Sickle cell disease is an inherited disorder that affects over 5 million people worldwide. Current maintenance therapy has been successful in reducing complications and enhancing life expectancy; yet subclinical complications persist. To date, allogeneic haematopoietic stem cell transplant (HSCT) remains the only available curative therapy for sickle cell disease. With declining incidences of rejection and transplant- related mortality, disease-free survival after human leucocyte antigen-identical sibling transplant exceeds 90%. However, the majority of individuals with sickle cell disease do not have an human leucocyte antigen (HLA)-identical sibling; therefore, research is expanding to focus on new approaches to alternative donor transplant. Advances in supportive care and conditioning regimens have led to expansion of the pool of donors to unrelated donors and haploidentical donors. Challenges remain in improving the safety and efficacy of HSCT from alternate donors. Early results from gene therapy may provide another curative option in patients with sickle cell disease. These approaches show early promise, but larger, longitudinal studies are needed to better determine the optimal clinical circumstances for transplant in sickle cell disease. Abstract source Full text

Effective medical management for sickle cell disease (SCD) remains elusive. As a prevalent and severe monogenic disorder, SCD has been long considered a logical candidate for gene therapy. Significant progress has been made in moving toward this goal. These efforts have provided substantial insight into the natural regulation of the globin genes and illuminated challenges for genetic manipulation of the hematopoietic system. The initial γ-retroviral vectors, next-generation lentiviral vectors, and novel genome engineering and gene regulation approaches each share the goal of preventing erythrocyte sickling. After years of preclinical studies, several clinical trials for SCD gene therapies are now open. This review focuses on progress made toward achieving gene therapy, the current state of the field, consideration of factors that may determine clinical success, and prospects for future development. Abstract source Full text Full text (PMC)

Discovery and validation of genetic variants that influence disease severity in children with sickle cell anemia (SCA) could lead to early identification of high-risk patients, better screening strategies, and intervention with targeted and preventive therapy. We hypothesized that newly identified genetic risk factors for the general African American population could also impact laboratory biomarkers known to contribute to the clinical disease expression of SCA, including variants influencing the white blood cell count and the development of albuminuria and abnormal glomerular filtration rate. We first investigated candidate genetic polymorphisms in well-characterized SCA pediatric cohorts from three prospective NHLBI-supported clinical trials: HUSTLE, SWiTCH, and TWiTCH. We also performed whole exome sequencing to identify novel genetic variants, using both a discovery and a validation cohort. Among candidate genes, DARC rs2814778 polymorphism regulating Duffy antigen expression had a clear influence with significantly increased WBC and neutrophil counts, but did not affect the maximum tolerated dose of hydroxyurea therapy. The APOL1 G1 polymorphism, an identified risk factor for non-diabetic renal disease, was associated with albuminuria. Whole exome sequencing discovered several novel variants that maintained significance in the validation cohorts, including ZFHX4 polymorphisms affecting both the leukocyte and neutrophil counts, as well as AGGF1, CYP4B1, CUBN, TOR2A, PKD1L2, and CD163 variants affecting the glomerular filtration rate. The identification of robust, reliable, and reproducible genetic markers for disease severity in SCA remains elusive, but new genetic variants provide avenues for further validation and investigation. Abstract source Full text Full text (PMC)

BACKGROUND: Chronic blood transfusion is the standard of care in the management of overt stroke due to sickle cell anemia (SS) to prevent recurrence of stroke. The problem arises when children are transitioned to adult care where blood transfusion may be discontinued. The purpose of this study was to report the outcome of 22 patients with SS and overt stroke who were transitioned to our adult program between 1993 and 2009. STUDY DESIGN AND METHODS: Transitioned patients were kept on chronic blood transfusion they had as children. Blood bank data were performed and computerized according to FDA and AABB regulations. Records were kept prospectively. Blood counts and percent hemoglobin (Hb)S were obtained before and after transfusion. HbS was kept below 30% after transfusion. Metabolic profiles were obtained every 6 months or more often if needed. Statistical analysis was by the two-tailed t-test. RESULTS: Patients who were compliant with blood transfusion were rarely hospitalized for painful crises. Alloimmunization and iron overload were the major complications of blood transfusion. Eight patients who refused to be maintained on chronic blood transfusion or who were noncompliant died within 1 to 5 years after transition. Causes of death included stroke in two, sudden in three, and multiorgan failure in three. The overall rate of death after transition was 36% and the major cause was discontinuation of blood transfusion. CONCLUSION: Efforts must be made to maintain adequate chronic simple or exchange blood transfusion for children with SS and stroke after transition to adult care. Abstract source Full text

