Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established routine transcranial Doppler ultrasound (TCD) screening with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. To identify children at high-risk of stroke, annual TCD screening is recommended from ages 2 to 16 years, with more frequent monitoring if the result is not normal. A reduction in stroke incidence in children with SCD has been reported in several clinical series and analyses utilizing large hospital databases when comparing rates before and after the publication of the STOP study in 1998. We sought to determine the rate of first ischemic stroke in a multicenter cohort of children who had previously participated in the STOP and/or STOP 2 trials and to determine whether these strokes were screening or treatment failures. Subjects and Methods: Between 1995 and 2005, STOP and STOP 2 (STOP/2) were conducted at 26 sites in the US and Canada. These studies included 3,835 children, ages 2 to 16 y with SCD type SS or S-beta-0-thalassemia. Participation in STOP/2 ranged from a single screening TCD to randomization. STOP 2 also had an observational arm for children on CRCT for abnormal TCD whose TCD had not reverted to normal. The Post-STOP study was designed to follow-up the outcomes of children who participated in one or both trials. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3,539 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 (depending on site) including follow-up TCD and brain imaging results, clinical information, and laboratory results. Two vascular neurologists, blinded to STOP/2 status and prior TCD and neuroimaging results, reviewed source records to confirm all ischemic strokes, defined as a symptomatic cerebral infarction; discordant opinions were resolved through discussion. For the first Post-STOP ischemic stroke, prior TCD result and treatment history subsequently were analyzed. Abstract source

Complications affecting multiple organs, including the liver, contribute to early mortality in patients with sickle cell disease (SCD). Earlier diagnosis and monitoring of “sickle hepatopathy”, preferably using non-invasive methods, would enable earlier intervention and therefore, potentially a better outcome for patients. In many non-SCD chronic liver diseases, fibrosis stage is the most important predictor of morbidity and mortality. Two non-invasive methods of assessing liver fibrosis are used: Transient Elastography (TE, Echosens) and Enhanced Liver Fibrosis Score™ (ELF, iQUR). TE detects fibrosis using ultrasound and low frequency elastic waves with a propagation velocity directly related to the stiffness of the liver. The ELF score examines the balance between matrix deposition and degradation using levels of three proteins analysed using a patented formula. We report a prospective study correlating liver function tests (LFTs) with the level of liver fibrosis (as ascertained by TE and ELF) in a cohort of patients with SCD. Ethical approval for this study was obtained from the NHS ethics committee (11/LO/0005) and patients were consecutively recruited in the steady-state sickle cell clinic at Kings’ College Hospital, London, during 2012. Patients were excluded if they had viral hepatitis or were pregnant. Clinical (transfusion and hydroxyurea therapy), imaging (liver iron concentration, LIC) and laboratory data were collected during steady-state. TE and ELF were performed on 194 patients. The patients ranged from 17-72 years (mean age 35 years); 78 (40%) were male, 134 (68%) had HbSS or HbSb0 (SCA), 48 (26%) Hb SC, and the remainder, Hb Sβ+ (excluded due to low numbers). Statistical analysis was undertaken in IBM SPSS version 20. There was significant correlation between both TE and ELF with age, when corrected for sickle genotype (TE β = 0.19, p = 0.006 and ELF β = 0.2, p = 0.005) (Figure). Patients with SCA had significantly higher TE results and mean ELF scores than those with HbSC (TE, 6.8 vs 5.3, p In SCA patients, TE correlated significantly with all serum LFTs (Albumin R = -0.35 p<0.0001, AST R = 0.44 p<0.0001, ALP R = 0.29 p<0.0001, GGT R = 0.40 p<0.0001, conjugated bilirubin R = 0.26 p = 0.004). Positive correlation was found with LDH (R = 0.24 p = 0.004) and negative correlation with Hb (R= -0.25 p = 0.002). In the Hb SC group, TE correlations were weaker for AST (R = 0.39 p = 0.004), ALP (R = 0.30 p = 0.03), WBC (R = 0.39 p = 0.02) and reticulocyte count (R = 0.35 p = 0.01). All markers of iron loading correlated with TE values, when corrected for sickle genotype (serum ferritin β = 0.25, p <0.0001, total top-up units β = 0.22, p = 0.001, total units transfused β = 0.25, p In SCA patients, ELF score correlated with serum LFTs (Albumin R = -0.30 p<0.0001, AST R = 0.39 p<0.0001, ALP R = 0.25 p = 0.003, GGT R = 0.28 p = 0.001, conjugated bilirubin R = 0.36 p<0.0001). Positive correlation was seen with LDH (R = 0.26 p = 0.002) and negative correlation with Hb (R = -0.25 p = 0.004). Negative correlation was also seen with HbF levels (R = -0.24 p = 0.01). In the HbSC group, there were no significant correlations between ELF and serum LFTs. However associations were seen between ELF score and LDH (R = 0.40 p = 0.004) and Hb level (R = -0.31 p = 0.01). ELF score correlated with serum ferritin (β = 0.25 p <0.0001), and total blood transfusion units (β = 0.24 p = 0.001). These data show significant levels of liver dysfunction in our SCD population using both TE and ELF score which correlated significantly with abnormal LFTs and markers of hemolysis and iron overload. The role of TE and ELF in monitoring liver dysfunction in SCD needs to be further validated, preferably with longitudinal, and if possible histological data. Abstract source

