Landmark Article in New England Journal of Medicine
Health experts have long believed that sickle cell gene variants, which occur in about 1 in 13 African-Americans, increase the risk of premature death, even when people carry only a single copy of the variant. But health records of nearly 50,000 active-duty U.S. Army soldiers between 2011 and 2014 shows that’s not the case, according to a study led by researchers at the Stanford University School of Medicine. https://www.sciencedaily.com/releases/2016/08/160803214252.htm
People who carry two copies of the sickle cell gene variant have sickle cell disease, which brings a drastically shortened life span of only 40 to 60 years, as well as lifelong bouts of intense pain.
In contrast, those carrying just one copy of the gene variant have what’s called sickle cell trait. Earlier studies have suggested that the health consequences of sickle cell trait might be dire, including higher mortality from a potentially fatal condition called exertional rhabdomyolysis. ER, which occurs when molecules from the breakdown of muscles end up in the kidneys, has been known to fell football players, often when they are practicing too hard in the hot sun without drinking enough water. (ER is distinct from heat exhaustion, however.) Likewise, ER is a risk for soldiers on active duty.
Yet, in the first-ever longitudinal cohort study of sickle cell trait — which included African-American soldiers of all ages — researchers have found they suffered no increase in mortality. Lianne Kurina, PhD, an associate professor of medicine at Stanford, and a team of medical researchers found that having sickle cell trait does not increase the risk of death. A paper describing their findings will be published Aug. 3 in The New England Journal of Medicine. Kurina is senior author. D. Alan Nelson, PhD, PA-C, a postdoctoral scholar at Stanford and former Army medical officer, is the lead author.
Case reports suggesting a connection between sickle cell trait and deaths of individual patients have dominated the medical literature, according to the new study. A paper published in 1987 reported a 2,800 percent increase in the risk of exertion-induced sudden deaths among African-American military recruits thought to have sickle cell trait. But the actual sickle cell status of every individual was not known.
Despite relatively weak evidence, Kurina said, it’s been assumed that sickle cell trait increases the risk of death, of exertional rhabdomyolysis and of heat stroke. This assumption has led to mandated screening by organizations such as the Air Force, the Navy and the NCAA. But the American Society for Hematology and other organizations have argued that screening programs raise questions about job discrimination. The Army typically screens only before combat deployment and high-altitude activities, the study said.
For the study, the researchers reviewed the health records of 47,944 African-American soldiers who served on active duty between 2011 and 2014 and for whom sickle cell status was known. The researchers got the health records from the Stanford Military Data Repository data set, which Nelson and Kurina created. The repository includes all digitally recorded health encounters at military medical facilities or civilian institutions, general health information and official records of physical performance and mortality of all active-duty U.S. Army soldiers. The data in the repository are de-identified to protect privacy.
Kurina and her colleagues found that the risk of exertional rhabdomyolysis was only 54 percent higher among African-American soldiers with sickle cell trait than among those without it. A 54 percent increase might sound like a lot, but it’s far less than the 300 percent increase caused by some ordinary prescription drugs. And smoking, obesity and increasing age each incur a heightened risk of ER that is about the same as sickle cell trait, the study showed.
Why the difference?
A major reason for the difference between the current study and previous ones, Kurina said, may be better safety for active-duty soldiers. As of 2003, soldiers who are engaged in strenuous exercise are required to drink plenty of fluids, build up to strenuous exercise gradually and take regular rests when it’s hot. All of these measures are known to reduce exercise-related fatality rates, regardless of whether individuals have sickle cell trait, the study said.
“Another critical difference between our study and the earlier, population-based studies is that in our study, we knew the sickle cell status of everyone in the population,” said Kurina. She and her team looked only at soldiers whose sickle cell status was confirmed by blood tests taken during their years of service, instead of from self-reported sickle cell status or past medical history, as had been done in the other studies.
“The most important thing to come out of this study is the really reassuring news that under conditions of universal precautions against dehydration and overheating, we don’t see an elevation in the risk of mortality in people with sickle cell trait,” said Kurina. It happens, she noted, that the lead author of the 1987 paper went on to propose and validate the measures adopted by the Army to mitigate dehydration and overheating.
The study’s results call into question the need to screen service members with sickle cell trait, especially with better safety precautions during intense exertion, Kurina said.
Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers
Alan Nelson, Ph.D., Patricia A. Deuster, Ph.D., Robert Carter, III, Ph.D., Owen T. Hill, Ph.D., Vickee L. Wolcott, Ph.D., and Lianne M. Kurina, Ph.D.
N Engl J Med 2016; 375:435-442August 4, 2016DOI: 10.1056/NEJMoa1516257
Studies have suggested that sickle cell trait elevates the risks of exertional rhabdomyolysis and death. We conducted a study of sickle cell trait in relation to these outcomes, controlling for known risk factors for exertional rhabdomyolysis, in a large population of active persons who had undergone laboratory tests for hemoglobin AS (HbAS) and who were subject to exertional-injury precautions.
We used Cox proportional-hazards models to test whether the risks of exertional rhabdomyolysis and death varied according to sickle cell trait status among 47,944 black soldiers who had undergone testing for HbAS and who were on active duty in the U.S. Army between January 2011 and December 2014. We used the Stanford Military Data Repository, which contains comprehensive medical and administrative data on all active-duty soldiers.
There was no significant difference in the risk of death among soldiers with sickle cell trait, as compared with those without the trait (hazard ratio, 0.99; 95% confidence interval [CI], 0.46 to 2.13; P=0.97), but the trait was associated with a significantly higher adjusted risk of exertional rhabdomyolysis (hazard ratio, 1.54; 95% CI, 1.12 to 2.12; P=0.008). This effect was similar in magnitude to that associated with tobacco use, as compared with no use (hazard ratio, 1.54; 95% CI, 1.23 to 1.94; P<0.001), and to that associated with having a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30.0 or more, as compared with a BMI of less than 25.0 (hazard ratio, 1.39; 95% CI, 1.04 to 1.86; P=0.03). The effect was less than that associated with recent use of a statin, as compared with no use (hazard ratio, 2.89; 95% CI, 1.51 to 5.55; P=0.001), or an antipsychotic agent (hazard ratio, 3.02; 95% CI, 1.34 to 6.82; P=0.008).
Sickle cell trait was not associated with a higher risk of death than absence of the trait, but it was associated with a significantly higher risk of exertional rhabdomyolysis. (Funded by the National Heart, Lung, and Blood Institute and the Uniformed Services University of the Health Sciences.)
A pair of Georgia twins took center stage at the Rio Summer Olympics
They were part of a select group chosen to perform in the opening ceremony. J’son and Ja’kerria Walker are two of only eight American children chosen to stand on the worldwide stage when another Olympic torch was lit in Rio de Janeiro in front of 80,000 spectators and millions more watching around the world.
It’s been an emotional journey for J’son Walker. The 12-year-old was diagnosed with a serious form of sickle cell disease in 2005.
Ever since, he’s had to travel from Sylvester, Georgia, to Children’s Healthcare of Atlanta.
But his family always had the Ronald McDonald House.
Biogen Joins Partnership With CDC Foundation to Develop Longitudinal Data Collection System for Sickle Cell Disease
Effort With CDC to Collect, Analyze and Share Much-needed Sickle Cell Information
ATLANTA, GA–(Marketwired – July 20, 2016) – Sickle cell disease, estimated to affect nearly 100,000 Americans, is the most common inherited blood disorder in the United States. The estimated cost of care for people with sickle cell disease is approximately $1.1 billion dollars annually. The CDC Foundation announced a new partnership in 2015 with the U.S. Centers for Disease Control and Prevention’s (CDC) Division of Blood Disorders within the National Center on Birth Defects and Developmental Disabilities and other partners to support the development and operation of a longitudinal data collection system for Americans with sickle cell disease. Biogen is joining this partnership to help address this health problem. Data from the system will provide states, healthcare provider networks and pharmaceutical and insurance companies with the information needed to establish cost-effective practices to help improve and potentially extend the lives of people with sickle cell disease.
“Understanding the clinical history of individuals living with sickle cell disease continues to be of great importance,” said Coleen Boyle, Ph.D., M.S.Hyg., director of CDC’s National Center on Birth Defects and Developmental Disabilities. “The recent partnership fostered between Biogen and the CDC Foundation will further enable critical support for the collection and study of information leading to advances in sickle cell disease treatment.”
Other organizations participating in the partnership include the California Rare Disease Surveillance Program and Pfizer Inc. Although this initial stage of the project will be developed in California, the system will have the capacity to include information on every individual diagnosed with sickle cell disease in the United States.
