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News

 

The American Society of Hematology is seeking comments on draft clinical practice guidelines on sickle cell disease-related transfusion support.

Materials are available at www.hematology.org/Guidelines-Public-Comment. The deadline to comment is Monday October 1, 2018.

This comment period is open to all ASH members and the public. Feedback received will be provided to the guideline panels for review. Comments will also be considered during ASH organizational approval of the guidelines, peer review of the guidelines for journal publication, implementation and dissemination efforts following publication, and future revision efforts.

These guidelines were developed by ASH and supported by the Mayo Clinic Evidence-Based Practice Center, using a systematic process intended to meet recommendations of the Institute of Medicine. Recommendations were formed by guideline panels that include experts in SCD from multiple disciplines, methodologists, and patient representatives.

Please let your colleagues know about this public comment period. If you use social media, you may create your own tweet, using #ASHGuidelines.

Sample Tweet: New @ASH_hematology guidelines on SCD are posted for comment! Add your feedback: https://tinyurl.com/y9qnz4ye  #ASHGuidelines

 

Siklos, the first and only hydroxyurea-based treatment for pediatric patients with sickle cell anemia, now available in US retail pharmacies

ROSEMONT, PA, Aug. 21, 2018 /PRNewswire/ – Medunik USA, a company dedicated to improving the health and quality of life of Americans with rare diseases by making orphan drugs available in the U.S., announced today that Siklos® (hydroxyurea), an FDA-approved orphan drug, is now available in 100 mg tablets for pharmacies to order.

Siklos® is indicated to reduce the frequency of painful crises and the need for blood transfusions in pediatric patients, two years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises. It is the first and only FDA-approved hydroxyurea-based treatment for use in pediatric patients with sickle cell anemia.

Medunik USA holds the exclusive rights to market and distribute Siklos® in the United States, through an agreement with ADDMEDICA, a French pharmaceutical company specializing in hematology.

“We are pleased to partner with ADDMEDICA to provide access to an orphan drug therapy that can contribute to reducing painful crises, specifically for children with sickle cell anemia,” said Éric Gervais, Executive Vice President of Medunik. “The addition of Siklos® to the Medunik portfolio establishes our footprint in the United States in the area of orphan drug therapies and is the latest in a series of significant advances for our company.”

“Medunik USA is well positioned to ensure both the marketing and distribution of Siklos® in the United States, thanks to their knowledge of the orphan drug commercialization process. We are pleased to count them as a partner,” said Bernard Dauvergne, Executive Director of ADDMEDICA.

Sickle cell anemia (SCA) is the most common inherited blood disorder, resulting in the production of abnormal hemoglobin, known as hemoglobin-S (HbS), responsible for the sickling of red blood cells. This disease affects nearly 100,000 Americans, decreases life expectancy by 25 to 30 years, induces significant morbidity, and therefore, reduces quality of life1,2. Most of those affected are of African ancestry; a minority are of Hispanic or southern European, Middle Eastern or Asian Indian descent3.

“This approval is a major milestone in treatment for all children who suffer from devastating pain and disability associated with sickle cell anemia,” said Abbey Meyers, Founder and past-president of the National Organization for Rare Disorders (NORD) and member of Medunik’s Advisory Board.

FDA approval was granted based on tolerability and effectiveness data collected in a European sickle cell disease cohort (Escort-HU) study, which included 405 pediatric patients. Data showed that treatment with Siklos® increased the concentration of fetal hemoglobin (hemoglobin F or HbF), which prevents the sickling process within red blood cells. In the clinical trial, the number of pediatric patients experiencing at least one painful crisis in the 12 months prior to treatment with Siklos® was significantly reduced after 12 months of treatment4.

Siklos® offers flexible dosing to facilitate adjustment based on patient’s weight and maximum tolerated dose. This is particularly important in pediatric populations, where patient weight is constantly changing.

About SIKLOS® (hydroxyurea)

Siklos® is a prescription medicine that is used to reduce the frequency of painful crises and reduce the need for blood transfusions in children, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises. It is not known if Siklos® is safe and effective in children less than 2 years of age.

 

Howard University President Dr. Wayne A.I. Frederick says that sickle cell disease is not a death sentence. People living with SCD can still play sports, go to school, have careers and live productive lives. (Howard University)

It has been over 100 years since sickle cell disease (SCD), a hereditary blood disorder, was first discovered in the United States.

Despite the many years of research and study, SCD still affects millions of people throughout the world, according to the Centers for Disease Control and Prevention (CDC), and is particularly common among those with African ancestry, including individuals living within the United States, South America, Saudi Arabia, Italy, India and the Caribbean.

Every year, 1 in 365 Black babies are born with SCD and 1 in 13 are born with sickle cell trait (SCT). In comparison, SCD occurs in roughly 1 out of every 16,300 Hispanic-American births.

Trinidadian-born, U.S. physician and Howard University President, Dr. Wayne A.I. Frederick, who lives with SCD, recalled his own painful experiences with the disease and the inability of many loved ones and the community to properly embrace him.

