Abstract 4760
Nigeria has the largest population of children and adults with sickle cell disease (SCD) in the world. Approximately 150,000 children are born with SCD each year (incident cases) in ...Nigeria, compared to a total of approximately 100,000 children and adults living with SCD in the United States (prevalent cases). Pulmonary complications, including asthma and asthma-like symptoms are leading causes of morbidity and mortality in SCD. However, the natural history, risk factors and biological basis of asthma and SCD-associated asthma-like symptoms in SCD are poorly defined. The primary aim of this study is to determine the prevalence of asthma and asthma-like symptoms among children with and without SCD in Nigeria. In a 1:1 case-control study design, we tested the hypothesis that children with SCD would have a higher rate of asthma-like symptoms when compared to children without SCD.
We enrolled 250 cases with SCD and controls, children without SCD, from patients presenting for routine medical care at the Murtala Mohammed Specialist Hospital (MMSH) in Kano, Nigeria over a 4-month period (12/2011 to 04/2012). A structured questionnaire was employed to capture participants' demographic information, medical history (including history of asthma symptoms and allergies), environmental factors (e.g., cooking, presence of animals in the home) and parental behavior (e.g., smoking). Asthma symptoms were identified based on responses to questions adapted from the American Thoracic Society Division of Lung Disease (ATS-DLD-78) questionnaire. Chi-square test of association was used for categorical variables; Wilcoxon rank-sum tests and Kruskal-Wallis U test were used for continuous and ordinal variables.
No differences in sex, ethnicity, or place of residence were noted between cases and controls. The average age for the cases was 5.7 years and for controls was 2.8 years (P<0.01). In both cases and controls, affirmative responses to ATS-DLD questions were unrelated to age. Cases were more likely than controls to report a history of cough that worsens with a cold (28.0% vs. 16.8%, P<0.01), cough without a cold (16.0% vs. 9.6%, P=0.03), chest congestion that worsens with a cold (8.0% vs. 1.2%, P<0.01), wheezing that worsens with a cold (19.6% vs. 6.4%, P<0.01), and wheezing without a cold (5.6% vs. 1.6%, P=0.02). Participants with SCD were more likely to have eczema (4.4% vs. 0.4%, P<0.01). Surprisingly, despite the high prevalence of asthma-like symptoms in cases when compared to controls, the prevalence of physician diagnosis of asthma was low in both groups. Only two children were reported as having asthma among cases, compared to none in the control group. No participant reported a history of wheezing attacks with shortness of breath. No difference between cases and controls existed in the distribution of risk factors for asthma, namely: mode of delivery, gestational age at delivery, parental history of asthma, maternal smoking during pregnancy, and exposure to smoking as a child. No association was observed between respiratory symptoms in either group and age, household income, household size, mode of delivery, gestational age, parental history of asthma, or use of firewood/charcoal. Subgroup analysis was performed on participants 4 years of age and older (163 cases and 96 controls). No substantial differences in the results were noted when compared to the entire cohort of 250 cases and controls (results not shown).
Nigerian children with SCD have a much higher prevalence of asthma-like symptoms when compared to controls. Despite asthma symptoms being common, a diagnosis of asthma is rare in both cases and controls, suggesting under-ascertainment of an asthma diagnosis. Future work in low income countries directed towards improving co-morbid respiratory disease in children with SCD should focus on the presence of asthma-like symptoms and not a physician diagnosis of asthma. Better understanding of the biological basis for why children with SCD have a higher rate of asthma-like symptoms and atopy may lead to targeted therapy.
No relevant conflicts of interest to declare.
▪
The prevalence of renal disease in sickle cell disease (SCD) is strikingly high and is associated with morbidity and mortality (Becker et al 2010, Powars et al 2005). In SCD children there is ...initially hyperfiltration with high GFRs followed by increasing proteinuria in the adolescent and adult SCD pts. (Becker at al 2010). Historically, hypertension (HTN) has been associated with Renal Disease in the general population and a few adult sickle cell nephropathy studies. HTN has been associated with Stroke in SCD. In an ongoing multicenter, international Renal SCD Cohort Study, we investigated the association Microalbuminuria and Macroalbuminuria to Patients Blood Pressure (SBP and DBP), Hypertension based on CSSCD Group Age Defined BP for SCD patients >90%tile (Pegelow et al 1997), and Family history (FH) of Hypertension and Renal Disease in a Crossectional (Peds and Adults), International, Multicenter group of SCD patients.
272 pediatric and adult SCD (3-59 y/o) patients were recruited at baseline from 6 Centers (USA: Univ of Michigan, Case Medical Center/Rainbow Babies, Albert Einstein-Montefiore Medical Center, Univ of Connecticut; Italy: Univ. of Padova, Univ of Naples; Ghana: Korle-Bu Teaching Hospital). 88%(N=236) were severe SCD (SSorSBeta Zero) and 12%(N=31) were Mild Phenotype (SC or SBetaPlus). 58% were Children (<18y/o) and 42%(>18y/o) adults. FH of HTN and Renal Disease were obtained in 1st and 2nddegree relatives. Clinical history and laboratory studies including Pain crises patterns, SBP, DBP, BMI, CBC, Serum Crt, were collected. We obtained Urine Microalbumin/Crt(UMA) (mg/gm) obtained in 169 patients and categorized patients into 1) No Microalbuminuria(No UMA)<30mg/gm, 2) Microalbuminuria(MicroUMA) 30-299mg/gm and 3) Macroalbuminuria (MacroUMA) and obtained Urine protein/crt gm/gm(UProtCrt) in 101 SCD pts and were categorized 1) No proteinuria(NoUProt) <0.2 and 2) Macroproteinuria(MacroUProt)>0.2. Patient's HTN was defined based on CSSCD SBP or DBP> 90%tile for each specifically defined age group( Pegelow et al 1997).
