Background: Patients with sickle cell disease (SCD) or other rare anemias whose care includes chronic blood transfusions must receive iron chelation to prevent the morbidity of iron overload. ...Currently, only deferoxamine (DFO) and deferasirox (DFX) are approved chelators in these patient populations. This randomized open-label trial evaluated if the efficacy of deferiprone (DFP) was non-inferior to DFO. DFO was used as the comparator product since DFX was not approved as first-line treatment for SCD at trial initiation.
Methods: Participants at 27 sites in 8 countries were randomized in a 2:1 ratio to receive either DFP or DFO for up to 12 months. Those with lower transfusional iron input and/or less severe iron load were prescribed either DFP 25 mg/kg of body weight t.i.d. or DFO 20 mg/kg (children) or 40 mg/kg (adults); those with higher iron input and/or more severe iron load received either DFP 33 mg/kg t.i.d. or DFO up to 40 mg/kg (children) or 50 mg/kg (adults). Dosages could be adjusted over the course of the trial if necessary. Efficacy endpoints were the changes from baseline in liver iron concentration (LIC), cardiac iron, and serum ferritin (SF) at Month 12. The primary endpoint was based on LIC, and for the demonstration of non-inferiority of DFP to DFO, the upper limit of the 95% confidence interval for the difference between treatments had to be no more than 2 mg/g dry weight (dw). All patients had their neutrophil count monitored weekly, whereas other safety assessments and compliance with study therapy were evaluated monthly. Acceptable compliance was defined as taking 80% to 120% of the prescribed dosage.
Results: A total of 228 of the targeted 300 patients were dosed with 152 receiving DFP and 76 receiving DFO, to assess non-inferiority. There were no significant differences between the groups in any demographic measures: in each treatment group, 84% of patients had SCD and the remainder had other, rarer forms of transfusion-dependent anemia. Mean age at enrollment was 16.9 years (± 9.6); 53.1% of patients were male; and 77.2% were white, 16.2% black, and 6.6% multi-racial. Over the course of the study, 69% of patients in the DFP group and 79% in the DFO group had acceptable compliance with treatment.
Based on the Pocock's α spending function, a more stringent confidence level of 96.01% was applied to the calculation of confidence interval for the evaluation of non-inferiority. For the primary efficacy endpoint, the least squares (LS) mean change in LIC (measured as mg/g dw) was -4.04 for DFP, -4.45 for DFO; the upper limit of the 96.01% confidence interval for the difference was 1.57, thereby demonstrating non-inferiority of DFP to DFO. The upper limit for the subpopulation of patients with SCD also met the non-inferiority criterion. For the secondary endpoints, the change in cardiac iron (measured as ms on MRI T2*, log-transformed) was approximately -0.02 for both; and for SF (measured as μg/L), it was -415 vs. -750 for DFP vs. DFO, respectively. The difference between the groups was not statistically significant for both endpoints.
With respect to safety, there was no statistically significant difference between the groups in the overall rate of adverse events (AEs), treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis was seen in 1 DFP patient vs. no DFO patients, while events of less severe episodes of neutropenia occurred in 4 vs. 1, respectively. All episodes of agranulocytosis and neutropenia resolved. There was no significant treatment group difference in the rates of any of the serious AEs.
Conclusion: The efficacy of DFP for the treatment of iron overload in patients with SCD or other rare anemias is not inferior to that of DFO, as assessed by changes in liver iron concentration. non-inferiority was supported by the endpoints on cardiac iron load and SF. The safety profile of DFP was acceptable and was similar to that previously seen in thalassemia patients, and its use was not associated with unexpected serious adverse events. The results of this study support the use of DFP for the treatment of iron overload in patients with SCD or other rare transfusion-dependent anemias.
Note: The authors listed here are presenting these findings on behalf of all investigators who participated in the study.