“When I was three years old, I was diagnosed with sickle cell disease and would often find myself being hospitalized three to six times a year, because of the disorder,” Dr. Frederick recounted. “In Trinidad, the life expectancy for someone with the disease is just eight years old. Growing up, I can’t really recall ever meeting anyone with the same disease and so, oftentimes I would find myself feeling alone and left out…sometimes, I find that people don’t fully understand the scheme of struggles that I go through myself.”

For people living with SCD, those struggles come with a myriad of symptoms, including swelling in the hands and feet; chronic pain; spikes of severe pain; anemia; yellowing of the eyes; frequent infections and vision problems.

Even though the crippling disease has proven to be fatal for many, Dr. Frederick said that he refuses to give in to the statistics of the disorder and chooses life over mortality.

“Sickle cell is a painful disease,” Dr. Frederick said. “But people need to know that it is not a [death] sentence. Having the disease does not mean a person cannot live. I want people to know that there are no limits…that they can still play sports, go to school, have careers and live productive lives.”

Despite his own personal struggles with SCD, Dr. Frederick said that things started to look up for him when he moved to the United States to go to college, earning his Bachelor of Science and his medical degree by the age of 22.

“Attending Howard University, as a student, gave me a huge boost,” Dr. Frederick said. “At [Howard] I was able to meet people my age with the same disease, who understood a lot of my struggles.”

Not surprised by Dr. Frederick’s positive experiences on Howard’s campus, Dr. James G. Taylor VI, the director of the Center for Sickle Cell Disease at Howard University Hospital, credited the institutions longstanding commitment to improving the lives of people living with SCD.

“The Center for Sickle Cell Disease is committed to further expanding Howard University’s clinical and translational research programs with a focus on new treatments and opportunities for curative therapy,” Dr. Taylor said. “We have a long-standing commitment to research advocacy and community outreach, particularly screening for the sickle cell trait.”

 

 

Articles in the Medical Literature

 

Am J Hematol. 2018 Aug 24. doi: 10.1002/ajh.25263. [Epub ahead of print]

Clinical and Metabolomic Rick Factors Associated with Rapid Renal Function Decline in Sickle Cell Disease.

Xu JZ1, Garrett ME2, Soldano KL2, Chen ST3, Clish CB4, Ashley-Koch AE2, Telen MJ5.

Abstract

Sickle cell disease (SCD) nephropathy and lower estimated glomerular filtration rate (eGFR) are risk factors for early mortality. Furthermore, rate of eGFR decline predicts progression to end-stage renal disease in many clinical settings. However, factors predicting renal function decline in SCD are poorly documented. Using clinical, laboratory, genetic, and metabolomic data, we evaluated predictors of renal function decline in a longitudinal cohort of 288 adults (mean age 33.0 years). In 193 subjects with 5-year follow-up data, mean rate of eGFR decline was 2.35 mL/min/1.73 m2 /year, nearly twice that of African American adults overall. Hyperfiltration was prevalent at baseline (61.1%), and 36.8% of subjects experienced rapid eGFR decline (≥3 mL/min/1.73 m2 /year). Severe Hb genotype; proteinuria; higher platelet, reticulocyte counts, and systolic BP; and lower Hb level and BMI were associated with rapid decline. A risk scoring system was created using these 7 variables and was highly predictive of rapid eGFR decline, with odds of rapid decline increasing 1.635-fold for every point increment (P<0.0001). Rapid eGFR decline was also associated with higher organ system severity score and peak creatinine. Additionally, two metabolites (asymmetric dimethylarginine and quinolinic acid) were associated with rapid decline. Further investigation into longitudinal SCD nephropathy (SCDN) trajectory, early markers of SCDN, and tools for risk stratification should inform interventional studies targeted to slowing GFR decline and improving SCD outcomes. This article is protected by copyright. All rights reserved.

PMID: 30144150

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Mol Ther Methods Clin Dev. 2018 Aug 4;10:268-280. doi: 10.1016/j.omtm.2018.07.012. eCollection 2018 Sep 21.

An Optimized Lentiviral Vector Efficiently Corrects the Human Sickle Cell Disease Phenotype.

Weber L1,2, Poletti V3, Magrin E4, Antoniani C5,6, Martin S3, Bayard C1, Sadek H1, Felix T5,6, Meneghini V5,6, Antoniou MN7, El-Nemer W8,9,10, Mavilio F5,11, Cavazzana M1,4,5, Andre-Schmutz I1,5, Miccio A3,5,6.