In our SCD Renal Cohort Study, NoUMA in 71%(110/169), MicroUMA in 29%(48/169), MacroUMA in 2.2%(6/169) were observed. We also found NoUProt in 75%(N=75) and MacroUProt in 25%(n=25) within our cohort. Severe SCD pts represented 96%(n=46) of the MicroUMA pts, 100% or MacroUMA pts(N=6), and 92% MacroUProt pts(N=23). Proteinuria was disproportionately represented within the Adult SCD pts : 50% of Adults with MicroUMA(n=31) while only 16%(n=17) of Peds. UMA Mean Adult levels was 102(mean) vs. Peds UMA levels of 22(mean),(p=0.009); Also, Adult UProtCrt=0.21(mean)levels were >Peds=0.16, (p<0.001). HTN defined as SBP>90%tile or DBP >90%tile was present in 30%of the subjects(n=77).Thirty-One Percent(n=32) of Adults and 30%(n=45) of Peds pts had HTN. In a Bivariate Analysis(Pearson's Correlation), HTN was not associated with UMA levels(p=0.919) or UPrtCrt levels(p=0.330). Further, mean UMA was lower in HTN SCD pts( m=24) vs NonHTN(SBP) pts(m=51). Mean UProt levels lower in the HTN group(0.15 ) vs NonHTN(0.20). SBP alone was not associated with UMA( p=0.083), UPrt( p=0.804) levels, MicroUMA(p=0.596). While FH of HTN was common in 75% of pts, FH HTN was not associated with UMA and UProtCrt levels, MicroUMA, MacroUMA, MacroUProt( p>0.05) patients. FH of Renal Disease was not associated with Proteinuria within our Cohort. However, Age( p<0.001: UProtCrt levels, UMA levels, MicroUMA, SBP) and hemoglobin(p=0.034: UProt Crt levels) was significantly associated with proteinuria within our cohort based on Bivariate Analysis. BMI was associated with SBP(p<0.001) and DBP(p<0.001) but not UProt or UMA levels. Further analysis revealed increasing proteinuria(UMA) within aging SCD pts:( 6-10 UMA= 15, 11-19 UMA =42, >20y/o UMA=114)(p=.035 One Way Anova)
Systolic Blood Pressure, HTN defined as SBP>90%tile or DBP >90%tile from the CSSCD Group, FH of HTN was not associated with Micro or Macroproteinuria based on UProtCrt and UMA levels in an international, cross-sectional cohort of SCD patients. Hemoglobin level and older age were strongly associated with proteinuria within our cohort of patients, consistent with previously well established studies. These findings are supportive of other factors outside of HTN including those intrinsic to SCD contributing to early onset SCD nephropathy.
Perrotta:Novartis: Research Funding.
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.
Background
Studies of interventions to prevent the many neurological complications of sickle cell disease must take into account multiple outcomes of variable severity, with limited sample size. The ...goals of the studies presented were to use investigator preferences across outcomes to determine an attitude-based weighting of relevant clinical outcomes and to establish a valid composite outcome for a clinical trial.
Methods
In Study 1, investigators were surveyed about their practice regarding hydroxyurea therapy and opinions about outcomes for the “Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease Trial” (HU Prevent), and their minimally acceptable relative risk reduction for the two outcome components, motor and neurocognitive deficits. In Study 2, HU Prevent investigators provided overall weights for these two components. In Study 3, they provided more granular rankings, ratings, and maximum number acceptable to harm. A weighted composite outcome, the Stroke Consequences Risk Score, was constructed that incorporates the major neurologic complications of sickle cell disease. The Stroke Consequences Risk Score represents the 3-year risk of suffering the adverse consequences of stroke. In Study 4, the results of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) and Silent Infarct Transfusion Trials were reanalyzed in light of the composite outcome.
Results
In total, 22 to 27 investigators participated per study. In Study 1, across three samplings between 2009 and 2015, the average minimally acceptable relative risk reduction ranged from 0.36 to 0.50, at or below the target effect size of 0.50. In 2015, 21 (91%) reported that a placebo-controlled trial is reasonable; 23 (100%), that it is ethical; and 22 (96%), that they would change their practice, if the results of the trial were positive. In Studies 2 and 3, the weight elicited for a cognitive decline (of 10 IQ points) from the overall assessment was 0.67 (and for motor deficit, the complementary 0.33); from ranking, 0.6; from rating, 0.58; and from maximal number acceptable to harm, 0.5. Using data from two major clinical trials, Study 4 demonstrated the same conclusions as the original trials using the Stroke Consequences Risk Score, with smaller p-values for both reanalyses. An assessment of acceptability was performed as well.
Conclusion
This set of studies provides the rationale, justification, and validation for the use of a weighted composite outcome and confirms the need for the phase III HU Prevent study. Surveys of investigators in multi-center studies can provide the basis of clinically meaningful outcomes that foster the translation of study results into practice while increasing the efficiency of a study.
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.
PDF