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NIH launches new collaboration to develop gene-based cures for sickle cell disease and HIV on global scale 

Initial investment aims to advance accessible and scalable candidate interventions into clinical trials within 10 years. https://www.nih.gov/news-events/news-releases/nih-launches-new-collaboration-develop-gene-based-cures-sickle-cell-disease-hiv-global-scale

The National Institutes of Health plans to invest at least $100 million over the next four years toward an audacious goal: develop affordable, gene-based cures for sickle cell disease (SCD) and HIV. The Bill & Melinda Gates Foundation will also invest $100 million toward this goal. The intention is for these cures to be made globally available, including in low-resource settings.

This initiative follows a bold announcement made earlier this year by President Donald J. Trump during the State of the Union Address to end the HIV epidemic in the United States in the next 10 years. Ending the HIV Epidemic: A Plan for Americaaims to leverage the powerful data and tools now available to reduce new HIV diagnoses in the United States by 75% in five years and by 90% by 2030. The Trump Administration has also elevated the attention paid to sickle cell disease, identifying it as an intractable health challenge with the potential for dramatic advances in the coming years.

Dramatic advances in genetics over the last decade have made effective gene-based treatments a reality, including new treatments for blindness and certain types of leukemia. Yet these breakthroughs are largely inaccessible to most of the world by virtue of the complexity and cost of treatment requirements, which currently limit their administration to hospitals in wealthy countries. To make these treatments effective and available for SCD and HIV, which disproportionately affect populations living in Africa or of African descent, new investment is needed to focus research on the development of curative therapies that can be delivered safely, effectively and affordably in low-resource settings.

The collaboration between the NIH and the Gates Foundation sets out a bold goal of advancing safe, effective and durable gene-based cures to clinical trials in the United States and relevant countries in sub-Saharan Africa within the next seven to 10 years. The ultimate goal is to scale and implement these treatments globally in areas hardest hit by these diseases.

“This unprecedented collaboration focuses from the get-go on access, scalability and affordability of advanced gene-based strategies for sickle cell disease and HIV to make sure everybody, everywhere has the opportunity to be cured, not just those in high-income countries,” said NIH Director Francis S. Collins, M.D., Ph.D. “We aim to go big or go home.”

The collaboration will align aggressive, high-reward research efforts to accelerate progress on shared gene-based strategies to cure SCD and HIV. Both organizations also will continue to invest in other parallel research efforts on cures for SCD and HIV outside of this collaboration.

“In recent years, gene-based treatments have been groundbreaking for rare genetic disorders and infectious diseases,” said Trevor Mundel, M.D., Ph.D., President, Global Health Program, Bill & Melinda Gates Foundation. “While these treatments are exciting, people in low- and middle-income countries do not have access to these breakthroughs. By working with the NIH and scientists across Africa, we aim to ensure these approaches will improve the lives of those most in need and bring the incredible promise of gene-based treatments to the world of public health.”

SCD and HIV are major burdens on health in low-resource communities around the world. Approximately 95% of the 38 million people living with HIV globally are in the developing world, with 67% in sub-Saharan Africa, half of whom are living untreated. Fifteen million babies will be born with SCD globally over the next 30 years, with about 75% of those births occurring in sub-Saharan Africa. An estimated 50-90% of infants born with SCD in low-income countries will die before their 5th birthday and SCD is identified as the underlying cause of about 1 in 12 newborn deaths in sub-Saharan Africa.

Collaboration Details

The collaboration will focus on two areas of coordination:

  • First, identify potential candidate cures for SCD and HIV for pre-clinical and clinical evaluation, co-funded by the NIH and Gates Foundation
  • Second, define long-term opportunities to work together and with African partners on advancing promising candidates to late-phase clinical trials, with funding to be determined as candidates progress

Though SCD, a genetically inherited disease, and HIV, an acquired infectious disease, present significantly different scientific challenges, gene-based treatments hold promise for both, and many of the technical challenges for gene-based cures are expected to be common to both diseases.

To achieve the goals of the collaboration, both projects will require new delivery systems that can get prospective therapies to the right places in the body and optimize treatments to target the cells involved in the respective diseases efficiently and specifically. For SCD, that would mean repairing or compensating for the mutations in hemoglobin that cause SCD in hematopoietic stem cells. For HIV, that would mean targeting the reservoir of proviral DNA that continues to lurk inside a small number of cells, even after many years of effective antiviral treatment.

Such treatments that happen entirely within the body, known as in vivotreatments, would be a major step forward from current treatments, which apply genetic therapies to cells taken outside the body (ex vivo) and then reinfused.

“We are losing too much of Africa’s future to sickle cell disease and HIV,” said Matshidiso Rebecca Moeti, M.B.B.S., Regional Director for Africa, World Health Organization. “Beating these diseases will take new thinking and long-term commitment. I’m very pleased to see the innovative collaboration announced today, which has a chance to help tackle two of Africa’s greatest public health challenges.”

SCD

The collaboration’s goal for SCD is to develop an easy-to-administer, gene-based intervention to either correct the SCD gene mutations or promote fetal hemoglobin gene expression to achieve normal hemoglobin function. The path to a cure will rely in part on the development of gene-based delivery systems capable of selectively targeting hematopoietic stem cells. This will result in the precise correction of gene mutations or addition of a gene to promote sufficient levels of normal hemoglobin expression and function.