Abstract

Autologous transplantation of hematopoietic stem cells transduced with a lentiviral vector (LV) expressing an anti-sickling HBB variant is a potential treatment for sickle cell disease (SCD). With a clinical trial as our ultimate goal, we generated LV constructs containing an anti-sickling HBB transgene (HBBAS3), a minimal HBB promoter, and different combinations of DNase I hypersensitive sites (HSs) from the locus control region (LCR). Hematopoietic stem progenitor cells (HSPCs) from SCD patients were transduced with LVs containing either HS2 and HS3 (β-AS3) or HS2, HS3, and HS4 (β-AS3 HS4). The inclusion of the HS4 element drastically reduced vector titer and infectivity in HSPCs, with negligible improvement of transgene expression. Conversely, the LV containing only HS2 and HS3 was able to efficiently transduce SCD bone marrow and Plerixafor-mobilized HSPCs, with anti-sickling HBB representing up to ∼60% of the total HBB-like chains. The expression of the anti-sickling HBB and the reduced incorporation of the βS-chain in hemoglobin tetramers allowed up to 50% reduction in the frequency of RBC sickling under hypoxic conditions. Together, these results demonstrate the ability of a high-titer LV to express elevated levels of a potent anti-sickling HBB transgene ameliorating the SCD cell phenotype.

PMCID: PMC6105766 Free Article

PMID: 30140714

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Pediatr Res. 2018 Jul 24. doi: 10.1038/s41390-018-0125-6. [Epub ahead of print]

The association of nocturnal hypoxia and an echocardiographic measure of pulmonary hypertension in children with sickle cell disease.

Mondal P1, Stefek B2, Sinharoy A3, Sankoorikal BJ4, Abu-Hasan M5, Aluquin V2.

Abstract

BACKGROUND:

Pulmonary hypertension (PH) is multifactorial in origin and may develop early in children with sickle cell disease (C-SCD). Potential etiologies are hemolysis-induced endothelial dysfunction, left ventricular (LV) dysfunction, and chronic hypoxia. Nocturnal hypoxia (NH) in C-SCD is known to be a sequela of obstructive sleep apnea (OSA). The primary objective of this study is to correlate polysomnographic evidence NH with echocardiographic measures of PH in C-SCD.

METHODS:

We performed a retrospective chart review of 20 C-SCD (Hemoglobin SS), who had polysomnography and echocardiogram performed within a narrow time interval, and 31% of them had pre-existing cardiac conditions. Tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/s was considered as an indicator of PH.

RESULTS:

Twenty-five percent of the subjects had NH. Forty percent of C-SCD, predominantly male, had evidence of PH based on an elevated TRJV. Children with NH compared to non-NH had significantly worse baseline hypoxemia (p < 0.001), higher TRJV (p = 0.005), and higher LV end-diastolic diameters (p = 0.009). The severity of NH was influenced by OSA. However, PH was not associated with OSA or duration of hydroxyurea therapy.

CONCLUSION:

Our study indicates that NH is associated with PH in C-SCD, and that screening for NH may help to identify C-SCD with higher morbidity risk.

PMID: 30135591

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Mol Med. 2018 Mar 23;24(1):11. doi: 10.1186/s10020-018-0011-z.

Erythropoiesis: insights into pathophysiology and treatments in 2017.

Zivot A1,2, Lipton JM1,2,3, Narla A4, Blanc L5,6,7.

Erythropoiesis is a tightly-regulated and complex process originating in the bone marrow from a multipotent stem cell and terminating in a mature, enucleated erythrocyte.Altered red cell production can result from the direct impairment of medullary erythropoiesis, as seen in the thalassemia syndromes, inherited bone marrow failure as well as in the anemia of chronic disease. Alternatively, in disorders such as sickle cell disease (SCD) as well as enzymopathies and membrane defects, medullary erythropoiesis is not, or only minimally, directly impaired. Despite these differences in pathophysiology, therapies have traditionally been non-specific, limited to symptomatic control of anemia via packed red blood cell (pRBC) transfusion, resulting in iron overload and the eventual need for iron chelation or splenectomy to reduce defective red cell destruction. Likewise, in polycythemia vera overproduction of red cells has historically been dealt with by non-specific myelosuppression or phlebotomy. With a deeper understanding of the molecular mechanisms underlying disease pathophysiology, new therapeutic targets have been identified including induction of fetal hemoglobin, interference with aberrant signaling pathways and gene therapy for definitive cure. This review, utilizing some representative disorders of erythropoiesis, will highlight novel therapeutic modalities currently in development for treatment of red cell disorders.

PMCID: PMC6016880 Free PMC Article

PMID: 30134792

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Am J Hematol. 2018 Aug 21. doi: 10.1002/ajh.25260. [Epub ahead of print]

Prognostic factors of disease severity in infants with sickle cell anemia: A comprehensive longitudinal cohort study.

Brousse V1,2, El Hoss S2, Bouazza N3,4, Arnaud C5, Bernaudin F5, Pellegrino B6, Guitton C7, Odievre-Montanié MH8, Mames D9, Brouzes C10, Picard V11, Nguyen-Khoa T10, Pereira C2, Lapoumeroulie C2, Pissard S12, Gardner K13,14, Menzel S13, Le Van Kim C2, Colin Aronovicz Y2, Buffet P2, Mohandas N15, Elie C3, Maier-Redelsperger M9, El Nemer W2, De Montalembert M1.