Data will come from a combination of sources including newborn screening, administrative data sets (for example, hospital discharge, emergency department, and state Medicaid data), medical charts, and may include personal interviews. The information gathered through this system will allow for a better understanding of medical and educational interventions for sickle cell disease, as well as improved patient outcomes over time. The goals of the program are to ensure better care for individuals with sickle cell disease and better data for healthcare providers.
“We are grateful to Biogen for joining this important partnership,” said Dr. Judith Monroe, president and CEO of the CDC Foundation. “This longitudinal data collection system will be the first system of its kind for sickle cell disease in the United States.”
To learn more about how to support this effort, please contact Laura Angel at the CDC Foundation (firstname.lastname@example.org).
The Haemo-Globe Inn – A Sickle Cell Exhibition at Tanzanian’s largest national exhibition
Sabasaba Fair is the most popular national exhibition in Tanzania. Annually it attracts over 1,000,000 people that visit the 30+ manufacturer’s booth, government departments, and research and higher education institutions.
To tie in with this year’s theme of ‘linking production to the market’, the Sickle Cell Exhibition aimed at engaging with the public more closely by finding practical and hands on activities that would demonstrate Sickle Cells and Haematology as a whole. The exhibition was as well for the Department of Haematology and Blood Transfusion at MUHAS.
As a result, the exhibition featured 3 hands- on activities for the public to be engaged in. These were:-
* Cell morphology: to demonstrate the structures of the difference cells in the body, the public got to see blood slide preparations and then witness first hand on the microscope the different cells including a sickled cell. The aim of this activity was to make the disease ‘real’. That it was not just abstract cells that were being talked about but rather in real sense as part of one’s body.
* Haemocue: the attending public got to have their haemoglobin levels checked. This was especially important for the Sickle Cell individuals that attended the exhibition. It also raised awareness on the importance of blood donation, which is crucial in the management of Sickle Cell Disease.
* Blood Group Testing: in the last 4 days of the exhibition, 76 members of the public had known their blood group. Testing for one’s blood group is not a common practice in Tanzania; in fact it can lead to delays when one needs blood transfusion. On top of trying to help with this problem and linking it again to blood transfusion, blood group testing was essential in highlighting the fact that blood group is an inherited factor just as Sickle Cell Disease is purely an inherited blood disorder.
Together with the hands-on activities, a nurse was handy to give public education and engage on Sickle Cell Disease. This opened a dialogue with the public with regards to Sickle Cell Disease. They got to ask questions about the disease, while we got audience to clear up common myths on SCD.
All in all, the exhibition was a huge success with the people that visited. It was also evident from the exhibition of the need to have a rapid Sickle Cell test as over half of the people that visited the booth asked to know about their sickle cell status.
Sickle Cell Partners of the Carolinas has launched its new website! Please take a look at [sicklecellpartnersofhecarolinas.org]sicklecellpartnersofthecarolinas.org
Take a look around and tell us what you think. We are also beginning a daily blog so look for that and while you’re on the site, register for “Sickle Cell Disease… Let’s Talk About It.” The day conference will be held during Sickle Cell Awareness month. Join us Saturday, September 10, 2016 from 8am to 1pm at Friendship Missionary Baptist Church.
Articles in the medical literature
Anal Chem. 2016 Jul 21. A Quantitative, Point-of-Care Immunoassay Platform to Guide and Monitor Sickle Cell Disease Therapy. Yang X, Reavis HD, Roberts CL, Kim JS.
Sickle cell patients often require monthly healthy blood transfusions to treat the many complications of the disease. In this therapy, the clinician lowers the amount of hemoglobin S (HbS) containing red blood cells (RBCs) with healthy normal (hemoglobin A, HbA) blood units. We have developed a point-of-care (POC) quantitative immunoassay for HbS to serve as a diagnostic aid for clinicians providing this life-saving treatment. The test consists of a small-footprint reader and cartridges that quantify the percentage of HbS in a small volume of patient blood. The test reports %HbS values in the range from 0 to 90% that highly correlate (slope 1.03, R2 = 0.97) with currently used central laboratory HPLC systems. The test also shows a 1% limit of blank, 2% limit of detection, and 5% limit of quantitation. The test was also shown to encounter minimal effects from potential interferents. This cost-effective, POC HbS quantitative approach will allow for real-time transfusion monitoring in sickle cell treatment settings, and therefore improve workflow and allow clinicians to quickly make informed therapeutic decisions.
