Baba Inusa

Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.).

Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease

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.

Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure

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.

Infection in sickle cell disease: a review.

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.

Long-term safety and efficacy of deferasirox (Exjade®) for up to 5 years in transfusional iron-overloaded patients with sickle cell disease

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.

A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events

BACKGROUND Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso-occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events. METHODS Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries. RESULTS A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person-year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups. CONCLUSIONS Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).

Health-related quality of life in children with sickle cell anemia: impact of blood transfusion therapy

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 childs 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. Am. J. Hematol. 90:139–143, 2015.

Primary Stroke Prevention in Nigerian Children with Sickle Cell Disease (SPIN): Challenges of Conducting a Feasibility Trial

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.

Dilemma in differentiating between acute osteomyelitis and bone infarction in children with sickle cell disease: the role of ultrasound.

Background Distinguishing between acute presentations of osteomyelitis (OM) and vaso-occlusive crisis (VOC) bone infarction in children with sickle cell disease (SCD) remains challenging for clinicians, particularly in culture-negative cases. We examined the combined role of ultrasound scan (USS), C - reactive protein and White blood counts (WCC) in aiding early diagnosis in children with SCD presenting acutely with non-specific symptoms such as bone pain, fever or swelling which are common in acute osteomyelitis or VOC. Methods We reviewed the records of all children with SCD who were discharged from our department from October 2003 to December 2010 with a diagnosis of osteomyelitis based on clinical features and the results of radiological and laboratory investigations. A case control group with VOC who were investigated for OM were identified over the same period. Results In the osteomyelitis group, USS finding of periosteal elevation and/or fluid collection was reported in 76% cases with the first scan (day 0–6). Overall 84% were diagnosed with USS (initial +repeat). 16% had negative USS. With VOC group, USS showed no evidence of fluid collection in 53/58 admissions (91%), none of the repeated USS showed any fluid collection. Mean C-reactive protein (CRP), and white cell count (WCC) were significantly higher in the OM. Conclusion The use of Ultrasound in combination with CRP and WCC is a reliable, cost-effective diagnostic tool for differentiating osteomyelitis from VOC bone infarction in SCD. A repeat ultrasound and/or magnetic resonance imaging (MRI) scan may be is necessary to confirm the diagnosis.

The measurement of urinary hydroxyurea in sickle cell anaemia

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.