“Our excitement around this partnership rests not only in its ability to leverage the expertise in two organizations to reduce childhood mortality rates in low-resource countries, but to bring curative therapies for sickle cell disease and HIV to communities that have been severely burdened by these diseases for generations,” said Gary H. Gibbons, M.D., Director, National Heart, Lung, and Blood Institute (NHLBI), part of the NIH. “A person’s health should not be limited by their geographic location, whether rural America or sub-Saharan Africa; harnessing the power of science is needed to transcend borders to improve health for all.”

In addition, more needs to be done to understand the burden of SCD in sub-Saharan Africa and to screen newborns for SCD in high-risk geographic areas. NHLBI has already begun to establish a clinical research infrastructure in sub-Saharan Africa. However, additional clinical research and capacity-building efforts are needed to deliver point-of-care screening, such as at the time of infant vaccinations, and to initiate a standard of care. These activities will be undertaken by NIH and Gates Foundation outside of the collaboration, but will support collaboration efforts.

HIV

Nearly 38 million people worldwide are living with HIV, with 770,000 deaths due to AIDS in 2018 alone. Like SCD, people in sub-Saharan Africa face a disproportionate risk of HIV. Antiretroviral therapy is highly effective and has made it possible for people with HIV to live long, healthy lives without transmitting the disease to sexual partners. However, treatment must be maintained for a lifetime. A low-cost, safe, effective and durable cure that also prevents reinfection upon sexual exposure has long been a goal to curb the HIV global pandemic.

A number of approaches will be considered to meet the goal of a scalable HIV cure. Both the Gates Foundation and National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, are already funding cure research, exploring gene-based treatments in concert with long-acting therapeutics, monoclonal antibodies and other immune-based targets. This collaboration will allow the partners to intensify and better coordinate ongoing research efforts on these strategies, accelerating studies into early phase clinical trials to safely test promising tools and interventions. A particularly appealing approach is to identify the location of the reservoir of infected cells that still harbor integrated HIV genomes after treatment and target those DNA sequences with gene editing technology.

“This collaboration is an ambitious step forward, harnessing the most cutting-edge scientific tools and NIH’s sizable global HIV research infrastructure to one day deliver a cure and end the global HIV pandemic,” said NIAID Director Anthony S. Fauci, M.D. “We are taking into account those with the greatest need at the foundation of this effort, to ensure that, if realized, this exceptional public health achievement will be made accessible to all.”

About the National Institutes of Health (NIH):NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

A Patient Hopes Gene-Editing Can Help With Pain Of Sickle Cell Disease

https://www.npr.org/sections/health-shots/2019/10/10/766765780/after-a-life-of-painful-sickle-cell-disease-a-patient-hopes-gene-editing-can-hel

Victoria Gray slides open a closet door, pulls out a suitcase and starts packing piles of clothes.

“My goodness,” says Gray. “Did I really bring all this?”

Gray, who has sickle cell disease, is the first patient with a genetic disorder whom doctors in the United States have tried to treat using the powerful gene-editing technique CRISPR.

Today, Gray is getting ready to finally go home to Forest, Miss., after months away from her four children so she could undergo the experimental treatment, which involves infusions of genetically modified bone marrow cells. 

“I’m very excited,” says Gray, who has been living in a temporary apartment in Nashville, Tenn., for several weeks since getting discharged from the nearby TriStar Centennial Medical Center. “I know it’s going to be emotional for me. I miss the hugs and the kisses and just everything.”

NPR has exclusive access to chronicle Gray’s journey through the highly anticipatedclinical trial.

“Victoria is a pioneer in this. And we are very excited,” says her doctor, Haydar Frangoul

New Resources

Free online CME course on evidence-based practices for blood transfusion (now expiring in October 2021), The series can be found on the Georgia Health Policy Centerwebpage at https://ghpc.gsu.edu/cme/#1562858869576-17a192a1-ecb3

New Book: All Rise! The Sickle Cell Community vs the Medical Establishment by Simone Uwan, MD has captured the voices of many with sickle cell who must interact with the medical community on a regular basis. This book should be required reading for any medical provider caring for those with sickle cell disease.

