Implementation of hospital-based sickle cell newborn screening and follow-up programs in Haiti.

ABSTRACT: One in 120 children are born with sickle cell disease (SCD) in Haiti. However, health care challenges include isolated newborn screening (NBS) activities and lack of transcranial Doppler (TCD) ultrasound to assess stroke risk. The implementation activities of the Comparative Study of Children in Haiti and Miami with Sickle Cell Disease involved both NBS and TCD ultrasound implementations at 4 Haitian clinical sites. We hypothesized that hospital-based newborn SCD screening and follow-up programs would be feasible at Haiti. A traditional NBS laboratory method with dried blood samples was performed at 3 Port-au-Prince sites, and the traditional method plus point-of-care (POC) testing was used at the 2 northern sites. The rate of clinical follow-up for newborns with SCD as the outcome for the NBS intervention was compared with that of the NBS method. The NBS programs identified SCD in 0.77% of 8224 newborns over a 24-month period. In the rural hospital assigned to the combination screening, 56% of newborns identified with POC testing returned for follow-up, compared with 0% when POC was not available (P = .044). Newborns who tested positive for SCD and children aged <6 years with SCD at the clinical sites were eligible for study follow-up. Accrual was successful: 165 participants (mean age, 42 months; 53% males; 93% hemoglobin SS) were recruited and received oral penicillin. TCD ultrasound screening was hampered by poor internet connections and trained staff leaving Haiti, with only 1 active site conducting screening. Despite challenges, the implementation of NBS and sickle cell programs in Haiti is feasible. We are in the process of understanding how to mitigate implementation limitations.

Rapid electrical impedance detection of sickle cell vaso-occlusion in microfluidic device.

Sickle cell disease is characterized by painful vaso-occlusive crises, in which poorly deformable sickle cells play an important role in the complex vascular obstruction process. Existing techniques are mainly based on optical microscopy and video processing of sickle blood flow under normoxic condition, for measuring vaso-occlusion by a small fraction of dense sickle cells of intrinsic rigidity but not the vaso-occlusion by the rigid, sickled cells due to deoxygenation. Thus, these techniques are not suitable for rapid, point-of-care testing. Here, we integrate electrical impedance sensing and Polydimethylsiloxane-microvascular mimics with controlled oxygen level into a single microfluidic chip, for quantification of vaso-occlusion by rigid, sickled cells within 1 min. Electrical impedance measurements provided a label-free, real-time detection of different sickle cell flow behaviors, including steady flow, vaso-occlusion, and flow recovery in response to the deoxygenation-reoxygenation process that are validated by microscopic videos. Sensitivity of the real part and imaginary part of the impedance signals to the blood flow conditions in both natural sickle cell blood and simulants at four electrical frequencies (10, 50, 100, and 500 kHz) are compared. The results show that the sensitivity of the sensor in detection of vaso-occlusion decreases as electrical frequency increases, while the higher frequencies are preferable in measurement of steady flow behavior. Additional testing using sickle cell simulants, chemically crosslinked normal red blood cells, shows same high sensitivity in detection of vaso-occlusion as sickle cell vaso-occlusion under deoxygenation. This work enables point-of-care testing potentials in rapid, accurate detection of steady flow and sickle cell vaso-occlusion from microliter volume blood specimens. Quantification of sickle cell rheology in response to hypoxia, may provide useful indications for not only the kinetics of cell sickling, but also the altered hemodynamics as obseved at the microcirculatory level.

Successful quality improvement project to increase hydroxyurea prescriptions for children with sickle cell anaemia.

Hydroxyurea (HU) is an effective but underused disease-modifying therapy for patients with sickle cell anaemia (SCA). EMBRACE SCD, a sickle cell disease treatment demonstration project, aimed to improve access to HU by increasing prescription (Rx) rates by at least 10% from baseline in children with SCA.The Model for Improvement was used as the quality improvement framework. HU Rx was assessed from clinical databases in three paediatric haematology centres. Children aged 9 months-18 years with SCA not on chronic transfusions were eligible for HU treatment. The health belief model was the conceptual framework to discuss with patients and promote HU acceptance. A visual aid showing erythrocytes under the effect of HU and the American Society of Hematology HU brochure were used as educational tools. At least 6 months after offering HU, a Barrier Assessment Questionnaire was given to assess reasons for HU acceptance and refusals. If HU was declined, the providers discussed with family again. We conducted chart audits to find missed opportunities to prescribe HU as one plan-do-study-act cycle.At initial measurement, 50.2% of 524 eligible patients had HU prescribed. During the testing and initial implementation phase, the mean performance after 10 data points was 53%. After 2 years, the mean performance was 59%, achieving an 11% increase in mean performance and a 29% increase from initial to the last measurement (64.8% HU Rx). During a 15-month period, 32.1% (N=168) of the eligible patients who were offered HU completed the barrier questionnaire with 19% (N=32) refusing HU, mostly based on not perceiving enough severity of their children's SCA or fearing side effects.Reviewing patient charts for missed opportunity of offering HU with feedback and evaluating the reasons of declining HU via a questionnaire were key components in increasing HU Rx in our population.