Kwiatkowski:Terumo: Research Funding; Imara: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy; Apopharma: Research Funding. Fradette:ApoPharma: Employment. Kanter:Sangamo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; Modus: Consultancy, Honoraria. Tsang:Apotex Inc.: Employment. Stilman:ApoPharma: Employment. Rozova:ApoPharma: Employment. Sinclair:ApoPharma: Employment. Shaw:ApoPharma: Employment. Chan:ApoPharma: Employment. Toiber Temin:ApoPharma: Employment. Lee:ApoPharma: Employment. Spino:ApoPharma: Employment. Tricta:ApoPharma: Employment.
Deferiprone is an oral iron chelator.
Introduction: Millions are affected by Sickle Cell Disease (SCD) worldwide with the greatest burden in sub-saharan Africa. Its origin thought to lie within the malaria belt of the world, SCD ...continues to affect thousands of lives worldwide partly due to the migration patterns of the human race to different continents. We created the Consortium for the Advancement of Sickle Cell Research (CASiRe) to better understand the different phenotypes of SCD and compare the clinical profiles of patients living in different environments through a validated questionnaire and medical chart review, standardized across 4 countries (United StatesU.S. United KingdomU.K., Italy and Ghana). For this report, we recorded the multi-generational ethnic and racial background of 877 SCD patients across the CASIRE cohort for our final analysis.
Methods: CASiRe included 6 sites in the U.S. (Univ. of Michigan, Rainbow Babies & Children's Hospital, Promedica Toledo Children's Hospital, Children's Hospital at Montefiore, Connecticut Children's Medical Center, Univ.of Connecticut Health Center), 2 in Ghana(Ghana Institute of Clinical Genetics, Pediatric SCD Clinic at Korle Bu Teaching Hospital), 2 in Italy( Univ. of Campania Luigi Vanvitelli, Univ. of Padua, Italy), and U.K.(Guys & St. Thomas Hospital, Evelina Children's Hosp). Between 2011 and 2017, after obtaining IRB approval at each site and written informed consent, demographic, clinical and laboratory data were collected by interviewing the patient and/or parent/guardian At the 2 sites (Guys and St Thomas Hospital, UK; Univ. of Padua, Italy) with existing IRB approved SCD registries data were abstracted directly from their respective databases. Descriptive statistics were performed on a subset of demographic data that included: age, race, gender, sickle cell genotype, country of birth of patient, parents, and grandparents. The geographic region and country of origin was based on parents' country of birth and separated into 10 regions: W.Africa, C.Africa, N Africa, Caribbean, C. America, N America, Europe, S America, Asia, Middle East.
Results: 877 patients were enrolled with a median age 19.3 years. 451 (51.4%) patients were children, 424 (48.3%) male. Ghanaians represented 41.6% (365) of patients, while 254 patients (29%) were from the U.S. Italy enrolled 81 patients (9.2%), and 177 patients (20.2%) were from the U.K. West Africa represented the largest geographic region of origin of(577/65.8%), followed by N. America (184/21%), Caribbean (51/5.8%), Europe (27/3.1%), and Central Africa (24/2.7%). Overall(Fig. 1), 75% of patients (658) had Hgb SS, 168 patients (19.2%) had Sickle C disease, 29 (3.3%) had Sβ+thal and 22 patients (2.5%) of patients had Sβ0 thal. Racially, 820 patients (93.5%) identified themselves as African American or Black, while 30 patients (3.4%) identified themselves as Caucasian and 21 patients (2.4%) identified themselves as Latino or Hispanic. All Ghanaians identified as Black, while in the US and UK, over 90% of patients identified themselves as Black, and about 3% reported themselves as Caucasian. In comparison, in Italy, over 76% of patients reported a Black racial background, while 21% reported Caucasian background. (Table 1 and 2)>98%Ghanaian patients and their parents were born in Ghana. In contrast, 66.7% of patients and <15% of parents in Italian sites were born in Italy with the 64% of parents emanating from West Africa (38% Nigeria).Over 85% of patients in the UK were born in the UK while only 5.1% of parents were born there (54% in Nigeria). In the US, >90% of patients were born within the US; Parents of patients were born in America 70% of the time. Caribbean (12.5%) and West African countries(9.5%) were the next highest parent countries of origin. 32 different countries of origin were reported within our cohort with the US leading with 22 different countries.