Objective: A comparative cost analysis of sickle cell admissions vs. stem cell transplants in sickle cell patients. Hypothesis:We believe the overall cost of a bone marrow transplant for a sickle cell patient will be less than that of a patient with multiple sickle cell admissions. Background: Sickle cell disease remains an increasing burden to the cost of health care and health care providers. The disease results in a variety of serious organ system complications that can lead to life-long disabilities and/or early death. Despite the advent of hydroxyurea, sickle cell admissions and cost have been increasing over the course of several years. Various contributing factors may include socioeconomic status, complications of sickle cell anemia itself, narcotic dependence and noncompliance with medications. Bone marrow transplants were introduced in 1982 as an option for the treatment of sickle cell anemia, and are currently the only curative option in this disease. A study conducted at the NIH from 2004-2013, found that bone marrow transplant reversed the disease in 26 of 30 patients (87%) (Hseih et al, N Engl J Med 2009; 361:2309-2317). The patients ultimately had a normal hemoglobin, fewer hospitalizations, and lower use of narcotics to treat pain from the disease. However, the underutilization of bone marrow transplant continues to exist and may in part be secondary to a lack of fully matched donors. To overcome this challenge, the Johns Hopkins group developed a nonmyeloablative bone marrow transplantation platform using HLA haploidentical donors for patients using posttransplant cyclophosphamide. As a result, 17 patients were successfully transplanted, 14 from HLA-haploidentical and 3 from HLA-matched related donors (Meade et al, Blood. 2012; 120(22):4285-4291). Due to this, most patients with sickle cell disease have the potential to undergo a successful bone marrow transplant. However, an analysis comparing the cost of admissions vs. transplant has yet to be determined. In order to create an effective cost comparison, we utilized a nationwide database. Methods: US hospital admissions were identified from discharge data from the Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality from 1998 to 2011 using ICD9 codes. Admissions were included if they had an ICD9 code for Sickle cell anemia (282.5). Abstract source

Background: Osteonecrosis (ON) is a prevalent (30-50% by age 30) yet underdiagnosed complication in patients with sickle cell disease (SCD), commonly affecting the femoral and humeral head. SCD ON is progressive resulting in chronic intractable pain and disability. Various imaging modalities are available for the diagnosis of ON and a number of staging methods have been proposed to classify its severity. Numerous surgical and non-surgical treatments exist for different stages of ON. There is a lack of consensus on how to best investigate, classify and treat patients with SCD ON. A previous systematic review included only 1 randomized controlled trial (RCT) but the majority of the literature are non-randomized studies. Objectives: To systematically review and summarize the available evidence from randomized and non-randomized studies with regard to the classification, diagnosis, treatment options and outcome of ON of the hips in SCD adults. Methods: Searches were conducted using the following search concepts: (sickle cell disease OR sickle cell anemia OR hemoglobin SC disease) AND (osteonecrosis OR avascular necrosis OR bone and joint complications) NOT Bisphosphonate-Associated Osteonecrosis of the Jaw. Related terms were also searched in order to maximize sensitivity. MEDLINE, Embase, CINAHL, Current Controlled Trials, and Cochrane Central Register of Controlled Trials were queried. Two independent reviewers (DM-A and AP) excluded abstracts based on pre-defined criteria. A third reviewer (KK) resolved all conflicts. Full-text of included abstracts were translated to English as needed, extracted by DM-A, AP, KK and YP and screened based on the inclusion/exclusion criteria. Two assessors (DM-A and KK) independently assessed trial quality of extracted data. Study limitations (risk of bias) and confidence in effect estimates (quality of evidence) were assessed using the Newcastle-Ottawa Quality Assessment Scale for cohort studies. Abstract source