Consensus definition of essential, optimal, and suggested components of a pediatric sickle cell disease center.

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers.

Accuracy of transcranial Doppler in detecting intracranial stenosis in patients with sickle cell anemia when compared to magnetic resonance angiography.

BACKGROUND: Stroke, the most devastating consequence of sickle cell anemia (SCA), is associated with endothelial damage and intracranial artery stenosis. We aimed to assess transcranial Doppler (TCD) ultrasound accuracy in detecting intracranial stenosis when compared to magnetic resonance angiography (MRA). METHODS: Children with SCA and at least one TCD and MRA within 1 month were identified from a retrospectively collected database. Sensitivity and specificity were obtained to assess the overall accuracy of TCD mean flow velocity (mFV) ≥200 cm/s in detecting vessel stenosis of ≥50%. Multivariate analysis identified independent factors associated with MRA stenosis. RESULTS: Among 157 patients in the database, 64 had a TCD and MRA within 1 month (age 11.8 ± 5.3 years, 56% female, 20% with cerebral infarcts on MRI, 8 or 13% had mFV ≥200 cm/s and 20% or 21%, had intracranial stenosis ≥50% on MRA). TCD mFV ≥200 cm/s had a high specificity (95%) but low sensitivity (29%) to detecting intracranial stenosis. As a continuous variable, TCD mFV of 137.5 cm/s had maximal specificity (77%) and sensitivity (72%). After adjustment for age, hemoglobin level, transfusion status, hydroxyurea treatment, and vessel, for every increase in cm/sec on TCD, there was a 2% increase in the odds of ≥50% stenosis on MRA (p < 0.001). CONCLUSION: Our study reports TCD mFV is a positive predictor of MRA stenosis in SCA, independent of patient characteristics, including hemoglobin. A mFV ≥200 cm/s is highly specific but less sensitive in detecting stenosis ≥50%. Lower mFV cut points may be needed for the early detection of intracranial stenosis.

Real-world effectiveness of voxelotor for treating sickle cell disease in the US: a large claims data analysis.

BACKGROUND: Sickle cell disease (SCD) is a genetic disease that impacts patients' quality of life, healthcare costs, and life expectancy. Elevated sickle hemoglobin (HbS), which readily polymerizes, causes red blood cell sickling, leading to chronic hemolytic anemia and complications often requiring hospitalization and transfusions. In 2019, voxelotor, which inhibits HbS polymerization, was approved for SCD treatment. OBJECTIVES: This study uses real-world evidence to assess voxelotor's effectiveness in SCD patients in typical clinical practice from 2019 to 2021 using a national medical claims database (N = 3128). RESULTS: After initiating voxelotor, 60.8% of patients with available hemoglobin (Hb) laboratory data (n = 74) showed a Hb increase >1 g/dL. Mean transfusion rate per patient-year dropped 52% in patients with ≥1 transfusion before treatment (n = 190). In patients with ≥1 of the corresponding events (n = 1065), decreases were observed in mean vaso-occlusive crisis (VOC) frequency (-23%); mean VOC-related hospitalizations and length of stay (LOS) time (-34% and -30%, respectively); mean all-cause hospitalization and LOS time (-37% and -23%, respectively); outpatient visits (-10%); iron chelation use (-46%); and prescribed opioids (-13%). CONCLUSION: These data align with randomized controlled trial results showing voxelotor improvements and support that voxelotor may lower transfusion and VOC rates in clinical practice.

Assessment of Liver Fibrosis by Transient Elastography in Children and Young Adults With Sickle Cell Disease With and Without Iron Overload.

Transfusion-associated iron overload may cause liver fibrosis. We compared transient elastography (TE) and aspartate aminotransferase-platelet ratio index (APRI), noninvasive markers for hepatic fibrosis, to liver histology in children and young adults with sickle cell disease (SCD) who were iron overloaded (cohort 1). Age-matched subjects with SCD but without iron overload (cohort 2) were enrolled for APRI and TE assessments. Nineteen subjects ages 10 to 21 years were transfused for a mean of 9.67 years, had a mean serum ferritin of 4899±2849 ng/mL, and a liver iron concentration of 15.56±10.12 mg/g dry liver weight by R2-magnetic resonance imaging. Mean APRI was 0.33±0.13 in cohort 1 and 0.27±0.10 in cohort 2. The mean liver stiffness measures (LSM) in cohort 1, assessed by TE, was 8.46±3.95 kPa, ranging from 3.5 to 14.6 kPa (expected normal <7 kPa). Cohort 2 had a mean LSM of 5.72±1.74 kPa (4.6 to 8.7 kPa). There was a good correlation between LSM and histologic fibrosis (t value 6.94, P<0.0001). There was no significant correlation between APRI and histologic fibrosis and between APRI and LSM. A high LSM suggests liver fibrosis in children and adults with SCD with iron overload and may merit histologic confirmation especially if persistent.