Conclusion: This study is the first to describe the geographic distribution of these migrations in a very large cohort of nearly 900 patients with SCD.West Africa represented the largest geographic region of origin for SCD patients in Europe while Caribbean was the leading Non-US geographic region of origin in American patients. The diverse ethnic backgrounds observed in our cohort raises the possibility of how genetic and environmental heterogeneity within each SCD population subgroup can have implications on the clinical phenotype and clinical research outcomes.
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Campbell:Novartis: Research Funding; Cyclerion: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Colombatti:Novartis: Consultancy; Global Blood Therapeutics: Consultancy; AddMedica: Consultancy. Andemariam:NovoNordisk: Membership on an entity's Board of Directors or advisory committees; New Health Sciences: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: DSMB Member; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Emmaus: Membership on an entity's Board of Directors or advisory committees; Cyclerion: Membership on an entity's Board of Directors or advisory committees; Imara: Research Funding; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Community Health Network of Connecticut: Consultancy; Terumo BCT: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Strunk:Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Speakers Bureau. Piccone:Hemex Health, Inc.: Patents & Royalties. Manwani:GBT: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy. Perrotta:Novartis: Honoraria, Research Funding; Acceleron Pharma: Research Funding.
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Background: Sickle cell anemia (SCA) is a monogenic disease resulting in polymerization of hemoglobin in hypoxic conditions. This leads to red blood cell (RBC) membrane damage and sickling, causing ...vaso-occlusion and hemolysis. Continual, excessive release of lysed RBC contents within the vascular space can activate the inflammasome, a multiprotein oligomer that promotes maturation and secretion of pro-inflammatory cytokines, including interleukin 1-beta (IL-1β). The intravascular inflammation associated with SCA, e.g., increased serum c-reactive protein (CRP) and absolute counts of neutrophils and monocytes, is predictive of long-term morbidity and mortality. Inflammation is a major component of many of the clinical complications of SCA, including vaso-occlusive pain episodes, acute chest syndrome, vascular-endothelial dysfunction, renal disease and other forms of end organ damage. Standard of care for SCA is hydroxyurea, which augments fetal hemoglobin levels and may have some anti-inflammatory effects by reducing neutrophil and monocyte counts. Canakinumab is a fully human monoclonal antibody targeting IL-1ß and blocking its downstream pro-inflammatory activities with potential to ameliorate the inflammatory complications of SCA.
Objective:To clinically validate in pediatric and young adult SCA patients the hypothesis that IL-1ß blockade by canakinumab is safe and provides clinical benefits.
Methods: A multi-center, randomized, parallel group, double-blind, placebo-controlled trial recruited SCA patients (HbSS or HbS/ß0thalassemia) with history of ≥2 major pain episodes/year, screening baseline detectable pain (using pain e-diaries) and serum high sensitivity CRP level ≥1.0 mg/L. Patients were randomized with 1:1 ratio to receive six monthly s.c. injections of either canakinumab 300 mg (4 mg/kg for patients ≤40 kg) or placebo. The concurrent use of hydroxyurea was a stratification factor at randomization. Outcomes were measured at baseline and at weeks 4, 8, 12, 16, 20, 24, after which all patients moved to open label canakinumab treatment for additional 6 months. Electronic patient reported outcomes included daily pain intensity with a 0-10 cm visual analog scale, school/work absences secondary to SCA, fatigue and analgesic use. The primary outcome was change from baseline in the 4-week average daily pain intensity at week 12. Other secondary and exploratory outcomes included daily activity measured by wrist actigraphy, rate of hospitalization and adverse events, serious adverse events, transcranial Doppler velocities, percent oxygen saturation and laboratory markers of inflammation and hemolysis.