 Link for the book at https://www.amazon.com/dp/1696143144

Articles in the medical literature

1. Front Genet. 2019 Oct 10;10:943. doi: 10.3389/fgene.2019.00943. eCollection 2019.Establishing a Multi-Country Sickle Cell Disease Registry in Africa: Ethical Considerations.Munung NS1,2Nembaware V2,3de Vries J1Bukini D4Tluway F4Treadwell M5,6Sangeda RZ4,7Mazandu G2,3Jonas M2,3Paintsil V8Nnodu OE9Balandya E4Makani J4Wonkam A2,3.AbstractSickle cell disease (SCD) is one of the most prevalent genetic conditions in sub-Saharan Africa. It is a chronic, lifelong disease often characterized by severe pain. However, SCD has received little investment terms of health research, though there is currently a growing pool of SCD data from health and research facilities in different countries. To facilitate research on SCD in Africa, the SickleInAfrica consortium has established a SickleInAfrica registry. The registry will store a systematic collection of longitudinal data from persons with SCD across sub-Saharan Africa, and currently, participants are being enrolled in Ghana, Nigeria, and Tanzania. In establishing this registry, the SickleInAfrica consortium decided to actively identify and anticipate possible ethical issues that may arise in the development and management of the registry. This was motivated, in part, by the near absence of well documented ethical issues for registry research in Africa, more-so for registries enrolling participants across multiple countries and for a genetic condition. The consortium aims to establish standards for the equitable use of data stored in the registry. This paper presents a comprehensive report on the ethical considerations that came up in setting up a genetic disease registry across multiple African countries and how they were addressed by the SickleInAfrica consortium. Major issues included: active involvement of patients in the initiation and management of the registry; questions of assent and re-consent; the importance of ensuring that fears of exploitation are not replicated in African-African research collaborations; and the importance of public engagement in the management of registries. Drawing on this experience, SickleInAfrica plans to set up an ethics helpdesk for genetic disease registries and research in Africa.Copyright © 2019 Munung, Nembaware, de Vries, Bukini, Tluway, Treadwell, Sangeda, Mazandu, Jonas, Paintsil, Nnodu, Balandya, Makani, Wonkam.PMCID: PMC6795756 
PMID: 31649726 
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3. Blood Adv. 2019 Oct 22;3(20):3170-3180. doi: 10.1182/bloodadvances.2019000193.Role of the coagulation system in the pathogenesis of sickle cell disease.Nasimuzzaman M1,2Malik P1,2.AbstractSickle cell disease (SCD) is an inherited monogenic red blood cell disorder affecting millions worldwide. SCD causes vascular occlusions, chronic hemolytic anemia, and cumulative organ damage such as nephropathy, pulmonary hypertension, pathologic heart remodeling, and liver necrosis. Coagulation system activation, a conspicuous feature of SCD that causes chronic inflammation, is an important component of SCD pathophysiology. The key coagulation factor, thrombin (factor IIa [FIIa]), is both a central protease in hemostasis and thrombosis and a key modifier of inflammation. Pharmacologic or genetic reduction of circulating prothrombin in Berkeley sickle mice significantly improves survival, ameliorates vascular inflammation, and results in markedly reduced end-organ damage. Accordingly, factors both upstream and downstream of thrombin, such as the tissue factor-FX complex, fibrinogen, platelets, von Willebrand factor, FXII, high-molecular-weight kininogen, etc, also play important roles in SCD pathogenesis. In this review, we discuss the various aspects of coagulation system activation and their roles in the pathophysiology of SCD.© 2019 by The American Society of Hematology.
PMID: 31648337 
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4. Rev Bras Enferm. 2019 Oct 21;72(6):1554-1561. doi: 10.1590/0034-7167-2018-0635. eCollection 2019.“Waiting for a miracle”: Spirituality/Religiosity in coping with sickle cell disease.[Article in English, Portuguese]Gomes MV1Xavier ADSG1Carvalho ESS1Cordeiro RC2Ferreira SL3Morbeck AD1.AbstractOBJECTIVE: To understand spirituality/religiosity as experienced by people with sickle cell disease, and its influence on coping with the disease.METHOD: A qualitative, descriptive, and exploratory study conducted in the State of Bahia. Twenty-nine respondents participated in semi-structured interviews. Content analysis was used to analyze the empirical material.RESULTS: Individuals with sickle cell disease experience spirituality/religiosity motivated by their hope for a miracle, and fear of death; among their rites are: reading religious materials, individual and group prayer, and attendance at worship services. The effects on their health include: comfort by means of coping by comparing two evils, anxiety relief, social support, and lifestyle changes; however, spirituality/religiosity may be impaired.FINAL CONSIDERATIONS: This study demonstrates the need to qualify health professionals to address spiritual issues of these individuals during illness, with the aims of diagnosing suffering and anguish, and providing care, comfort and strengthening of the spiritual bonds of these individuals.Free Article 
PMID: 31644744 
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5. Transfusion. 2019 Oct 23. doi: 10.1111/trf.15562. [Epub ahead of print]Posttransfusion hyperhemolysis is arrested by targeting macrophage activation with novel use of Tocilizumab.Lee LE1Beeler BW1Graham BC2Cap AP1Win N3Chen F4.AbstractBACKGROUND: Hyperhemolysis syndrome (HHS) is a posttransfusion complication most frequently seen in sickle cell disease (SCD), characterized by rapid destruction of transfused and autologous red blood cells (RBCs), resulting in reticulocytopenia and a decrease in hemoglobin to below pretransfusion levels. Additional RBC transfusion can be life threatening. Most patients improve with intravenous immune globulin and steroids, but in refractory cases, hyperhemolysis may result in multiorgan failure and death in the absence of salvage therapy. The exact pathophysiology of HHS remains uncertain, yet new insights suggest that RBC destruction is driven by activated macrophages. Therefore, we propose that antimacrophage therapy may represent an effective treatment.CASE REPORT: A case of life-threatening HHS, refractory to intravenous immune globulin and steroids, in a patient with SCD is presented. Marked elevation in ferritin, an indirect marker of macrophage activation, a negative direct antiglobulin test, and the absence of RBC alloantibodies was noted. A hemoglobin nadir of 2.1 g/dL and resultant hypoxemia-induced organ failure prompted the use of tocilizumab, an interleukin-6 receptor monoclonal antibody. Hemoglobin-based oxygen carrier-201, a cell-free polymerized bovine hemoglobin, was used to support the patient during critical anemia.RESULTS: Hemolysis resolved and ferritin dramatically decreased after administration of tocilizumab, which was well tolerated. A full recovery was achieved.CONCLUSION: This case highlights both a novel and successful approach to managing refractory transfusion-induced hyperhemolysis with tocilizumab and provides further evidence supporting the role for macrophage activation in the destruction of RBCs in antibody-negative HHS. We propose that tocilizumab is an effective and rapid salvage therapy for refractory HHS.© 2019 AABB.
