Background: Nigeria has the highest prevalence of sickle cell disease (SCD), a common cause of pediatric ischemic stroke. In sub-Saharan Africa monthly blood transfusions for primary stroke ...prevention carries risks; hydroxyurea (HU) may be an alternative. We conducted the first, US NIH funded, SCD feasibility trial in sub-Saharan Africa (5R21NS080639-02) to: 1) assess the acceptability and willingness of families to participate in a HU trial; 2) develop a safety protocol for using HU in a trial setting in sub-Saharan Africa; and 3) prepare for a definitive phase III Trial. In the Sickle Cell Disease Stroke Prevention in Nigeria (SPIN) trial, our primary hypothesis in the internal feasibility trial is that 80% adherence for daily HU administration is feasible.
Procedure: The internal pilot is a single site; single arm trial enrolling 40 children aged 5 to 12 years with hemoglobin SS or SB0 thalassemia at risk of developing stroke with a high transcranial Doppler (TCD) velocity in the middle cerebral artery (MCA) ≥ 200 cm/sec. Each participant is scheduled to receive low dose HU therapy (~20mg/kg/day) for 36 months. Acceptability was determined by the number of families who consented for screening. The adherence rate of HU was based on monthly parental assessment of the Morisky Medical Adherence Sore (MMAS) and monthly complete blood count (CBC) to monitor the serial change in mean corpuscular volume (MCV) from baseline level. Assessment of toxicity attributable to HU was based on comparing adverse events between the HU and control groups. Controls were identified as participants that met the criteria for the trial, but had TCD measurements < 200 cm/sec. From Baby HUG, adverse events were defined as hospitalization for any cause, severe anemia and myelosuppression (severe neutropenia and thrombocytopenia based on monthly CBC).
Results: A total of 269 participants were approached, of which 96% (23 of 24) and 86% (211 of 245) with an elevated or normal TCD measurement agreed to enroll in the HU therapy or control groups with a median age of 8 and 7.6 years, respectively. At the current milestone, 100% of the participants enrolled in the treatment arm demonstrated at least average to high monthly adherence rate (MMAS of 6-8 points). This adherence rate was consistent with an increase in MCV from baseline to 3 months after starting HU therapy with a minimum increase in MCV of at least 3 fl in 8 of 11 participants. One child on HU therapy was hospitalized for 5 days for hypovolemia and dehydration associated with cholera. The table below shows no excessive rate of adverse events when HU therapy and control groups are compared.
Conclusion: These early results demonstrate the ability for a sub-Saharan African clinical research team to plan and initiate a complex SCD trial. Our preliminary data provide strong evidence for acceptability and potential safety of low dose HU therapy in Nigerian children with SCD. Completion of the internal pilot should provide sufficient evidence to pursue a phase III trial of low dose HU therapy to prevent strokes in children living in sub-Saharan Africa.
TableRates of Hospitalization within the first 12 months of the SCD Stroke Prevention in Nigeria (SPIN) Trial.Reason for HospitalizationHydroxyurea Therapy Group(15 total person years; n = 23)Rate per 100 patient yearsControl Group(52 total person years; n = 211)Rate per 100 patient yearsAcute Chest Syndrome02Osteomyelitis02Infection requiring hospitalization06Pain requiring hospitalization072Transfusion08Malaria requiring hospitalization734Fever requiring hospitalization70Other reasons for hospitalizations010
Neville:American Academy of Pediatrics; Food and Drug Administration; NICHD: Membership on an entity’s Board of Directors or advisory committees; Children’s Oncology Group; Therapeutic Advances in Childhood Leukemia; Neuroblastoma/Medulloblastoma Treatment Consortium; Pediatric Oncology Experimental Therapeutics Investigators Consortium; Midwest Cancer Alliance; Dell; Braden’s Hope Foundation: Research Funding; Sanofi; Novartis; Amgen; Medimmune; United Therapeutics; Bristol Myers Squibb: IND for hydroxyurea, IND for hydroxyurea Other.
This article reviews data about transition from paediatric to adult services in patients with sickle cell disease, the most common inherited disease in the UK, and outlines how this has been ...addressed in a large UK sickle cell centre.
Acute Chest Syndrome (ACS) is the second most common cause of hospitalisation in patients with Sickle Cell Disease (SCD) and up to 25% of those admitted will require intensive care management. ACS is ...a leading cause of death in SCD. It may also play a role in the development of chronic lung disease in SCD patients and the prevalence of Asthma in SCD patients is high. The pathogenesis of ACS is complex. Previous work has suggested a relationship between asthma and higher risk of ACS in children with SCD. Data in the UK is limited. Our aim therefore was to describe the presentation, course and outcome of ACS in our local SCD pediatric population, compared with those children who had ACS with SCD and physician diagnosed Asthma (Asthma).
