, of increased prevalence in those of African descent, but to date not described in the literature to occur concurrently.

Hydroxyurea is increasingly used in the treatment of sickle cell disease (SCD) although there is little evidence on how best to monitor treatment and compliance. It is also not known why 10-50% patients do not benefit from the drug and whether some of this resistance is because of pharmacokinetic factors. We have developed an assay using mass spectrometry (MS) to measure urinary concentrations of hydroxyurea. We have used this assay to study 12 children and six adults with SCD taking hydroxyurea and found that urinary hydroxyurea was present for at least 12 h following tablet ingestion. Thirty-five urine samples were analysed that were expected to contain hydroxyurea, based on the reported timing of the last dose and hydroxyurea was detected in 29 (83%) of these. There were also marked differences in urinary hydroxyurea concentrations, suggesting pharmacokinetic variability may explain some of the differences in response to hydroxyurea. Urine samples were also analysed by MS for penicillin metabolites and 43 of the 57 (75%) contained phenoxyacetate, suggesting the ingestion of penicillin within the last 12 h. These assays are potentially useful to study hydroxyurea metabolism further, develop optimal dosing regimes and monitor compliance with treatment.