Results: A planned interim analysis for futility and safety was performed on the first 30 enrolled patients (canakinumab, n=16; placebo, n=14), of whom 26 patients completed the Week 12 assessments (canakinumab, n=14; placebo, n=12), and 13 patients completed the Week 24 assessments. Enrolled patients (median age 17 years, range 12-20; 19 male, 11 female) were evenly distributed between treatment arms. All except one patient were maintained on a stable hydroxyurea regimen. Baseline overall disease activity levels (median, range) included average daily pain 3.93 0.29, 6.57; high sensitivity CRP 3.93 mg/L 1, 64.7; transcranial Doppler velocities 85.0 m/s 23, 267; hemoglobin 94.8 g/L 73.5, 121. Futility criteria were not met and no canakinumab-associated safety issues were identified in this first interim analysis.
Conclusions: Canakinumab was well tolerated and not associated with any major side effects in SCA. Results from a second interim analysis of study outcomes for all currently enrolled patients (n=49) completing the blinded, 24-week treatment period will be available in November 2019.
Rees:Agios: Other: Grants; TauRx (methylene blue): Other: Data monitoring committees; Astra Zeneca (ticagrelor): Other: Data monitoring committees; Novartis: Other: Strategic advisory role,Principal investigator,sickle cell disease2.6 Investigator; Emmaus: Other: Strategic advisory role; Celgene: Other: Strategic advisory role; Global Blood Therapeutics: Other: Strategic advisory role; Alnylam: Other: Principal investigator. Dampier:Micelle Biopharma: Consultancy, Research Funding; Merck: Research Funding; Hudson Publishing Company: Consultancy; Global Blood Therapeutics: Consultancy; Ironwood: Consultancy; Epizyme: Consultancy; Modus Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mahlangu:Sanofi Genzyme: Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding; Baxalta: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Biomarin: Research Funding; uniQure: Research Funding; Spark: Consultancy, Speakers Bureau; Chugai: Consultancy; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Freeline Therapeutics: Research Funding; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; World Federation of Haemophilia: Speakers Bureau. Mortier:Novartis Pharma AG: Employment. McNamara:Novartis Pharma AG: Employment. Li:Novartis Pharma AG: Employment. Oliver:Novartis Pharma AG: Employment, Equity Ownership.
canakinumab use in the treatment of sickle cell anemia.
The diagnosis of acute autoimmune rheumatic disorders in sickle cell disease (SCD) can be challenging. Polymyositis is an inflammatory myopathy which, like SCD, may present with myalgia but is ...usually associated with proximal muscle weakness. We describe an adolescent boy presenting with limb pain, difficulty in mobilisation, with progressive loss of motor function and later bulbar weakness. Investigations showed massive elevation of creatine kinase, and MRI and muscle biopsy findings consistent with severe polymyositis. The patient was treated with corticosteroids, intravenous immunoglobulin and intensive rehabilitation therapy. He made a good recovery and was discharged on azathioprine and prednisolone. In the context of SCD, multisystem symptoms, unexplained muscle pain and weakness, unresponsive to conventional treatment in the presence of steady state haemoglobin, should alert the clinician to autoimmune phenomena. Key factors in making a diagnosis are an autoimmune screen and early discussion with a rheumatology expert.
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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.
Introduction: BMT is the only proven curative treatment available for haemoglobinopathies. However, the number of patients who can benefit is seriously restricted by the lack of HLA-matched related ...donors not suffering from the condition and the limited number of unrelated donors available for the ethnic groups in which these conditions are prevalent. In order to expand the donor pool, haploidentical transplantation with a post-infusion of stem cells cyclophosphamide approach has been developed for young adults, but whilst well tolerated it has resulted in relatively high rates of rejection and the need for a prolonged period of immunosuppression1.