Abstract

In order to identify very early prognostic factors that can provide insights into subsequent clinical complications, we performed a comprehensive longitudinal multi-center cohort study on 57 infants with sickle cell anemia (55 SS; 2 Sβ°) during the first two years of life (ClinicalTrials.gov: NCT01207037). Time to first occurrence of a severe clinical event – acute splenic sequestration (ASS), vaso-occlusive (VOC) event requiring hospitalization, transfusion requirement, conditional/ abnormal cerebral velocities, or death – was used as a composite endpoint. Infants were recruited at a mean age of 4.4 ± 1 mo. Median follow-up was 19.4 months. During the study period, 38.6% of infants experienced ≥ 1 severe event: 14% ASS, 22.8% ≥ 1 VOC (median age: 13.4 and 12.8 mo. respectively) and 33.3% required transfusion. Of note, 77% of the cohort was hospitalized, with febrile illness being the leading cause for admission. Univariate analysis of various biomarkers measured at enrollment showed that fetal hemoglobin (HbF) was the strongest prognostic factor of subsequent severe outcome. Other biomarkers measured at enrolment including absolute neutrophil or reticulocyte counts, expression of erythroid adhesion markers, % of dense red cells, cellular deformability or Υ-globin genetic variants, failed to be associated with severe clinical outcome. Multivariate analysis demonstrated that higher Hb concentration and HbF level are the two independent protective factors (adjusted HRs (95% CI) 0.27 (0.11-0.73) and 0.16 (0.06-0.43) respectively). These findings imply that early measurement of HbF and Hb levels can identify infants at high risk for severe complications who might maximally benefit from early disease modifying treatments. This article is protected by copyright. All rights reserved.

PMID: 30132969

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J Natl Med Assoc. 2018 Jun 22. pii: S0027-9684(18)30092-0. doi: 10.1016/j.jnma.2018.05.003. [Epub ahead of print]

Quality Metrics and Health Care Utilization for Adult Patients with Sickle Cell Disease.

Ter-Minassian M1, Lanzkron S2, Derus A3, Brown E2, Horberg MA3.

Abstract

BACKGROUND:

To date, there are no standardized, well-accepted, quality metrics that guide care for adults with sickle cell disease (SCD). The primary objective of this study was to evaluate the quality metrics that are in use at the Adult Sickle Cell Disease Program at Johns Hopkins Hospital (JHH) and the applicability of the metrics to Kaiser Permanente Mid-Atlantic States (KPMAS), an integrated healthcare system with a developing adult sickle cell disease program.

METHODS:

We performed a retrospective cross-sectional study of 146 KPMAS and 308 JHH patients from January 1, 2014-December 31, 2015. Demographics, genotype and data on several key quality metrics (yearly screening labs, documented vaccinations and appropriate hydroxyurea prescriptions) were collected from electronic health records (EPIC Systems). We defined hydroxyurea adherence as having had at least 6 months of refills prescribed during the two years of study by either EHR or patient report.

RESULTS:

Patients at KPMAS were older than those at JHH (median age 44 and 33 respectively) and less likely to have hemoglobin SS disease (29% and 66% respectively). Among KPMAS patients, 85% had documentation of any pneumococcal vaccination compared to 87% at JHH. 21 of 54 eligible patients at KPMAS and 95 of 165 eligible patients at JHH were prescribed hydroxyurea. At both institutions, 62% of patients were adherent to hydroxyurea. There were limitations to diagnosis coding and availability of vaccination and refill documentation.

CONCLUSIONS:

Interventions to improve preventative care adherence are needed to improve outcomes in both academic medical centers and integrated health systems.

Copyright © 2018 National Medical Association. Published by Elsevier Inc. All rights reserved.

PMID: 30129484

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J Natl Med Assoc. 2018 Apr 7. pii: S0027-9684(17)30170-0. doi: 10.1016/j.jnma.2018.03.004. [Epub ahead of print]

Implementation of the NCAA Sickle Cell Trait Screening Policy: A Survey of Athletic Staff and Student-athletes.

Baker C1, Powell J2, Le D2, Creary MS3, Daley LA2, McDonald MA2, Royal CD4.

Abstract

OBJECTIVE:

To describe the perspectives and experiences of athletic trainers, coaches, and student-athletes approximately three years post-implementation of the NCAA sickle cell trait (SCT) screening policy.

PARTICIPANTS:

Two-hundred and eight student-athletes, 32 athletic trainers, and 43 coaches from 10 NCAA Division I (DI) institutions in North Carolina from January to June 2014.

METHODS:

Two online surveys were used to assess knowledge, perspectives, and experiences.

RESULTS:

Athletic staff were more supportive than student-athletes of the need for the policy. Noted challenges included variation in implementation and follow-up for SCT-positive athletes, financial costs to institutions and athletes, and timing of the screening.