PMID: 27442043 [PubMed – as supplied by publisher]
Child Neuropsychol. 2016 Jul 21:1-18. Executive functioning and health-related quality of life in pediatric sickle cell disease. Allen TM1, Anderson LM1, Rothman JA2, Bonner MJ1,3.
Research consistently indicates that children with sickle cell disease (SCD) face multiple risk factors for neurocognitive impairment. Despite this, no empirical research to date has examined the impact of neurocognitive functioning on quality of life for this pediatric group. Thus, the current study aims to examine the relationship between executive functioning and quality of life in a sample of children with SCD and further explore psychosocial and family/caregiver resources as moderators of this relationship. A total of 45 children with SCD aged 8 to 16 years and their caregivers completed measures of quality of life, behavioral ratings of executive functioning, and psychosocial functioning. Hierarchical linear regression models were utilized to determine the impact of executive functioning on quality of life and further test the interaction effects of proposed moderating variables. Controlling for age, pain, and socioeconomic status (SES), executive functioning was found to significantly predict child- and parent-reported quality of life among youth with SCD. Psychosocial resources of the primary caregiver or family was not found to moderate the relationship between executive functioning and quality of life. These results provide the first empirical evidence that lower executive skills negatively predict quality of life for children with SCD, supporting clinical and research efforts which aim to establish efficacious interventions that target cognitive decrements within this pediatric population.
PMID: 27439898 [PubMed – as supplied by publisher]
J Thromb Haemost. 2016 Jul 19. doi: 10.1111/jth.13416. Thrombin generation and cell-dependent hypercoagulability in sickle cell disease. Whelihan MF1, Lim MY1, Mooberry MJ1, Piegore MG1, Ilich A1, Wogu A2, Cai J2, Monroe DM1,Ataga KI1, Mann KG3, Key NS1,4.
Sickle cell disease (SCD) is a hypercoagulable state with chronic activation of coagulation and an increased incidence of thromboembolic events. However, while plasma pre-thrombotic markers such as TAT and D-dimer are elevated, there is no consensus on whether global assays of thrombin generation in plasma are abnormal in patients with SCD. Based on our recent observation that normal red blood cells (RBCs) contribute to thrombin generation in whole blood, we hypothesized that the cellular components in blood (notably phosphatidylserine-expressing erythrocytes) contribute to enhanced thrombin generation in SCD.
Whole blood and plasma thrombin generation assays were performed on blood samples from 25 SCD patients in a non-crisis, “steady state” and 25 healthy race-matched controls.
Whole blood thrombin generation was significantly elevated in SCD while plasma thrombin generation was paradoxically reduced compared to controls. Surprisingly, whole blood and plasma thrombin generation were both negatively correlated with phosphatidylserine exposure on RBCs. Plasma thrombin generation in the presence of exogenous activated protein C or soluble thrombomodulin revealed deficiencies in the protein C/S anticoagulant pathway in SCD. These global changes were associated with significantly lower plasma protein S activity in SCD that correlated inversely with RBC phosphatidylserine exposure.
Increased RBC phosphatidylserine exposure in SCD is associated with acquired protein S deficiency. In addition, these data suggest a cellular contribution to thrombin generation in SCD (other than RBC phosphatidylserine exposure) that explains the elevated thrombin generation in whole blood. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
PMID: 27430959 [PubMed – as supplied by publisher]
J Pediatr Health Care. 2016 Jul 13. pii: S0891-5245(16)30135-3. doi: 10.1016/j.pedhc.2016.06.005. Primary and Secondary Stroke Prevention in Children With Sickle Cell Disease. Mack AK, Thompson AA.
Children with sickle cell disease (SCD) have numerous acute and chronic complications, including central nervous system (CNS) disease, which can be debilitating over their life span. Recognition of risk factors for CNS disease and overt CNS disease should be properly identified by primary care providers, including physicians, physician assistants, and nurse practitioners. Here, we discuss an emerging and important early indicator of CNS disease in the form of silent cerebral infarcts and review overt stroke in patients with SCD. We also discuss transcranial Doppler ultrasonography, when and how often transcranial Doppler ultrasounds should be performed, and management of abnormal results. Lastly, we review the clinical data for the management and prevention of silent cerebral infarcts and overt stroke in children with SCD.
Copyright © 2016 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.