Evolving Strategies in the Management of Sickle Cell Disease in the 21st Century and the Role of the Pediatrician.

Sickle cell disease (SCD) is one of the most common genetic disorders in the United States. Once a fatal disease of childhood, the majority of patients born with SCD who live in a developed country will survive to adulthood (albeit with slightly shortened life spans). Despite numerous novel therapeutic advancements in recent years that serve to mitigate the symptoms associated with SCD, the only cure for SCD is a hematopoietic stem cell transplant. The overall survival for patients with a matched sibling donor transplant is greater than 90%. However, fewer than 20% of patients with SCD in the US have a 12/12 human leukocyte antigen (HLA) matched sibling donor. In contrast, most patients have at least one HLA haploidentical first-degree relative, which expands the donor pool for patients who have diseases amenable to stem cell transplantation such as SCD. [Pediatr Ann. 2022;51(1):e34-e39.].

Stroke and stroke prevention in sickle cell anemia in developed and selected developing countries.

This comprehensive review provides an insight into the pathophysiology, epidemiology, evaluation, and treatment of sickle cell anemia (SCA)-related stroke in developed and developing countries. Vascular injury, hypercoagulability and vaso-occlusion play a role in the pathophysiology of stroke in SCA. Transcranial Doppler ultrasound (TCD) has lowered the incidence of ischemic stroke from 11% to 1% as TCD identifies children who are at risk for stroke, providing opportunities for interventions to reduce this risk. Whereas blood exchange is indicated in acute stroke, chronic transfusions (either simple or exchange on a monthly basis) are used for primary as well as secondary stroke prevention in developed countries. Children with abnormally high TCD velocities (≥ 200 cm/s) are at high risk of stroke and might benefit from hydroxyurea or hydroxycarbamide (HU) after a period of a successful transition from chronic transfusions. Hematopoietic stem cell transplant presents a cure for SCA. Gene therapy is currently investigated and may be offered to patients with SCA who had a stroke or who are at high risk of stroke if proven efficacious and safe. However, gene therapy is not likely to be implemented in low-income countries due to cost. Alternatively, HU is utilized for primary and secondary stroke prevention in developing countries. Further expansion of TCD implementation should be a priority in those settings.

Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.

Newborn Screening for Sickle Cell Disease Using Point-of-Care Testing in Low-Income Setting.

BACKGROUND: Newborn screening provides early diagnosis for children with sickle cell disease (SCD), reducing disease-related mortality. We hypothesized that rapid point-of-care (POC) Sickle SCAN would be reliable in Haiti and would assist newborn screening. METHODS: Dried blood specimens were obtained from infant heel sticks and analyzed by isoelectric focusing (IEF) at a public hospital in Cap-Haïtien during a 1-year period. A total of 360 Guthrie cards were also analyzed for quality assurance by high-performance liquid chromatography at the Florida Newborn Screening Laboratory. In addition, two-thirds of the infants were also screened by the POC to assess differences with the IEF. The hemoglobinopathy incidence and the specificity and sensitivity of the POC scan were assessed. RESULTS: Overall, 1.48% of the children screened positive for SCD. The specificity and the sensitivity of POC Sickle SCAN were 0.97 (confidence interval 0.95-0.99) and 0.90 (confidence interval 0.55-1.00), respectively, relative to high-performance liquid chromatography gold standard. The confirmatory testing rate was 75% before POC and improved to 87% after POC was added for dual screening. Confirmatory testing revealed that 0.83% of children screened had SCD. Children who screened positive for SCD by POC started penicillin earlier, had their first pediatric follow-up a median of 38 days earlier, and received antipneumococcal vaccination on time when compared with those who screened positive for SCD by IEF alone. CONCLUSIONS: The observational study revealed a high incidence of SCD among Haitian newborns. Sickle SCAN had excellent specificity and sensitivity to detect SCD during newborn screening and shortened health care access for children positive for SCD.

Electrical Impedance Characterization of Erythrocyte Response to Cyclic Hypoxia in Sickle Cell Disease.