PMID: 31642065 
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6. Ann Hematol. 2019 Oct 23. doi: 10.1007/s00277-019-03813-9. [Epub ahead of print]Non-invasive urinary biomarkers of renal function in sickle cell disease: an overview.Laurentino MR1Parente Filho SLA2Parente LLC3da Silva Júnior GB4Daher EF2Lemes RPG5.AbstractSickle cell disease (SCD) is a hereditary condition characterized by homozygosis of the hemoglobin S (HbS) gene. Marked morbimortality is observed due to chronic hemolysis, endothelial injury, and episodes of vaso-occlusion, which leads to multi-organ damage. Renal impairment is common and may have different presentations, such as deficiency in urinary acidification or concentration, glomerulopathies, proteinuria, and hematuria, frequently resulting in end-stage renal disease (ESRD). Novel biomarkers of renal function, such as kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein 1 (MCP-1) are being studied in order to enable early diagnosis of kidney damage in SCD.
PMID: 31641850 
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7. J Opioid Manag. 2019 Jul/Aug;15(4):323-331. doi: 10.5055/jom.2019.0517.Prescription Opioid Misuse Index in sickle cell patients: A brief questionnaire to assess at-risk for opioid abuse.Smith WR1McClish DK2Roberts JD3Kandalaft O4Dahman B5Knisely J6Levenson J7Roseff S8Aisiku IP9..AbstractOBJECTIVE: To develop a survey instrument to identify adult sickle cell disease (SCD) patients on chronic opioid therapy who are at-risk for opioid abuse.DESIGN: Prospective survey and interview.SETTING: Adult SCD clinic in a large urban teaching facility.PATIENTS/PARTICIPANTS: Convenience sampling of adult patients presenting to the sickle cell clinic.INTERVENTIONS: None.MAIN OUTCOME: Primary outcome was “at-risk for opioid misuse,” defined as at least 3/8 “yes” answers (a positive composite score) on the Prescription Opioid Misuse Index (POMI) questionnaire. Secondary outcome was DSM-IV criteria for substance abuse using the DSM IV Diagnostic Interview Schedule.RESULTS: Of the 99 patients who completed the POMI, the mean age was 36 years; 58.6 percent were female, 48 percent were hemoglobin SS (47/99), and 26 percent were SC (26/99). Twenty-four percent (24/99) were identified as at-risk for opioid misuse using the POMI. There were no differences in demographic, SCD genotype, or socioeconomic variables for at-risk versus not-at-risk patients.CONCLUSION: Twenty-four percent of unselected adult SCD patients on opioids were identified as at-risk for opioid misuse using a quick survey. This may represent as much as 2.5-7 times the national misuse rate. This group of patients may benefit from additional diagnostic and therapeutic interventions to help understand and manage their opioid usage.
PMID: 31637684 [Indexed for MEDLINE]
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8. J Clin Med. 2019 Oct 18;8(10). pii: E1728. doi: 10.3390/jcm8101728.Evaluation of a Non-Parenteral Opioid Analgesia Protocol for Acute Sickle Cell Pain Episodes in Children.Telfer P1Barroso F2Newell K3Challands J4Kaya B5.AbstractWe evaluated a protocol comprising intranasal diamorphine (IND) combined with oral short and modified-release morphine for children at the emergency department (ED) with acute painful episodes of sickle cell disease (SCD). In a retrospective audit of 83 episodes in 38 children, the mean time between arrival in the treatment area and the administration of IND was 10 min (range <5 min to 1.39 h). IND was administered in <5 min in 43 (51.6%), and in <20 min in 75 (90.4%) episodes. Persisting pain, requiring background analgesia with modified-release oral morphine, was required in 25 (30.1%) episodes. Inadequate control of pain requiring a switch to intravenous morphine PCA was required in eight episodes in four patients. Acute chest syndrome (ACS) developed in four of 83 episodes (4.8%, 95% CI 0.2-9.4%) and in four of 38 children (10.5%, 95% CI 0.7-20.5%). In conclusion, this protocol enabled the rapid administration of strong opioid analgesia in an ED setting, and may reduce the short and long-term adverse effects associated with parenteral opioids in children. There was no evidence of an increased incidence of ACS associated with use of oral morphine.Free Article 
PMID: 31635344 
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9. J Clin Med. 2019 Oct 16;8(10). pii: E1701. doi: 10.3390/jcm8101701.Optimizing Hydroxyurea Treatment for Sickle Cell Disease Patients: The Pharmacokinetic Approach.Nazon C1Sabo AN2,3Becker G4,5Lessinger JM6Kemmel V7,8Paillard C9,10AbstractBACKGROUND: Hydroxyurea (HU) is a FDA- and EMA-approved drug that earned an important place in the treatment of patients with severe sickle cell anemia (SCA) by showing its efficacy in many studies. This medication is still underused due to fears of physicians and families and must be optimized.METHODS: We analyzed our population and identified HU pharmacokinetic (PK) parameters in order to adapt treatment in the future. Working with a pediatric population, we searched for the most indicative sampling time to reduce the number of samples needed.RESULTS: Nine children treated by HU for severe SCA were included for this PK study. HU quantification was made using a validated gas chromatography/mass spectrometry (GC/MS) method. Biological parameters (of effectiveness and compliance) and clinical data were collected. None of the nine children reached the therapeutic target defined by Dong et al. as an area under the curve (AUC) = 115 h.mg/L; four patients were suspected to be non-compliant. Only two patients had an HbF over 20%. The 2 h sample was predictive of the medication exposure (r2 = 0.887).CONCLUSIONS: It is urgent to be more efficient in the treatment of SCA, and pharmacokinetics can be an important asset in SCA patients.Free Article 
PMID: 31623213 
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10. Characteristics of Inpatient Hospital Stays Involving Sickle Cell Disease, 2000–2016: Statistical Brief #251 [Internet].AuthorsFingar KROwens PLReid LDMistry KBBarrett ML.Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006-.