CONCLUSIONS:

More education about SCT is needed for student-athletes and athletic staff in order to help make the implementation more successful. All parties need to be in agreement regarding the importance of knowing which student-athletes have SCT and how that information will be utilized.

Copyright © 2018 National Medical Association. Published by Elsevier Inc. All rights reserved.

PMID: 30129496

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Cochrane Database Syst Rev. 2018 Aug 20;8:CD011199. doi: 10.1002/14651858.CD011199.pub3. [Epub ahead of print]

Conjugate Haemophilus influenzae type b vaccines for sickle cell disease.

Allali S1, Chalumeau M, Launay O, Ballas SK, de Montalembert M.

Abstract

BACKGROUND:

People affected with sickle cell disease (SCD) are at high risk of infection from Haemophilus influenzae type b (Hib). Before the implementation of Haemophilus influenzae type b conjugate vaccination in high-income countries, this was responsible for a high mortality rate in children under five years of age. In African countries, where coverage of this vaccination is still extremely low, Hib remains one of the most common causes of bacteraemias in children with SCD. The increased uptake of this conjugate vaccination may substantially improve the survival of children with SCD. This is an update of a previously published Cochrane Review.

OBJECTIVES:

The primary objective was to determine whether Hib conjugate vaccines reduce mortality and morbidity in children and adults with SCD.The secondary objectives were to assess the following in children and adults with SCD: the immunogenicity of Hib conjugate vaccines; the safety of these vaccines; and any variation in effect according to type of vaccine, mode of administration (separately or in combination with other vaccines), number of doses, and age at first dose.

SEARCH METHODS:

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group’s Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched trial registries (04 July 2018) and contacted relevant pharmaceutical companies to identify unpublished trials.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group’s Haemoglobinoapthies Trials Register: 18 December 2017.

SELECTION CRITERIA:

All randomised controlled trials (RCTs) and quasi-RCTs comparing Hib conjugate vaccines with placebo or no treatment, or comparing different types of Hib conjugate vaccines in people with SCD.

DATA COLLECTION AND ANALYSIS:

No trials of Hib conjugate vaccines in people with SCD were found.

MAIN RESULTS:

There is an absence of evidence from RCTs relating to the subject of this review.

AUTHORS’ CONCLUSIONS:

There has been a dramatic decrease in the incidence of invasive Hib infections observed in the post-vaccination era in people with SCD living in high-income countries. Therefore, despite the absence of evidence from RCTs, it is expected that Hib conjugate vaccines may be useful in children affected with SCD, especially in African countries where there is a high prevalence of the disease. The implementation of childhood immunisation schedules, including universal Hib conjugate vaccination, may substantially improve the survival of children with SCD living in low-income countries. We currently lack data to evaluate the potential effect of Hib vaccination among unvaccinated adults with SCD. Further research should assess the optimal Hib immunisation schedule in children and adults with SCD.

PMID: 30125338

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Transfus Med Rev. 2018 Jul 26. pii: S0887-7963(18)30040-3. doi: 10.1016/j.tmrv.2018.07.003. [Epub ahead of print]

Impact of Red Blood Cell Antigen Matching on Alloimmunization and Transfusion Complications in Patients with Sickle Cell Disease: A Systematic Review.

Fasano RM1, Meyer EK2, Branscomb J3, White MS4, Gibson RW5, Eckman JR6.

Abstract

Red blood cells (RBC) transfusion is critical in managing acute and chronic complications in sickle cell disease (SCD); however, it is complicated by RBC alloimmunization, iron overload, transfusion reactions and infection. Several reports documented an increased incidence of alloantibodies in transfused individuals with SCD, especially for Rh and Kell antigens. As a result, the National Institutes of Health Expert Panel and British Society for Haematology guidelines recommend primary matching for C/c, E/e and K antigens in addition to ABO/RhD for RBC transfusions. However, the evidence supporting these recommendations was cited as limited and understanding of alloimmunization in SCD is evolving. To examine the limitations of the evidence, we undertook a systematic review of evidence behind recommendations for limited and extended serologic and genotypic RBC antigen matching to reduce alloimmunization, autoimmunization and transfusion reactions. Searches of PubMed, Embase, Cochrane, and Web of Science databases using MeSH index and free text terms between 1976 through October 2015 and papers and captured through July 2016 through review references in papers, word of mouth, and ongoing Google Scholar and Medline Alerts identified 303 unique articles. Nineteen articles met inclusion criteria and were classified by the Oxford Centre Evidence Based levels of evidence. Strengthening the Reporting of Observational Studies in Epidemiology checklists were completed for 18 of the 19 studies. There were no prospective randomized controlled trials. Sixteen of the articles were cohort studies, two were cross-sectional studies, and one decision tree model examining costs. Low-quality evidence from observational cohort studies supports that alloimmunization prevalence can be decreased by extending serological RBC antigen matching. Transfusion reactions are generally poorly and inconsistently reported. There was no evidence reporting the effect prophylactic genotypic matching has on alloimmunization, autoimmunization or transfusion reactions. There were no studies comparing prophylactic genotypic matching to serologic matching. High-quality evidence was lacking to support clinical decision making regarding best transfusion practices. Multicenter prospective randomized clinical trials are needed to determine best strategies for reducing the rate of alloimmunization using serologic and genotypic matching.