Materials (or patients) and methods: 16 consecutive related haploidentical transplants (13 for sickle cell disease and 3 for β halassaemia major) were performed at St. Mary's Hospital, London, from June 2013 to May 2015. The donor was a parent in 15 cases and a sibling in one case. The median age was 10 years of age (range 3 to 18). All patients lacked a suitable HLA-matched related donor and an unrelated search had not identified a 10/10 or 9/10 donor. Endogenous haemopoieis was suppressed with hypertransfusions, hydroxycarbamide 30 mg/kg and azathioprine 3 mg/kg for at least two months pre-transplantation. The conditioning included fludarabine 150 mg/m2, thiotepa 10 mg/kg was added, cyclophosphamide 29 mg/kg, TBI 2 Gy and ATG (Thymoglobulin) 4.5 mg/kg. GvHD prophylaxis was provided with cyclophosphamide 50 mg/kg on days +3 and +4, MMF and sirolimus. The median survival was 8.19 months post-transplantation (1.28-22.96) and half of the patients are >150 days post-transplantation and have completed all treatment. The source of stem cells was G-CSF primed bone marrow in all cases, aiming ≥8 x 108 TNC/kg median 9.97 x 108 TNC/kg (2.35-20.5), 3.88 x 106 CD34+/kg (1.12-9.21).
Results: All patients engrafted, though one patient subsequently suffered secondary graft failure following macrophage activation syndrome and died. The median neutrophil engraftment was 17 days (range 16 to 29). The median platelet engraftment >50 x109/L was 32 days (range 20 to 64). All 15 surviving patients are cured from the manifestations of the original disease. One patient suffered VOD following autologous rescue with limited conditioning for secondary graft failure. Infectious complications occurred at a higher rate than seen for related transplants for the same conditions at our institution. Acute GvHD ≥ grade II occurred in two patients (12.5%, skin and gut GvHD respectively) responding to treatment with MSC and one patient was treated for chronic GvHD (6.3%). The median time to cessation of immunosuppression was 124 days (108-189). All patients but one achieved ≥90% donor fraction both in whole blood and T cells at day +180, with only such patient requiring continuation of immunosuppression (day +28: 93.3% patients ≥95% donor and 6.7% patients ≥90-94% in whole blood, and 73.3% patients ≥95% donor, 13.3% patients ≥90-94%, 6.7% donor ≥50-89% and 6.7% donor <50% in T cells, n=15; day +180: 70% patients ≥95% donor, 20% patients ≥90-94% and 10% patients ≥50-89% in whole blood, and 80% patients ≥95% donor, 10% patients ≥90-94% and 10% donor <50% in T cells, n=10).
Conclusion: Related haploidentical transplantation providing sufficient myelosuppression to avoid rejection is feasible, leading to outcomes which approach the results for related transplantation and allowing all patients with haemoglobinopathies requiring a transplant to benefit fromm such treatment.
References: 1. Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, Brodsky RA. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012 Nov 22;120(22):4285-91.
No relevant conflicts of interest to declare.
Background:
Sickle cell disease (SCD) is a very variable condition, with some patients being asymptomatic and others admitted frequently to hospital. Genetic factors have been extensively ...investigated but only explain a small amount of the variability to date. Environmental factors are undoubtedly important, but have not been studied in depth, at least in part because of the difficulty of conducting these studies.
We have analysed the role of climatic, environmental and temporal factors in determining the frequency of hospital admissions in children with SCD to 4 large sickle cell centres in London and Paris.
Participants and Methods:
Clinical data were collected from 1st January 2007 to 31st December 2012. Inclusion criteria were children with SCD (HbSS and HbSC) between the ages of 0 and 17 years, admitted to hospital with acute pain, acute chest syndrome or fever. All children lived within 4 miles radius (London) or 10km (Paris) of the hospital. Data were collected using specific electronic patient records of SCD patients. Data were collected on the reason for admission, date and length of admission. Daily air quality records were collected from sites around Paris and London, including details of black smoke, particulate matter, nitric oxide, carbon monoxide, sulphur dioxide and ozone. Daily meteorological records were obtained from weather stations in London and Paris including wind speed, temperature, rainfall and humidity. Statistical analysis including time series studies were conducted using R software version 3.1.1.