2019 Sep 03. ExcerptThis Healthcare Cost and Utilization Project (HCUP) Statistical Brief presents statistics on inpatient stays among patients with SCD. Historical trends are presented by patient age from 2000 through 2016 using the National (Nationwide) Inpatient Sample (NIS). Characteristics of inpatient stays with and without SCD are examined in 2016, overall and by whether SCD (i.e., a principal diagnosis) or a secondary diagnosis (i.e., a condition that coexists at the time of the inpatient stay) was the reason for the stay. SCD-related stays are examined with respect to whether a pain crisis was present. Additionally, costs, length of stay, and 30-day all-cause readmission rates following stays involving SCD are provided. Finally, the location of inpatient hospital care for patients with SCD is shown. Because of the large sample size of the HCUP NIS, small differences can be statistically significant. Thus, only percentage differences greater than or equal to 10 percent are noted in the text. For further information on the methodology, see the Data Source and Definitions sections at the end of this Statistical Brief.Free Books & Documents 
PMID: 31622075 
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11. J Clin Med. 2019 Oct 15;8(10). pii: E1688. doi: 10.3390/jcm8101688.Serum Immunoglobulin Levels in Children with Sickle Cell Disease: A Large Prospective Study.Cherif-Alami S1Hau I2Arnaud C3Kamdem A4Coulon B5Idoux E6Bechet S7Creidy R8Bernaudin F9Epaud R10,11Pondarré C12,13.AbstractOver the past 3 decades, the pediatric department of the university Intercommunal Créteil hospital, a referral center for sickle cell disease (SCD), has prospectively evaluated immunoglobulin (Ig) levels in a cohort of 888 children with SCD, including 731 with severe sickle genotypes (HbSS and HbSβ0thalassemia) and 157 with milder genotypes (HbSC and HbSβ+thalassemia). We found consistent sickle genotype differences in levels of IgG and IgA, with increased levels of IgA and IgG in the severe versus milder genotype, from early childhood to late adolescence. Additionally, our results revealed a low serum IgM level, irrespective of sickle genotype. Finally, we found that IgA and IgG levels were significantly increased after therapeutic intensification with hydroxyurea but were stabilized in children receiving a transfusion program. The mechanisms contributing to these changes in Ig levels are unclear as is their clinical significance. We believe they should be further investigated.Free Article 
PMID: 31618899 
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12. Clin Pharmacol Ther. 2019 Oct 16. doi: 10.1002/cpt.1682. [Epub ahead of print]Innovations in Targeted Anti-Adhesion Treatment for Sickle Cell Disease.Kanter J1.AbstractSickle Cell Disease (SCD) is an inherited hemoglobinopathy that leads to significant lifetime morbidity and early mortality. An enhanced understanding of the complex pathophysiology of the disease has elucidated novel therapeutic targets for which new therapies are in development. In order to increase the therapeutic landscape, it has been important to identify the blood vessel and more specifically the endothelium as the target organ in this complex disease. Through this lens, we present a review of new anti-adhesion therapies for SCD in development. The long-term promise of multi-modal therapies for SCD are finally on the horizon.© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.
PMID: 31617585 
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13. BMC Pediatr. 2019 Oct 15;19(1):354. doi: 10.1186/s12887-019-1746-6.HABIT efficacy and sustainability trial, a multi-center randomized controlled trial to improve hydroxyurea adherence in youth with sickle cell disease: a study protocol.Smaldone A1,2Manwani D3Aygun B4Smith-Whitley K5Jia H6,7Bruzzese JM6Findley S7Massei J6Green NS8.AbstractBACKGROUND: Hydroxyurea (HU) is recommended as standard practice for youth with sickle cell disease (SCD). Yet, despite its efficacy, HU adherence in adolescents and young adults is often poor. Poor medication adherence increases disease burden, healthcare cost and widens health disparities. Adolescence is a critical time to improve adherence through improved chronic disease self-management. This study aims to test the efficacy of an intervention delivered to youth/parent dyads by community health workers (CHWs), augmented by tailored text messages on HU adherence (primary outcome). Secondary outcomes are intervention sustainability, youth health-related quality of life, self-management responsibility concordance, acute hospital use and self-reported disease symptoms.METHODS: Hydroxyurea Adherence for Personal Best in Sickle Cell Disease, “HABIT,” is a 12 month multi-center randomized controlled trial. One hundred four youth, 10 to 18 years of age prescribed HU who meet eligibility criteria, enrolled with their parent as dyads, will be randomized 1:1 to either the HABIT intervention or to usual clinical care plus education handouts. All subjects will complete clinic visits at months 0, 2, 4, 6 (efficacy component), 9 and 12 (sustainability component) for assessment of HbF biomarker, other hematologic parameters, and to complete questionnaires. In addition, dyads assigned to the HABIT intervention will work with CHWs to identify a daily habit (e.g., brushing teeth) on which to build a HU adherence habit. Tailored daily text message reminders to support the habit will be developed by the dyad in collaboration with the CHWs and sent to parent and youth. At the 6 month visit, the intervention will end and the sustainability portion of the trial will begin. All data analyses will be based on intention to treat with all randomized subjects included in the analyses.DISCUSSION: Prior retrospective studies demonstrate that a majority of adolescents are poorly adherent to HU. If efficacious, the HABIT intervention has the potential to improve the lives of youth with SCD.TRIAL REGISTRATION: Clinicaltrials.gov NCT03462511 . Registered March 6, 2018, last updated July 26, 2019.PMCID: PMC6792326 Free PMC Article 
PMID: 31615480 
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14. Am J Health Syst Pharm. 2019 Oct 12. pii: zxz228. doi: 10.1093/ajhp/zxz228. [Epub ahead of print]Inpatient pain management in sickle cell disease.Zassman SM1Zamora FJ1Roberts JD2.AbstractPURPOSE: A novel strategy for management of acute pain associated with sickle cell disease (SCD), referred to as the oral tier approach, is described.SUMMARY: SCD is an inherited blood disorder characterized by episodic acute pain known as vaso-occlusive crisis (VOC), which is the most common reason for emergency department visits and hospital admissions in patients with SCD; these patients are often treated with parenteral opioids on admission and then transitioned to oral opioids prior to discharge. In this report, experience with use of the oral tier approach in 3 patients with SCD hospitalized for management of VOC is reported. As per usual practice, acute pain was initially managed with parenteral opioids via patient-controlled analgesia (PCA). Once pain control was established, an oral tier was added. The oral tier consisted of 3 orders. The first order was for an oral opioid, to be administered every 3 hours on a scheduled basis; however, the patient could refuse 1 or more of these scheduled doses. Two additional orders specified that the patients could receive additional oral opioids in incremental doses for moderate (grade 4-7) or severe (grade 8-10) pain if appropriate. To facilitate transition to an oral regimen with which the patients might be discharged, they were encouraged to use oral opioids in preference to parenteral opioids. Opioid usage and average daily pain scores for the 3 patients are reported.CONCLUSION: Healthcare providers can use the oral tier approach to facilitate rapid inpatient conversion from i.v. PCA to oral opioids while providing adequate pain control in patients with SCD who develop VOC.© American Society of Health-System Pharmacists 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PMID: 31605120 