PMID: 30122266

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Biomed Res Int. 2018 Jul 18;2018:8296139. doi: 10.1155/2018/8296139. eCollection 2018.

Association between Participants’ Characteristics, Patient-Reported Outcomes, and Clinical Outcomes in Youth with Sickle Cell Disease.

Badawy SM1,2, Barrera L2, Cai S3, Thompson AA1,2.

Abstract

Background:

Sickle cell disease (SCD) is a chronic debilitating illness. SCD-related complications result in substantial impairment in quality of life (QOL). Our study objective was to assess the relationship of participants’ characteristics, QOL, hydroxyurea adherence, and SCD-related clinical outcomes in youth with SCD.

Procedure:

A single-center cross-sectional study. Thirty-four youth with SCD enrolled from clinic between January and December 2015. Participants completed PROMIS® measures and ©Modified Morisky Adherence Scale.

Results:

Participants had a mean age of 14.8 (SD 2.9) years and 41% were female. Participants’ age correlated with fatigue (rs=0.48; P=0.006), pain (rs=0.32; P=0.07), and anxiety (rs=0.33; P=0.06) scores. Participants with chronic pain had worse upper extremity physical function (P=0.05), pain (P=0.04), anxiety (P=0.05), and depression (P=0.05). Males reported significantly higher hydroxyurea adherence (5.4 versus 3.6, P=0.02) compared to females. Participants with chronic pain had more frequent hospitalizations (P=0.02), emergency room visits (P=0.04), and longer total length of hospital stays over 12-month period (P=0.01).

Conclusions:

Older and female participants had worse QOL scores, and males reported higher hydroxyurea adherence. Participants with chronic pain reported significant impairment in different QOL domains and had increased healthcare utilization. Future longitudinal studies examining the relationship between participants’ characteristics, QOL, hydroxyurea adherence, and SCD-related clinical outcomes are needed.

PMCID: PMC6076920 Free PMC Article

PMID: 30105252

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Blood Adv. 2018 Aug 14;2(15):1969-1979. doi: 0.1182/bloodadvances.2018021444.

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

Daak AA1, Dampier CD2, Fuh B3, Kanter J4, Alvarez OA5, Black LV6, McNaull MA7, Callaghan MU8, George A9, Neumayr L10, Hilliard LM11, Sancilio F1, Rabinowicz AL1, Heeney MM12.

Abstract

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.

PMCID: PMC6093734 Free PMC Article

PMID: 30097463

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PLoS One. 2018 Aug 10;13(8):e0201860. doi: 10.1371/journal.pone.0201860. eCollection 2018.

Enuresis in children and adolescents with sickle cell anaemia is more frequent and substantially different from the general population.

Esezobor CI1,2, Akintan P1,2, Nwaogazie U2, Akinwunmi E2, Temiye E1,2, Akinsulie A1,2, Gbadegesin R3,4.

Abstract

BACKGROUND:

No large studies have examined the prevalence of enuresis, its various forms and risk factors in children with sickle cell anaemia (SCA) in Sub-Saharan Africa using standardised definitions. We determined age and gender-specific prevalence of enuresis and compared the nature of enuresis in children with and without SCA. We also identified predictors of enuresis in children with SCA.

METHODS:

Caregivers of children with SCA attending a tertiary centre haematology clinic in Nigeria were interviewed using a questionnaire. In addition, a separate questionnaire was completed for every sibling aged 5-17 years whose haemoglobin genotype was known. Enuresis and its various forms were defined using the definitions of the International Children’s Continence Society.

RESULTS:

The study involved 243 children with SCA and 243 controls matched for age and sex. The mean age of the study cohort was 9.9 (3.4). Females made up 45.7% of the cohorts. The prevalence of enuresis was 49.4% and 29.6% in children with and without SCA, respectively (p = 0.009). In both groups, the prevalence of enuresis declined with age but remained five times higher at 25% in children with SCA aged 14-17 years compared with controls. Also, children with SCA and enuresis were older, more likely to have non-monosymptomatic enuresis and wet at least three nights per week than controls. Independent predictors of enuresis in children with SCA were a family history of enuresis and young age.

CONCLUSION:

Children with SCA had more frequent and more severe enuresis which persisted to late adolescence than age and sex-matched controls. These features indicate a subset of enuresis that is difficult to treat in the general population. Young age and enuresis in a family member define a subset of children with SCA more likely to have enuresis. Healthcare workers need to discuss enuresis with parents of children with SCA and offer referral to continence services.

Free Article

PMID: 30096167

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Conflict of interest statement

The authors have declared that no competing interests exist.