Erythrocytapheresis is an important procedure in the management of certain complications of sickle cell disease, including acute stroke, stroke prevention, acute chest syndrome, and multiorgan failure. Erythrocytapheresis in sickle cell disease simply entails the removal of the patient's red blood cells containing the abnormal sickle hemoglobin and replacing them with normal red blood cells carrying normal hemoglobin. In these procedures, the patient's plasma is not exchanged but is returned to the patient. Several studies have demonstrated that the plasma of patients with sickle cell disease contains several components that increase blood viscosity and initiate or promote vaso-occlusion. These factors include increased levels of globulins, especially immunoglobulin G, acute-phase reactants, fibrinogen, coagulation factors, inflammatory mediators, and heme in the steady state and increase further during painful crises. This may explain why, in certain complications of sickle cell disease, such as acute chest syndrome, hepatic crisis, and priapism, erythrocytapheresis by itself may not be effective despite repetitive cycles of red blood cell exchange. The use of therapeutic plasma exchange in addition to erythrocytapheresis in these situations seems to be useful in resolving them more efficiently. The role of therapeutic plasma exchange in the management of certain complications of sickle cell disease needs further evaluation. This commentary addresses the role of therapeutic plasma exchange in the management of complications of sickle cell disease. Abstract source Full text

Pulmonary complications result in mortality in adults with sickle cell anemia (SCA). We tested the hypothesis that abnormal pulmonary function was associated with earlier death. A prospective cohort of adults with SCA, followed in the Cooperative Study for Sickle Cell Disease, was constructed using the first pulmonary function test at >21 years of age. Spirometry measures: forced expiratory volume in 1 second (FEV1), forced vital capacity, and total lung capacity were categorized based on age, gender, height, and race. Pulmonary function patterns were categorized based on the American Thoracic Society guidelines using both spirometry and lung volumes. A cohort of 430 adults with SCA, mean age 32.6 ± 9.5 (range, 21.0-67.8) years at time of first pulmonary function test, and a median follow-up of 5.5 years, was evaluated. A total of 63 deaths occurred. At baseline, 47% had normal, 29% restrictive, 8% obstructive, 2% mixed, and 14% nonspecific lung function patterns. In the final multivariable model, lower FEV1 percent predicted was associated with increased hazard ratio of death (HR per % predicted 1.02; 95% confidence interval [CI] 1.00-1.04; P = .037), as was older age (HR 1.07; 95% CI 1.04-1.10; P < .001), male sex (HR 2.09; 95% CI 1.20-3.65; P = .010), higher lactate dehydrogenase levels (HR per mg/dL 1.002; 95% CI 1.00-1.003; P = .015), and higher acute chest syndrome incidence rate (HR per event/year 10.4; 95% CI 3.11-34.8; P < .001). Presence of obstructive (HR 1.18; 95% CI: 0.44-3.20; P = .740) and restrictive (HR 1.31; 95% CI: 0.64-2.32; P = .557) pulmonary function patterns were not associated with earlier death. Understanding the pathophysiology of a low FEV1 percent predicted in individuals with SCA is warranted, enabling early intervention for those at risk. Abstract source Full text Full text (PMC)