Results: There were a total of 2717 admissions over the six year study period. Overall for the London hospitals there was a mean of 0.39 admissions/patient/year, with 1406 admissions for pain, 153 for acute chest syndrome and 417 for fever. The rate of admission/patient/year by cause for HbSS and HbSC across the London hospitals is shown in table below:
Table 1Rates of admission/patient/year by causeSickle genotype/cause of admissionAll London hospitalsInstitution AInstitution BInstitution CHbSS (Pain)0.310.180.400.43HbSS (Fever)0.090.030.150.11HbSS (acute chest syndrome)0.040.030.040.04HbSC (pain)0.070.030.080.10HbSC (fever)0.030.010.040.05HbSC (acute chest syndrome)0.0040.0080.0020.002
Overall admission numbers were significantly higher on Mondays and Tuesdays in London but there was no such variation in Paris (Table 2).
Table 2Mean number of admissions on days of week in Paris (1 hospital) and London (3 hospitals). ** denotes significant difference from mean of other days (P<0.001).LondonParisWeekdayMonday0.75**0.35Tuesday0.77**0.36Wednesday0.660.36Thursday0.640.32Friday0.600.32Saturday0.510.20Sunday0.570.27
There was no seasonal variation in admission numbers in London, but significantly higher numbers of patients admitted in Paris during autumn and winter.
Table 3Mean number of seasonal admissions in Paris (1 hospital) and London (3 hospitals). ** denotes significant difference from mean of other days (P<0.001).LondonParisSeasonAutumn0.700.35**Spring0.600.31Summer0.640.25Winter0.620.34**
Conclusion
In London, there is a 2-3 fold variation in admission rates for the same complications between different hospitals. Similarly there is a significant difference on the effects of season and weekday between Paris and London. These results are statistically stronger than many effects which are identified in genetic and therapeutic studies, and show the importance of environmental and cultural factors, which are potentially modifiable. The effect of weather and pollution on hospital admissions is currently being analysed.
No relevant conflicts of interest to declare.
Background: Renal disease is a common end organ complication of sickle cell disease(SCD). Risk factors of sickle cell nephropathy include age, genotype, and anemia. We have investigated and ...discovered Lower Hemoglobin Oxygen Saturation levels associated with microalbuminuria. To further investigate this, we investigated a patient's history of asthma as a risk factor of renal disease. Asthma has been linked to increased mortality in adult and children with SCD from the National Cooperative SCD Study Group. In our ongoing International CASIRE Renal Cohort study, we investigated the clinical history of asthma and laboratory correlates of albuminuria and proteinuria as measured by Urine Protein/Creatinine and Urine Albumin/Creatinine .
Methods: 538pediatric 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;). Clinical history and laboratory studies, including Pain crisis patterns, SBP, DBP, BMI, CBC, Serum Crt, Urine ph, Urine SG were collected. For this report, we concentrated on patient’s comorbidities and sickle cell medical history, specifically pain crisis patterns, acute chest history and asthma. Urine Microalbumin/Crt(UMA) (mg/gm) was obtained in 172 patients and we categorized patients into No Albuminuria: (No UMA)<30mg/gm and Albuminuria(UMAlbum): Microalbuminuria(MicroUMA) 30-299mg/gm and Macroalbuminuria (MacroUMA)>300mg/gm.334 subjects answered the question of medical history of asthma and of those 172 had Urine Microalbumin (UMA) levels. 75% of SCD-Asthma group (N=56) and 78% of SCD-NoAsthma group (N=204) had severe SCD (SS or SBeta Zero). Children (<18y/o) comprised 58% of the SCD-Asthma group (N=43) and 62% of the SCD-NoAsthma group (N=161). Mean age was 16 y/o in both SCD-Asthma and SCD-NoAsthma Groups.
Results: No Albuminuria (NoUMAlbum) was reported in 80% (138/172) while Albuminuria(UMAlbum) was recorded in 20% (34/172) of the Cohort. Severe SCD pts represented 91% (n=33) of the Albuminuria pts. Adult UMA levels were higher (mean=61) than Peds UMA levels (mean=22) (p=0.025). Patients with History of Asthma had higher mean UMA levels ( 94 vs 21, p=0.005). Further, a history of asthma was associated with higher mean UMA levels (122 vs 23, p=0.003) within the Severe Genotype group (p=0.002), within all Pediatric SCD patients ( 60 vs 17, p=0.002), and within Severe Pediatric SCD patients ( 68 vs 19, p=0.004) (One Way Anova). Within the Medical history, BMI in the underweight range and a history of priapism were associated with elevated UMA levels.