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15. Cochrane Database Syst Rev. 2019 Oct 11;10:CD011808. doi: 10.1002/14651858.CD011808.pub2. [Epub ahead of print]Inhaled nitric oxide for treating pain crises in people with sickle cell disease.Aboursheid T1Albaroudi OAlahdab F.AbstractBACKGROUND: In people with sickle cell disease, sickled red blood cells cause the occlusion of small blood vessels which presents as episodes of severe pain known as pain crises or vaso-occlusive crises. The pain can occur in the bones, chest, or other parts of the body, and may last several hours to days. Pain relief during crises includes both pharmacologic and non-pharmacologic treatments. The efficacy of inhaled nitric oxide in pain crises has been a controversial issue and hypotheses have been made suggesting a beneficial response due to its vasodilator properties. Yet no conclusive evidence has been presented.This review aims to evaluate the available randomised controlled studies which address this topic.OBJECTIVES: To capture the available body of evidence evaluating the efficacy and safety of the use of inhaled nitric oxide in treating pain crises in people with sickle cell disease; and to assess the treatment’s relevance, robustness, and validity, in order to better guide medical practice in the fields of haematology and palliative care (since recent literature seems to favour the involvement of palliative care for those people).SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group’s Haemoglobinopathies Trials Register. Unpublished work is identified by searching the abstract books of the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting.Date of most recent search: 19 September 2019.We also searched ongoing study registries, date of most recent search: 26 September 2019.SELECTION CRITERIA: Randomised and quasi-randomised trials comparing inhaled nitric oxide with placebo, or standardized way of treatment of pain crises in people with sickle cell disease.DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data (including adverse event data). A third author helped clarify any disagreement. When the data were not reported in the text, we attempted to extract the data from any table or figure available. We contacted trial authors for additional information. We assessed the quality of the evidence using the GRADE criteria MAIN RESULTS: We identified six trials, three of which (188 participants) were eligible for inclusion in the review. There were equal numbers of males and females; and most participants were adults, although one small trial was conducted in a children’s hospital and recruited children over the age of 10 years. All three parallel trials compared inhaled nitric oxygen (80 ppm) to placebo (room air) for four hours; one trial continued administering nitric oxide (40 ppm) for a further four hours. This extended trial had an overall low risk of bias; however, in the remaining two trials we had concerns about the risk of bias from the small sample size and additionally a high risk of bias due to financial conflicts of interest in one of these smaller trials. We were only able to analyse some limited data from the eight-hour trial and report the remaining results narratively.The time to pain resolution was only reported in one trial (150 participants), showing there may be little or no difference between the two groups: with inhaled nitric oxide median 73.0 hours (95% confidence interval (CI) 46.0 to 91.0) and with placebo median 65.5 hours (95% CI 48.1 to 84.0) (low-quality evidence). No trial reported on the duration of the initial pain crisis. Only one large trial reported on the frequency of pain crises in the follow-up period and found there may be little or no difference between the inhaled nitric oxide and placebo groups for a return to the ED, risk ratio 0.73 (95% CI 0.31 to 1.71) or for re-hospitalisation, risk ratio 0.53 (95% CI 0.25 to 1.11) (150 participants; low-quality evidence).There may be little or no difference between treatment and placebo in terms of reduction in pain score at any time point up to eight hours (150 participants). The two smaller trials reported a beneficial effect of inhaled nitric oxide in reducing the visual analogue pain score after four hours of the intervention, but these trials were small and limited compared to the first trial.Analgesic use was reported not to differ greatly between the inhaled nitric oxide group and placebo group in any of the three trials, but no analysable data were provided. The median duration of hospitalisation was reported by two trials, in the largest trial the placebo group had the shorter duration and in the second smaller (paediatric) trial hospitalisation was shorter in the treatment group.Only the largest trial (150 participants) reported serious adverse events, with no increase in the inhaled nitric oxide group during or after the intervention compared to the control group (acute chest syndrome occurred in 5 out of 75 participants from each group, pyrexia in 1 out of 75 participants from each group, dysphagia and a drop in haemoglobin were each reported in 1 out of 75 participants in the inhaled nitric oxide group, but not in the placebo group) (low-quality evidence).AUTHORS’ CONCLUSIONS: The currently available trials do not provide sufficient evidence to determine the effects (benefits or harms) of using inhaled nitric oxide to treat pain (vaso-occlusive) crises in people with sickle cell disease. Large-scale, long-term trials are needed to provide more robust data in this area. Patient-important outcomes (e.g. measures of pain and time to pain resolution and amounts of analgesics used), as well as use of healthcare services should be measured and reported in a standardized form.PMCID: PMC6788324 [Available on 2020-10-11]
PMID: 31603241 