BACKGROUND: Sickle cell disease is a group of disorders that affects haemoglobin, which causes distorted sickle- or crescent-shaped red blood cells. It is characterized by anaemia, increased susceptibility to infections and episodes of pain. The disease is acquired by inheriting abnormal genes from both parents, the combination giving rise to different forms of the disease. Due to increased erythropoiesis in people with sickle cell disease, it is hypothesized that they are at an increased risk for folate deficiency. For this reason, children and adults with sickle cell disease, particularly those with sickle cell anaemia, commonly take 1 mg of folic acid orally every day on the premise that this will replace depleted folate stores and reduce the symptoms of anaemia. It is thus important to evaluate the role of folate supplementation in treating sickle cell disease. OBJECTIVES: To analyse the efficacy and possible adverse effects of folate supplementation (folate occurring naturally in foods, provided as fortified foods or additional supplements such as tablets) in people with sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also conducted additional searches in both electronic databases and clinical trial registries.Date of last search: 07 December 2015. SELECTION CRITERIA: Randomised, placebo-controlled trials of folate supplementation for sickle cell disease. DATA COLLECTION AND ANALYSIS: Four review authors assessed the eligibility and risk of bias of the included trials and extracted and analysed the data included in the review. We used the standard Cochrane-defined methodological procedures. MAIN RESULTS: One trial, undertaken in 1983, was eligible for inclusion in the review. This was a double-blind placebo-controlled quasi-randomised triaI of supplementation of folic acid in people with sickle cell disease. A total of 117 children with homozygous sickle cell (SS) disease aged six months to four years of age participated over a one-year period (analysis was restricted to 115 children).Serum folate measures, obtained after trial entry at six and 12 months, were available in 80 of 115 (70%) participants. There were significant differences between the folic acid and placebo groups with regards to serum folate values above 18 µg/l and values below 5 µg/l. In the folic acid group, values above 18 µg/l were observed in 33 of 41 (81 %) compared to six of 39 (15%) participants in the placebo (calcium lactate) group. Additionally, there were no participants in the folic acid group with serum folate levels below 5 µg/l, whereas in the placebo group, 15 of 39 (39%) participants had levels below this threshold. Haematological indices were measured in 100 of 115 (87%) participants at baseline and at one year. After adjusting for sex and age group, the investigators reported no significant differences between the trial groups with regards to total haemoglobin concentrations, either at baseline or at one year. It is important to note that none of the raw data for the outcomes listed above were available for analysis.The proportions of participants who experienced certain clinical events were analysed in all 115 participants, for which raw data were available. There were no statistically significant differences noted; however, the trial was not powered to investigate differences between the folic acid and placebo groups with regards to: minor infections, risk ratio 0.99 (95% confidence interval 0.85 to 1.15); major infections, risk ratio 0.89 (95% confidence interval 0.47 to 1.66); dactylitis, risk ratio 0.67 (95% confidence interval 0.35 to 1.27); acute splenic sequestration, risk ratio 1.07 (95% confidence interval 0.44 to 2.57); or episodes of pain, risk ratio 1.16 (95% confidence interval 0.70 to 1.92). However, the investigators reported a higher proportion of repeat dactylitis episodes in the placebo group, with two or more attacks occurring in 10 of 56 participants compared to two of 59 in the folic acid group (P < 0.05).Growth, determined by height-for-age and weight-for-age, as well as height and growth velocity, was measured in 103 of the 115 participants (90%), for which raw data were not available. The investigators reported no significant differences in growth between the two groups.The trial had a high risk of bias with regards to random sequence generation and incomplete outcome data. There was an unclear risk of bias in relation to allocation concealment, outcome assessment, and selective reporting. Finally, There was a low risk of bias with regards to blinding of participants and personnel. Overall the quality of the evidence in the review was low.There were no trials identified for other eligible comparisons, namely: folate supplementation (fortified foods and physical supplementation with tablets) versus placebo; folate supplementation (naturally occurring in diet) versus placebo; folate supplementation (fortified foods and physical supplementation with tablets) versus folate supplementation (naturally occurring in diet). AUTHORS' CONCLUSIONS: One doubIe-blind, placebo-controlled triaI on folic acid supplementation in children with sickle cell disease was included in the review. Overall, the trial presented mixed evidence on the review's outcomes. No trials in adults were identified. With the limited evidence provided, we conclude that, while it is possible that folic acid supplementation may increase serum folate levels, the effect of supplementation on anaemia and any symptoms of anaemia remains unclear.Further trials may add evidence regarding the efficacy of folate supplementation. Future trials should assess clinical outcomes such as folate concentration, haemoglobin concentration, adverse effects and benefits of the intervention, especially with regards to sickle cell disease-related morbidity. Trials should include people with sickle cell disease of all ages and both sexes, in any setting. To investigate the effects of folate supplementation, trials should recruit more participants and be of longer duration, with long-term follow up, than the trial currently included in this review. Abstract source Full text Full text (PMC)