Background: Nephropathy in sickle cell anemia (SCA) begins in childhood and portends chronic kidney disease, renal failure, and early mortality among affected adults. Individuals of African descent have disproportionately higher rates of developing non-diabetic renal disease. Several candidate genetic variants have been identified, including some specific to African Americans, which are associated with the development of albuminuria and renal disease. The influence of genetic polymorphisms on albuminuria and elevated glomerular filtration rate (GFR) in children with SCA, both early signs of sickle nephropathy, has not been investigated. Objectives: To determine the influence of selected single nucleotide polymorphisms (SNPs) on the development of albuminuria and elevated GFR in children with SCA; to identify novel genetic variants influencing albuminuria and GFR by whole exome sequencing (WES). Design/Methods: Genomic DNA was collected on children with SCA enrolled in two prospective studies with pre-hydroxyurea renal assessments (n=185): (1) Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175, n=79) with no prior disease-modifying therapy; and (2) Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH, NCT 01425307, n=106) on chronic transfusions for abnormal TCD velocities. Albuminuria was defined as ≥30mg albumin/gm creatinine on the pre-hydroxyurea urine specimen. GFR was measured in HUSTLE using plasma DTPA (technetium 99m-labeled diethylenetriaminepentaacetic acid) clearance, and estimated GFR (eGFR) in TWiTCH based on serum creatinine. DNA samples were genotyped for 8 candidate SNPs previously associated with renal disease, using PCR-based allelic discrimination, bidirectional Sanger sequencing, and analysis of variable number tandem repeats (VNTR). Associations between albuminuria and genetic polymorphisms were tested using an additive model and correlation trend test. Linked WES data from the same patients were analyzed to identify other variants associated with albuminuria and GFR. Abstract source

Diana Wells serves as a clinical social worker for the sickle cell program. She provides comprehensive psychosocial services to the patients and families, and assists with referral of patients in both the outpatient and inpatient setting. Her experience also includes over 15 years of providing advocacy services for victims, families and perpetrators in the area of violence and maltreatment. Diana holds an M.S.W., B.S. in Nursing, and a M.P.H in Maternal Child Health.   Representative Publication: Perceptions of young adults with sickle cell disease concerning their disease experience Online profile

Dr. Rana is Professor of Pediatrics at Howard University and Director of Pediatric Hematology with primary focus on sickle cell disease. He has been providing care in a “medical home setting” to individuals with sickle cell disease for more than 30 years with an aim to provide all primary and specialty services at one site. He has conducted and participated in numerous studies related to sickle cell disease and advocated for individuals with sickle cell disease. He has organized seminars related to pain and stigma in sickle cell disease and produced many videos related to pain. He has been listed among the best doctors in America numerous times and he is a recipient of several awards from the sickle cell community and other institutions.   Representative Video: Fighting the Stigma: Pain in Sickle Cell Disease - Elise 3     Representative Publications: Medical neglect by underprescription and underutilization of hydroxyurea in children with sickle cell disease Pharmacogenetics of morphine: potential implications in sickle cell disease Hydroxyurea and growth in young children with sickle cell disease Prospective echocardiography assessment of pulmonary hypertension and its potential etiologies in children with sickle cell disease Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG) Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia Differences in the clinical and genotypic presentation of sickle cell disease around the world Effect of hydroxyurea treatment on renal function parameters: results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia Online profile

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