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16. Public Health Rep. 2019 Oct 10:33354919881438. doi: 10.1177/0033354919881438. [Epub ahead of print]Reducing Health Care Disparities in Sickle Cell Disease: A Review.Lee L1Smith-Whitley K2,3Banks S4Puckrein G5.AbstractSickle cell disease (SCD) is an inherited blood disorder most common among African American and Hispanic American persons. The disease can cause substantial, long-term, and costly health problems, including infections, stroke, and kidney failure, many of which can reduce life expectancy. Disparities in receiving health care among African Americans and other racial/ethnic minority groups in the United States are well known and directly related to poor outcomes associated with SCD. As an orphan disease-one that affects <200 000 persons nationwide-SCD does not receive the research funding and pharmaceutical investment directed to other orphan diseases. For example, cystic fibrosis affects fewer than half the number of persons but receives 3.5 times the funding from the National Institutes of Health and 440 times the funding from national foundations. In this review, we discuss the health inequities affecting persons with SCD, describe programs intended to improve their care, and identify actions that could be taken to further reduce these inequities, improve care, control treatment costs, and ease the burden of disease.
PMID: 31600481 
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17. Neurosci Lett. 2019 Oct 5:134534. doi: 10.1016/j.neulet.2019.134534. [Epub ahead of print]Opioid treatment for acute and chronic pain in patients with sickle cell disease.Carroll P1.Sickle cell disease is a uniquely complex painful disease, with lifelong episodes of unpredictable acute pain and superimposed chronic pain in adulthood. Both painful crises and chronic pain in sickle cell disease lack strong objective pathological correlates and their mechanisms are poorly understood. Opioids have emerged as the standard of care for severe acute pain in sickle cell disease and many patients with chronic pain are maintained on chronic opioid therapy. The strong association between recurrent acute pain and chronic pain in SCD blurs the distinction between acute and chronic opioid management paradigms. In addition, opioid management for SCD is dogged by stigma and concerns regarding addiction. This review aims to synthesize the broad literature on opioids to highlight the clinical complexity of opioid management in sickle cell disease and suggest directions for future research and clinical innovation.Copyright © 2019. Published by Elsevier B.V.
PMID: 31593753 
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18. Cochrane Database Syst Rev. 2019 Oct 7;10:CD007175. doi: 10.1002/14651858.CD007175.pub5. [Epub ahead of print]Antibiotics for treating osteomyelitis in people with sickle cell disease.Martí-Carvajal AJ1Agreda-Pérez LH.AbstractBACKGROUND: Osteomyelitis (both acute and chronic) is one of the most common infectious complications in people with sickle cell disease. There is no standardized approach to antibiotic therapy and treatment is likely to vary from country to country. Thus, there is a need to identify the efficacy and safety of different antibiotic treatment approaches for people with sickle cell disease suffering from osteomyelitis. This is an update of a previously published Cochrane Review.OBJECTIVES: To determine whether an empirical antibiotic treatment approach (monotherapy or combination therapy) is effective and safe as compared to pathogen-directed antibiotic treatment and whether this effectiveness and safety is dependent on different treatment regimens, age or setting.SEARCH METHODS: We searched The Group’s Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched the LILACS database (1982 to 20 October 2016), African Index Medicus (20 October 2016), ISI Web of Knowledge (20 October 2016) and clinical trials registries (19 September 2019).Date of most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group’s Haemoglobinopathies Trials Register: 18 September 2019.SELECTION CRITERIA: We searched for published or unpublished randomised and quasi-randomised controlled trials.DATA COLLECTION AND ANALYSIS: Each author intended to independently extract data and assess trial quality by standard Cochrane methodologies, but no eligible randomised controlled trials were identified.MAIN RESULTS: This update was unable to find any randomised or quasi-randomised controlled trials on antibiotic treatment approaches for osteomyelitis in people with sickle cell disease.AUTHORS’ CONCLUSIONS: We were unable to identify any relevant trials on the efficacy and safety of the antibiotic treatment approaches for people with sickle cell disease suffering from osteomyelitis. Randomised controlled trials are needed to establish the optimum antibiotic treatment for this condition, however, we do not envisage further trials of this intervention will be conducted, and hence the review will no longer be regularly updated.PMCID: PMC6778815 [Available on 2020-10-07]
PMID: 31588556 
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19. West J Nurs Res. 2019 Oct 4:193945919878821. doi: 10.1177/0193945919878821. [Epub ahead of print]Randomized Pilot Study: A Mobile Technology-based Self-management Intervention for Sickle Cell Pain.Ezenwa MO1Yao Y1Nguyen MT2Mandernach MW2Hunter CT2Yoon SL1Fedele D3Lucero RJ4Lyon D1Wilkie DJ1.AbstractLittle is known about the effects of self-managed relaxation interventions on pain, stress, and autonomic responses in patients with sickle cell disease (SCD). This pre-post randomized controlled pilot study was conducted to determine the feasibility of using computer tablets for relaxation intervention delivery; acceptability of study procedures; and intervention effects on pain, stress, and indicators of relaxation. The 30 research participants ranged in age from 22 years to 59 years. All were African American; 53% were male. They were randomized to an experimental group that watched a relaxation video or a control group that discussed their disease. All participants completed the study, indicating feasibility. Acceptability rates were also high. Data were obtained for the intervention’s immediate effect on pain, stress, respiration, pulse, finger skin temperature, and self-reported relaxation. These preliminary findings will guide future, higher-powered studies to determine the intervention’s efficacy and mechanism in SCD. The ClinicalTrials.gov Identifier: NCT02729363.
PMID: 31583977 
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20. J Clin Med. 2019 Oct 2;8(10). pii: E1594. doi: 10.3390/jcm8101594.Evaluation of Outcomes and Quality of Care in Children with Sickle Cell Disease Diagnosed by Newborn Screening: A Real-World Nation-Wide Study in France.Brousse V1Arnaud C2Lesprit E3Quinet B3Odièvre MH4Etienne-Julan M5Guillaumat C6Elana G7Belloy M8Garnier N9Chamouine A10Dumesnil C11Montalembert M12Pondarre C2,9Bernaudin F2Couque N13Boutin E14Bardakjian J15Djennaoui F16Ithier G17Benkerrou M17Thuret I18.