Conclusions: Age and Severe Genotype was associated with Albuminuria. A history of asthma was strongly associated with renal disease in Pediatric SCD patients in addition to a very strong association within Pediatric Severe Genotype patients. Optimal control of asthma could possibly mitigate the risk of kidney disease with SCD patients. A more in-dept analysis of patient's history of asthma would provide stronger evidence of these findings.
Asare:Intramural University of Ghana Research fund: Research Funding; Vanderbilt University Medical Center Gift Funds: Research Funding. Piccone:Novartis: Other: Speaker. Rivers:Acetylon: Research Funding.
Abstract 4206
An integral part of an EU-UNDP funded pilot sickle cell screening project, was the installation, in Abuja (Federal Capital Territory) Nigeria, June 2010, of a High Performance Liquid ...Chromatography (HPLC) instrument. Prior to the installation, haemoglobinopathy screening was carried out using only unstained paper electrophoresis. Minor bands were difficult to visualise and the proportions of haemoglobins were not measured. Full blood count (FBC) data was also not routinely available. Therefore awareness of both alpha and beta thalassaemia was low as was the implications of coinheritance of beta thalassaemia with haemoglobin (Hb) S.
Stratified community surveys were carried out with samples collected as Guthrie card blood spots; children aged less than 6 months, and whole blood; children aged between 6 months and 5 years. Blood spot samples were analysed using newborn sickle cell screening reagents and whole blood samples using beta thalassaemia short reagents, the later allowing accurate Hb A2 and Hb F measurement. Samples were processed on a Biorad™ Classic (instrument and reagents, Biorad, Hercules, CA.). Reporting algorithms were defined for both reagent sets. Using the beta thalassaemia reagents, Hb S/beta thalassaemia was considered when Hb S was predominant, Hb A absent or significantly reduced and the Hb A2>5.
Over 10,000 samples were analysed, 410 had sickle cell disease, of which 370 were transported to London for further analysis, 70 of these had an Hb A2>5%, mean and range 5.9(5.1 – 9.1)%. To validate the algorithm 31 samples (Hb A2 3.5 – 7.4%), were selected for beta gene sequencing (Mai et al, 2004) and/or PCR analysis for the 7 common alpha gene deletions (3.7kb, 4.2kb, SEA, MED, THAI, FILL, 20.5kb and triplicated alpha gene locus, anti 3.7kb), (Chong et al, 2000, Wang et al, 2003). Five samples had an Hb A2of 3.5 – 4.9%, 2 with Hb A present (23 and 25%), all were Hb SS, 4 negative for alpha thalassaemia deletions and 1 heterozygous for the alpha 3.7kb deletion. Sixteen samples had an Hb A2 of 5.0 – 5.9%, all were Hb SS, 5 negative for alpha thalassaemia deletions and 11 heterozygous for the alpha 3.7kb deletion. Seven samples had an Hb A2 of 6.0 – 6.9%, 6 were Hb SS, 1 negative for alpha thalassaemia deletions, 1 heterozygous and 4 homozygous for the alpha 3.7kb deletion. One, Hb A2 6.9%, was a compound heterozygote for Hb S/ beta zero codon 106/107(+G) mutation. Three samples had an Hb A2 of 7.0 – 7.4%, review of chromatograms indicated that all showed poor chromatography due to lack of separation between Hb A2 and Hb S or shoulders to the left of the Hb A2 peak. All were Hb SS and heterozygous for the alpha 3.7kb deletion, with 1 also positive for the triplicated alpha globin gene, anti 3.7kb. Four other samples with Hb A2 >7% also showed poor chromatography, but were insufficient for molecular testing.