Methods: The data collection took place at The Evelina Children's Hospital, which is part of St Thomas' Hospital, a large teaching hospital in Central London, England. There are over 400 children with SCD registered, and around 30 new SCD births per year. A retrospective analysis of patient hospital electronic and paper records was performed of 63 ACS presentations over a three year period from 2003 to 2006. Inclusion in the study required a new infiltrate on chest radiograph plus acute respiratory symptoms in a patient with SCD under the age of 16 years. The group included 16 (25%) presentations in children with SCD and Asthma.
Results:No Known Asthma 47 Presentations; Mean age 6.2 yrs (range 1–15yrs); HbSS 87%, HbSC13%; Previous ACS 26% (n=12); Mean length of stay 5.4 days (range 1–27); Mortality 0; Mean C-Reactive protein (CRP) on admission 70 (normal <5); Mean oxygen saturations on presentation 92% in air (40% of patients presented with saturations <92% in air)
Physician Diagnosed Asthma 16 Presentations; Mean age 4.6 (range 1–15yrs); HbSS 94%, HbSC 6%; Previous ACS 63% (n=10); Mean length of stay 5.4 (range 2–14); Mortality 0; Mean CRP on admission 41; Mean oxygen saturations on presentation 92% in air (50% of patients presented with saturations <92% in air)
DISCUSSION:Demographics: Comparable in terms of age and haemoglobin genotype. Presentation: Patients with asthma were more likely to have had previous ACS. Children with asthma presented with a lower CRP. Treatment: The treatment in both groups including the use of blood transfusion, and need for transfer to intensive care were comparable. However there was an observed difference in the use of inhaled bronchodilators (non asthma 21% v asthma 50%). Steroids were rarely used (4%) to treat the patients who did not have a pre-existing diagnosis of asthma, however were used to treat most (94%) of those patients with asthma. Outcome: Length of stay was comparable, no deaths in either group.
CONCLUSION: Although patients in our study group with asthma had a higher frequency of previous ACS episodes, we did not demonstrate that patients with asthma suffer a more severe course of illness.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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Routine use of Transcranial Doppler (TCD) screening is standard management for the prevention of Stroke in children with Sickle Cell Disease (SCD). However, due to a number of factors including the ...lack of adequately trained TCD operators, less than 50% of children with SCD are enrolled in TCD screening programmes in the USA and Europe.
This prospective, multi-centre study focused on the provision of TCD skills delivered through an educational programme. The study objectives were to determine the effectiveness of modular TCD training, to improve the quality and standardisation of TCD assessment and thereby facilitate an increase in the number of children screened.
The modular training programme comprised of a two-day course, covering theory and practical aspects of TCD and incorporating significant hands-on instruction. This was followed by local scanning with continuous monitoring and feedback from the training centre in the United Kingdom (UK). Competency evaluations were undertaken at the end of the instructional course and 6-12 months later when a log book of at least 50 scans was completed.
TCD results were collected prospectively from a consecutive series of children by certified operators at each centre. Data were compared with that acquired from the same patients in the year prior to the training programme using imaging and/or non-imaging TCD. Statistical analysis was performed using Pearson Chi-Square controlling for possible treatment bias.
Data were obtained from 326 patients (male 168 (51.5%); female 158 (48.5%); mean age 7.6±3.5, range 1-17) in the UK, Ireland and Italy. Genotypes were; HbSS 79%, HbSC 19%, HbSbetathalassemia° 1%, HbSbetathalassemia+ 1%. 462 pre-training scans (imaging and/or non-imaging TCD); 134 from the UK, 193 from Ireland and 135 from Italy, and 377 post-training scans were available; 114 from the UK, 167 from Ireland and 43 from Italy (Table). Statistical analysis revealed a significant difference in the STOP distribution between the three centres (C2=53, p<0.001) prior to training, with no treatment bias (no treatment C2=47, p<0.001; treatment n=82, C2=23, p<0.001). Anomalous technique between centres pre-training included the erroneous use of Doppler angle correction, poor vessel/Doppler angle optimisation and inconsistent STOP velocity thresholds for imaging and non-imaging studies. After training the STOP distribution was similar in the three centres (C2=7.1, p=0.311; no treatment C2=11, p=0.074; treatment n=81, C2=7.8, p=0.252). The consistent STOP distribution post-training, achieved using either imaging or non-imaging TCD, was attributed to standardisation of both technique and STOP velocity thresholds.
This multi-centre study demonstrated the success of a modular TCD training program in achieving consistent STOP classification in three European countries. To our knowledge, this is the first modular TCD training programme that has demonstrated efficacy when delivered in different European countries. This was achieved by improving the quality and standardisation of TCD using either imaging or non-imaging techniques and should facilitate the more widespread availability of competent TCD screening. This will have a significant public health impact across Europe where SCD patients are increasing due to immigration.
No relevant conflicts of interest to declare.
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