 

 

Cochrane Database Syst Rev. 2018 Aug 1;8:CD012082. doi: 10.1002/14651858.CD012082.pub2. [Epub ahead of print]

Red blood cell transfusion to treat or prevent complications in sickle cell disease: an overview of Cochrane reviews.

Fortin PM1, Hopewell S, Estcourt LJ..

Abstract

BACKGROUND:

Globally, sickle cell disease (SCD) is one of the commonest severe monogenic disorders, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Red blood cell (RBC) transfusions are used to treat complications of SCD, e.g. acute chest syndrome (ACS) (this often involves a single transfusion episode), or they can be part of a regular long-term transfusion programme to prevent SCD complications.

OBJECTIVES:

To summarize the evidence in Cochrane Reviews of the effectiveness and safety of RBC transfusions versus no transfusion, or restrictive (to increase the total haemoglobin) versus liberal (to decrease the haemoglobin S level below a specified percentage) transfusion, for treating or preventing complications experienced by people with SCD.

METHODS:

We included Cochrane Reviews of randomised or quasi-randomised controlled trials published in the Cochrane Database of Systematic Reviews, that addressed various SCD complications and had RBC transfusion as an intervention or comparator. We assessed the methodological quality of included reviews according to the AMSTAR quality assessment.

MAIN RESULTS:

We included 15 Cochrane Reviews, 10 of which had no included studies with an RBC transfusion intervention (five reported RCTs with other interventions; and five contained no studies). Five of the 15 reviews included participants randomised to RBC transfusion, but in one of these reviews only 10 participants were randomised with no usable data. Four reviews (nine trials with 1502 participants) reported data comparing short- or long-term RBC transfusions versus standard care, disease-modifying agents, a restrictive versus a liberal transfusion strategy and long-term RBC transfusions versus transfusions to treat complications. All reviews were of high quality according to AMSTAR quality assessment, however, the quality of the included trials was highly variable across outcomes. Trials were downgraded according to GRADE methodology for risk of bias, indirectness (most trials were conducted in children with HbSS), and imprecision (outcomes had wide confidence intervals).In all four reviews and all comparisons there was little or no difference in the risk of death (very low-quality evidence). There were either no deaths or death was a rare event.Short-term RBC transfusion versus standard care (one review: two trials, 434 participants, GRADE very low- to low-quality evidence)In people undergoing low- to medium-risk surgery, RBC transfusions may decrease the risk of acute chest syndrome (ACS) in people with African haplotypes compared to standard care (low-quality evidence), but there was little or no difference in people with the Arabic haplotype (very-low quality evidence). There was also little or no difference in the risk of other SCD-related or transfusion-related complications (very-low quality evidence).Long-term RBC transfusion versus standard care (two reviews: three trials, 405 participants, very low- to moderate-quality evidence)In children and adolescents at high risk of stroke (abnormal transcranial doppler (TCD) velocities or silent cerebral infarct (SCI)), long-term RBC transfusions probably decrease the risk of stroke (moderate-quality evidence) and may decrease the risk of ACS and painful crisis compared to standard care (low-quality evidence). Long-term RBC transfusions may also decrease the risk of SCI in children with abnormal TCD velocities (low-quality evidence), but there may be little or no difference in the risk of SCI in children with normal TCD velocities and previous SCI (low-quality evidence).In children and adolescents already receiving long-term RBC transfusions for preventing stroke, in comparison to standard care, continuing long-term RBC transfusions may reduce the risk of SCI (low-quality evidence) but we do not know whether there is a difference in the risk of stroke (very-low quality evidence). In children with normal TCD velocities and SCI there was little or no difference in the risk of alloimmunisation or transfusion reactions, but RBC transfusions may increase the risk of iron overload (low-quality evidence).Long-term RBC transfusion versus RBC transfusion to treat complications (one review: one trial, 72 participants, very low- to low-quality evidence)In pregnant women, long-term RBC transfusions may decrease the risk of painful crisis compared to transfusion for complications (low-quality evidence); but there may be little or no difference in the risk of other SCD-related complications or transfusion reactions (very-low quality evidence).RBC transfusion versus disease-modifying agents (hydroxyurea) (two reviews: two trials; 254 participants, very low- to low-quality evidence)For primary prevention of stroke in children, with abnormal TCD and no severe vasculopathy on magnetic resonance imaging/magnetic resonance angiography (MRI/MRA), who have received at least one year of RBC transfusions, we do not know whether there is a difference between RBC transfusion and disease-modifying agents in the risk of stroke; SCI; ACS; or painful crisis (very-low quality evidence). There may be little or no difference in the risk of iron overload (low-quality evidence).Similarly, for secondary prevention of stroke in children and adolescents, we do not know whether there is a difference between these interventions in the risk of stroke; SCI; or ACS (very-low quality evidence); but hydroxyurea with phlebotomy may increase the risk of painful crisis and global SCD serious adverse events compared to RBC transfusion (low-quality evidence). There may be little or no difference in the risk of iron overload (low-quality evidence).Restrictive versus liberal RBC transfusion strategy (one review: one trial; 230 participants, very low-quality evidence)In people undergoing cholecystectomy, there was little or no difference between strategies in the risk of SCD-related or transfusion-related complications (very-low quality evidence).