Over the past 40 years, public health measures such as universal newborn screening, penicillin prophylaxis, vaccinations, and hydroxyurea therapy have led to an impressive decline in sickle cell disease (SCD)-related childhood mortality and SCD-related morbidity in high-income countries. We remain cautiously optimistic that the next 40 years will be focused on meeting current challenges in SCD by addressing chronic complications of SCD to reduce mortality and improve quality of life in a growing population of adults with SCD in high-income countries, while simultaneously decreasing the disparity of medical care between high and low-income countries. Abstract source Full text

PURPOSE: To evaluate macular vascular flow abnormalities identified by optical coherence tomography angiography (OCT-A) in patients with various sickle cell genotypes. DESIGN: Prospective, observational case series. METHODS: This is a single-institution case series of adult patients with various sickle cell genotypes. All patients underwent macular OCT-A (Avanti RTVue XR). Images were analyzed qualitatively for areas of flow loss and quantitatively for measures of foveal avascular area, parafoveal flow, and vascular density. The findings were compared by sickle cell genotype and retinopathy stage and correlated to retinal thickness and visual acuity. RESULTS: OCT-A scans of 82 eyes from 46 patients (60.9% female, mean age 33.5 years) were included. Sickle cell genotypes included 27 patients with hemoglobin SS (58.7%), 14 SC (30.4%), 4 beta-thalassemia (8.7%), and 1 sickle trait (2.2%). Discrete areas of flow loss were noted in 37.8% (31/82) of eyes overall and were common in both SS (40.0%, 20/50 eyes) and SC (41.7%, 10/24 eyes). Flow loss was more extensive in the temporal and nasal parafoveal subfields of the deep plexus with sickle SC or proliferative retinopathy. Retinal thickness measurements correlated with vascular density of the fovea, parafovea, and temporal and superior subfields. Visual acuity correlated with foveal avascular zone area and parafoveal vascular density in the superficial and deep plexi. CONCLUSIONS: Areas of abnormal macular vascular flow are common in patients with various sickle cell genotypes. These areas may be seen at any retinopathy stage but may be more extensive with sickle SC or proliferative retinopathy. Abstract source Full text

BACKGROUND: Patients with sickle cell anemia (SCA) have an increased prevalence of nephropathy and mortality from chronic kidney disease (CKD). METHODS: We evaluated the association of hyperuricemia and nocturnal hypertension with lower estimated glomerular filtration rate (eGFR) using cystatin-C in patients aged 10-21 years with the HbSS or HbSB0 form of the disease during a non-acute clinic visit. eGFR and uric acid measurements were obtained in 83 and 81 participants, respectively, and 24-h ambulatory blood pressure monitoring (ABPM) was performed in 44 participants. Annual testing included vital signs, complete blood count, comprehensive metabolic panel, medications, urine microalbumin/creatinine, and lactate dehydrogenase measurements. Hyperuricemia was defined as a uric acid level of ≥5.5 mg/dL. Nocturnal hypertension was defined as >25% of nocturnal readings at >95th percentile according to norms established by the American Heart Association Statement on ABPM in children and adolescents. RESULTS: The mean eGFR was statistically significantly lower in patients with hyperuricemia than in those with normal uric acid levels (143 vs. 161 mL/min/1.73 m2, respectively). Of the 44 participants for whom ABPM data were available, 14 (32%) had systolic nocturnal hypertension and 12 (27%) had diastolic nocturnal hypertension. The mean eGFR was statistically significantly lower in participants with nocturnal systolic and diastolic hypertension than in those with normal nocturnal blood pressure. In a regression model, nocturnal hypertension and hyperuricemia were associated with a lower eGFR. CONCLUSIONS: Two risk factors for CKD, i.e., nocturnal hypertension and hyperuricemia, were associated with lower eGFR in older children and adolescent patients with SCA. Long-term studies on their association with progression to CKD in this population are warranted. Abstract source Full text