Cell sickling is the process in which intracellular polymerization of deoxygenated sickle hemoglobin (HbS) leads to distorted, rigid cells, resulting in abnormal blood rheology and painful vaso-occlusion. Current methods for detection of this process mainly rely on optical microscopy of cellular morphology and measurements of cell deformability and blood rheology. As electrical impedance of cells is a sensitive indicator of changes in cellular structure and biophysical characteristics, it can be a promising marker for characterization of abnormal blood rheology and a means more convenient than optics to be integrated into point-of-care devices. In this work, a microfluidics-based electrical impedance sensor has been developed for characterizing the dynamic cell sickling-unsickling processes in sickle blood. The sensor is capable of measuring the continuous variation in the sickle cell suspension due to cyclic hypoxia-induced intracellular HbS polymerization and depolymerization. Simultaneous microscopic imaging of cell morphological change shows the reliability and repeatability of the electrical impedance-based measurements of cell sickling and unsickling processes. Strong correlation is found between the electrical impedance measurement and patients' hematological parameters such as levels of HbS and fetal hemoglobin. The combination of electrical impedance measurement and on-chip hypoxia control provides a promising method for rapid assessment of the dynamic processes of cell sickling and unsickling in patients with sickle cell disease.

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis.

The cell adhesion molecule P-selectin plays a key role in the pathogenesis of a vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD). In the double-blind, placebo-controlled phase 2 SUSTAIN study, crizanlizumab (humanized, anti-P-selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2-4/5-10), SCD genotype (HbSS/non-HbSS), and concomitant hydroxyurea use (yes/no). More patients were VOC event-free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5-10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%). Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time-to-first VOC vs placebo in these subgroups. The rates of treatment-emergent adverse events were similar between treatment arms across all subgroups. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event-free and delays time-to-first VOC.

Double-blind, randomized, multicenter phase 2 study of SC411 in children with sickle cell disease (SCOT trial).

Blood cell membranes in sickle cell disease (SCD) have low docosahexaenoic acid (DHA). DHA treatment reduces sickle cell crisis (SCC) rate and ameliorates the inflammation, oxidative stress, and hypercoagulable state of SCD. SC411 is a novel DHA ethyl ester formulation with a proprietary delivery platform (Advanced Lipid Technology) that enhances DHA bioavailability. The SCOT trial investigated the effect of 3 different doses of SC411 on clinical and biochemical endpoints in 67 children with SCD (5-17 years old). Seventy-six percent of subjects were also receiving hydroxyurea. After 4 weeks of treatment with SC411 at 20, 36, and 60 mg DHA/kg per day or placebo a statistically significant (P < .001) mean percentage increase of blood cell membrane DHA and eicosapentaenoic acid was seen vs baseline: 109.0% (confidence interval [CI], 46.7-171.3), 163.8% (CI, 108.3-219.2), 170.8% (CI, 90.2-251.4), and 28.6% (CI, 250.1 to 107.3), respectively. After 8 weeks of treatment, statistically significant changes vs placebo were also observed in D-dimer (P = .025) and soluble E-selectin (P = .0219) in subjects exposed to 36 mg/kg. A significant increase in hemoglobin was observed against placebo in subjects receiving 20 mg DHA/kg per day (P = .039). SC411 significantly reduced electronic diary recorded SCC, analgesic use at home, and days absent from school because of sickle cell pain. The lower rate of clinical SCC observed in the pooled active groups vs placebo did not reach statistical significance (rate ratio, 0.47; 95% CI, 0.20-1.11; P = .07). All tested doses were safe and well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02973360.

Electrical impedance microflow cytometry with oxygen control for detection of sickle cells.

Polymerization of intracellular sickle hemoglobin induced by low oxygen tension has been recognized as a primary determinant of the pathophysiologic manifestations in sickle cell disease. Existing flow cytometry techniques for detection of sickle cells are typically based on fluorescence markers or cellular morphological analysis. Using microfluidics and electrical impedance spectroscopy, we develop a new, label-free flow cytometry for non-invasive measurement of single cells under controlled oxygen level. We demonstrate the capability of this new technique by determining the electrical impedance differential of normal red blood cells obtained from a healthy donor and sickle cells obtained from three sickle cell patients, under normoxic and hypoxic conditions and at three different electrical frequencies, 156 kHz, 500 kHz and 3 MHz. Under normoxia, normal cells and sickle cells can be separated completely using electrical impedance at 156 kHz and 500 kHz but not at 3 MHz. Sickle cells, intra-patient and inter-patient show significantly different electrical impedance between normoxia and hypoxia at all three frequencies. This study shows a proof of concept that electrical impedance signal can be used as an indicator of the disease state of a red blood cell as well as the cell sickling events in sickle cell disease. Electrical impedance-based microflow cytometry with oxygen control is a new method that can be potentially used for sickle cell disease diagnosis and monitoring.

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease.

BACKGROUND: The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. METHODS: In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed. RESULTS: A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. CONCLUSIONS: In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).

Genetic Modifiers of White Blood Cell Count, Albuminuria and Glomerular Filtration Rate in Children with Sickle Cell Anemia.

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.