AbstractThis study’s objective was to assess, on a national scale, residual risks of death, major disease-related events, and quality of care during the first five years in children diagnosed at birth with sickle cell disease (SCD). Data were retrospectively collected from medical files of all children with SCD born between 2006-2010 in France. Out of 1792 eligible subjects, 1620 patients (71.8% SS or S/beta°-thalassemia -SB°-) had available follow-up data, across 69 centers. Overall probability of survival by five years was 98.9%, with 12/18 deaths related to SCD. Probability of overt stroke by five years in SS/SB° patients was 1.1%, while transcranial Doppler (TCD) was performed in 81% before three years of age. A total of 26 patients had meningitis/septicemia (pneumococcal in eight cases). Prophylactic penicillin was started at a median age of 2.2 months and 87% of children had received appropriate conjugate pneumococcal vaccination at one year. By five years, the probability of survival without SCD-related events was 10.7% for SS/SB° patients. In contrast, hydroxyurea was prescribed in 13.7% and bone marrow transplant performed in nine patients only. In this study, residual risks of severe complications were low, probably resulting from a good national TCD, vaccination, and healthcare system coverage. Nonetheless, burden of disease remained high, stressing the need for disease-modifying or curative therapy.Free Article 
PMID: 31581727 
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21. J Clin Med. 2019 Oct 1;8(10). pii: E1565. doi: 10.3390/jcm8101565.Allogeneic Hematopoietic Stem Cell Transplantation for Adults with Sickle Cell Disease.Saraf SL1Rondelli D2.AbstractSickle cell disease (SCD) is an inherited red blood cell disorder that leads to substantial morbidity and early mortality. Acute and chronic SCD-related complications increase with older age, and therapies are urgently needed to treat adults. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but has been used less frequently in adults compared to children. This is, in part, due to (1) greater chronic organ damage, limiting tolerability to myeloablative conditioning regimens, (2) a higher rate of HSCT-related complications in adults versus children with SCD, and (3) limited coverage by public and private health insurance. Newer approaches using nonmyeloablative and reduced-intensity conditioning HSCT regimens have demonstrated better safety and tolerability, with high rates of stable engraftment in SCD adults. This review will focus on the impacts of HSCT, using more contemporary approaches to SCD-related complications in adults.Free Article 
PMID: 31581479 
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Sickle Cell Conferences and Events

 5th Annual Sickle Cell Symposium:

Sickle Cell Disease: The Next Generation of Patients and Providers

Saturday November 9th, 2019

at the Charlotte Speedway Club in Concord, NC The link for the Symposium Registration: http://www.cvent.com/d/kyqpb5

The Keynote address will be given by Wayne Frederick, MD, MBA, the 17th President of Howard University. Join us for a day of education focused on the new understanding of sickle cell disease pathophysiology and novel therapeutic approaches to management, culminating with a live Q & A with experts in the field. We ‘re excited and look forward to you attending the event. Info Lawrence.Black@atriumhealth.org

Symposium Registrationhttp://www.cvent.com/d/kyqpb5

The Hemoglobinopathy Counselor Training Course will be held in Cincinnati on April 15-16, 2020.  The two-day course, presented by the Cincinnati Comprehensive Sickle Cell Center, will be held at Cincinnati Children’s Hospital Medical Center.  The course registration fee is $250.  The deadline to register is April 1, 2020 and registration space is limited.  For more information, please email: SCDEvents@cchmc.org.  Registration is available online at www.cincinnatichildrens.org/HemoglobinopathyCTC.