The results indicate that Hb A2values >5% were mainly due to co-existing alpha thalassaemia with 76% of those tested, positive for the 3.7kb deletion. Poor chromatography was also a contributor particularly at the higher Hb A2 levels. During the initial stages of the project air conditioning failure caused major temperature fluctuations on overnight runs, this problem was resolved, improving chromatography. One case of S/beta zero thalassaemia was detected confirming the presence in this population. The results suggest that the Hb A2 may be considered as a discriminator for S/beta thalassaemia screening in this setting, increasing the algorithm Hb A2 level to >6.0% may improve specificity and reduce the number of false positives, this warrants further investigation. Future aims of the project for children over 6 months of age, include initiating routine FBC analysis and testing parental samples as a cost effective means of confirming suspected cases.
No relevant conflicts of interest to declare.
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Background: As patient-centered care advances, measurement of health-related quality of life (HRQL) has become increasingly important when assessing the impact of a disease or therapy on a child. ...Red blood cell transfusions are an effective preventative therapy for some acute and chronic complications in children with sickle cell disease (SCD). This study aimed to determine the impact of transfusion therapy on health-related quality of life (HRQL) outcomes of children with SCD.
Procedure: Children (n = 196) who participated in the Multicenter Silent Infarct Transfusion (SIT) Trial were grouped per protocol into either those who received 18 months or more of transfusion or less than 18 months of transfusion (observation). Parents/guardians of children ages 5 to 18 years completed assessments of HRQL using the Child Health Questionnaire at baseline and at the time of study exit or neurological event, if that occurred.
Results: Children (43% female) had a mean age of 9.55 years (SD= 2.59) at study enrollment, and 92% were Black. There were no differences between study groups (effectively transfused vs. observation) in regards to gender, disease severity, rates of pain and acute chest syndrome, or baseline levels of HRQL.
At study exit, independent samples t-tests revealed children in the effectively transfused group had significantly higher scores than the observation group for the following HRQL domains: Physical Function (M = 12.68, SE = 3.52), t (174) = 3.61, p ≤ 0.001; Bodily Pain (M = 13.16, SE = 3.74), t (174) = 3.51, p ≤ 0.001; and Change in Health (M = 0.39, SE = 0.14), t(166) = 2.71, p=0.01. Additionally, children in the effectively transfused group scored 4.98 (SE = 1.98) points higher on Physical Summary Scores than children in the observation group, t (170) = 2.52, p= 0.01. Thus, parents report that children who received at least 18 months of transfusions had better overall physical functioning, less bodily pain, and more improved overall health than children who had fewer than 18 months of transfusions.
Both groups reported changes in HRQL over time. Compared to study entry, paired samples t-tests revealed children in the observation group indicated an increase of 0.42 (SE = 0.14) points for Change in Health scores t (77) = 3.06, p ≤ 0.001, but had a decrease of 5.95 (SE = 2.07) points for Self-Esteem at study exit, t (85) = -2.87, p = 0.01. Children in the transfusion group improved by 7.22 (SE = 3.11) points in regards to pain over the course of the study, t (78) = 2.32, p = 0.02. Additionally, these children had better overall health as exhibited by their Change in Health scores (MD = 0.93, SE = 0.14), t (72) = 6.80, p = ≤ 0.001, and General Health scores (MD = 4.13, SE = 1.83), t (77) = 2.26, p = 0.03. Further improvements over time were noted for the effectively transfused group for Physical Functioning (MD = 6.58, SE = 3.09), t (78) = 2.13, p = 0.04, and Physical Summary Scores(MD = 4.89, SE = 1.82), t (73) = 2.69, p= 0.01.
Although both study groups reported improvements in Change in Health scores over the course of the study (Effectively Transfused: MD = 0.93, SE = 0.14; Observation: MD = 0.42, SE = 0.14), an estimated Least Square Means analysis revealed children in the observation group did not improve as much as children in the effectively transfused group, Difference Estimate = -0.46, p= 0.02.
Conclusions: This study provides the first evidence that blood transfusion improves HRQL in children with SCD. Children in the SIT trial who received at least 18 months of chronic blood transfusion therapy felt better and had better overall HRQL than those who had less than 18 months of transfusion therapy.
Casella:Mast Therapeutics, previously Adventrix, ImmunoArray: Consultancy, Honoraria, Other, Patents & Royalties, Research Funding.
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