AUTHORS’ CONCLUSIONS:

This overview provides support from two high-quality Cochrane Reviews for the use of RBC transfusions in preventing stroke in children and adolescents at high risk of stroke (abnormal TCDs or SCI) and evidence that it may decrease the risk of SCI in children with abnormal TCD velocities. In addition RBC transfusions may reduce the risk of ACS and painful crisis in this population.This overview highlights the lack of high-quality evidence in adults with SCD and the number of reviews that have no evidence for the use of RBC transfusions across a spectrum of SCD complications. Also of concern is the variable and often incomplete reporting of patient-relevant outcomes in the included trials such as SCD-related serious adverse events and quality of life.

PMID: 30067867

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Pediatr Blood Cancer. 2018 Aug 1:e27379. doi: 10.1002/pbc.27379. [Epub ahead of print]

Outcomes of febrile events in pediatric patients with sickle cell anemia.

Sirigaddi K1, Aban I2, Jantz A1, Pernell BM1, Hilliard LM1, Bhatia S1,3, Lebensburger JD1.

Abstract

BACKGROUND:

Limited evidence exists to create institutional admission criteria guidelines for febrile sickle cell patients. In addition, evidence is lacking to understand readmission rates for febrile sickle cell patients discharged from the emergency department (ED) or hospital.

PROCEDURES:

We conducted a 16-year retrospective study of bacteremia outcomes for febrile sickle cell patients. Risk variables analyzed included fever (either ≥ 39.5°C or ≥40°C), abnormal white blood cell (WBC) (>30,000 or <5,000/mcL), tachycardia and hypotension, or “ill appearing.” Fourteen-day readmission rates were analyzed to determine outcomes for febrile sickle cell patients discharged from the ED or discharged within 72 h.

RESULTS:

Bacteremia was identified in 17 (2.6%) of 653 febrile events that are presented to the ED. “Ill-appearing” patients had an 8.5-fold increased odds of being diagnosed with bacteremia. Models using WBC count, “ill appearing,” and hypotension have the highest sensitivity and specificity (AUC > 0.75). Among 427 patients discharged from the ED or within 72 h of hospitalization, only 10 (2.3%) were readmitted for a new sickle cell complication.

CONCLUSIONS:

Institutions can develop admission criteria based on WBC count, hypotension, and “ill appearance.” Persistently febrile, well-appearing patient can be discharged at 48 h with minimal risk for new complications.

© 2018 Wiley Periodicals, Inc.

PMID: 30070043

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Sickle Cell Conferences and Events

 

2018 Sickle Cell in Focus

October 22-23, 2018 National Institutes of Health 

Natcher Conference Center

Bethesda, MD 20892

Click here for event details and to register!

To view the agenda click here. 

 

 

46TH ANNUAL Sickle Cell Disease Association NATIONAL CONVENTION

Celebrating the Diversity Within the Sickle Cell Community: Commitment, Innovation, and Practice

With over 600 researchers, physicians, nurses, social workers, individuals living with SCD & SCT in attendance, last year’s year’s convention was a major success and our largest to date. We are excited to unite again with you at the 46th Annual National Convention in Baltimore, MD on October 10-13, 2018 https://www.sicklecelldisease.org/2017/03/07/46th-annual-national-convention/

 

 

The 4th Annual Sickle Cell Disease Symposium for Carolinas Healthcare System

Atrium Health will be held on Saturday, October 27, 2018 at the Speedway Club in Charlotte, NC. The theme this year is: “4th Annual SCD Symposium: Racing to Improve the Access to Care & Outcomes for SCD”.

 

 

2018 (Re) imagining Health: Sickle Cell Anemia & Thalassaemia: An International Biomedical-Sociocultural Conference

November 16 – 17, 2018

Edmonton Clinic Health Academy, University of Alberta Edmonton, Alberta, Canada

This event will join our community of physicians, surgeons, researchers, medical practitioners and patients with a deep understanding and commitment to finding the cure for Sickle Cell Anemia.

We aim to bring together multiple voices to support and build inclusive and equitable teaching and learning environments, while increasing knowledge of the continued effects of the Sickle Cell Anemia trait. The Sickle Cell Foundation of Alberta is proud to announce the following expert speakers

Dr. Lakiea Bailey, of Georgia, USA
Dr. Carl James, of Toronto, ON
Dr. Emily Meier of Indiana, USA
Dr. Greg Guilcher of Calgary, AB
Dr. Santosh Saraf of Illinois, USA
Dr. Courtney Fitzhugh of Maryland, USA

REGISTRATION – Conference registration is now open. A variety of registration categories are available for the conference. Please see the fee details below or register online here. https://ourscfa.org/conference/

More information can be found on the conference website
www.ourscfa.org/conference  Contact us at SCFA@buksa.com