PMID: 27423528 [PubMed – as supplied by publisher]
Cytotherapy. 2016 Jul 13. pii: S1465-3249(16)30438-8. doi: 10.1016/j.jcyt.2016.06.011.Cellular therapy for sickle cell disease. Abraham A1, Jacobsohn DA2, Bollard CM3.
Sickle cell disease (SCD) is a monogenic red cell disorder affecting more than 300 000 annual births worldwide and leading to significant organ toxicity and premature mortality. Although chronic therapies such as hydroxyurea have improved outcomes, more durable therapeutic and curative options are still being investigated. Newer understanding of the disease has implicated invariant natural killer T cells as a critical immune profile that potentiates SCD. Hence, targeting this cell population may offer a new approach to disease management. Hematopoietic stem cell transplant is a curative option for patients with SCD, but the under-representation of minorities on the unrelated donor registry means that this is not a feasible option for more than 75% of patients. Work in this area has therefore focused on increasing the donor pool and decreasing transplant-related toxicities to make this a treatment option for the majority of patients with SCD. This review focuses on the currently available cell and gene therapies for patients with SCD and acknowledges that newer gene-editing approaches to improve gene therapy efficiency and safety are the next wave of potentially curative approaches.
Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
PMID: 27421743 [PubMed – as supplied by publisher]
Mol Ther. 2016 Jul 13. doi: 10.1038/mt.2016.148. CRISPR/Cas9-mediated correction of the sickle mutation in human CD34+ cells. Hoban MD1, Lumaquin D1, Kuo CY2, Romero Z1, Long J1,3, Ho M1, Young CS4,5, Mojadidi M1,Fitz-Gibbon S6,7, Cooper AR5, Lill GR1, Urbinati F1, Campo-Fernandez B1, Bjurstrom CF1,Pellegrini M6,7, Hollis RP1, Kohn DB1,8.
Targeted genome editing technology can correct the sickle cell disease (SCD) mutation of the ß-globin gene in hematopoietic stem cells. This correction supports production of red blood cells that synthesize normal hemoglobin proteins. Here, we demonstrate that Transcription Activator-Like Effector Nucleases (TALENs) and the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 nuclease system can target DNA sequences around the sickle-cell mutation in the ß-globin gene for site-specific cleavage and facilitate precise correction when a homologous donor template is co-delivered. Several pairs of TALENs and multiple CRISPR guide RNAs were evaluated for both on-target and off-target cleavage rates. Delivery of the CRISPR/Cas9 components to CD34+ cells led to over 18% gene modification in vitro. Additionally, we demonstrate the correction of the SCD mutation in bone marrow (BM) derived CD34+ hematopoietic stem and progenitor cells (HSPCs) from SCD patients, leading to the production of wild-type hemoglobin. These results demonstrate correction of the sickle mutation in patient-derived CD34+ cells using CRISPR/Cas9 technology.
PMID: 27406980 [PubMed – as supplied by publisher]
Acad Emerg Med. 2016 Jul 12. doi: 10.1111/acem.13048. Which Febrile Children with Sickle Cell Disease Need a Chest X-Ray? Eisenbrown K1, Nimmer M2, Ellison AM3, Simpson P4, Brousseau DC2.
Controversy exists regarding which febrile children with sickle cell disease (SCD) should receive a chest x-ray (CXR). Our goal is to provide data informing the decision of which febrile children with SCD presenting to the emergency department (ED) require a CXR to evaluate for acute chest syndrome (ACS).
Retrospective chart review of children ages 3 months to 21 years with SCD presenting to the ED at one of two academic children’s hospitals with fever ≥ 38.5°C between 1/1/10 and 12/31/12. Demographic characteristics, respiratory symptoms, and laboratory results were abstracted. The primary outcome was the presence of ACS. Binary recursive partitioning was performed to determine predictive factors for a diagnosis of ACS.
185 (10%) of 1837 febrile ED visits met ACS criteria. The current NHLBI consensus criteria for obtaining a CXR (shortness of breath, tachypnea, cough, or rales) identified 158 (85%) of ACS cases, while avoiding 825 CXRs. Obtaining a CXR in children with NHLBI criteria or chest pain and in children without those symptoms but with a white blood count (WBC) ≥ 18.75 K/μL or a history of ACS identified 181 (98%), while avoiding 430 CXRs.
Children with SCD presenting to the ED with fever and shortness of breath, tachypnea, cough, rales, or chest pain should receive a CXR due to high ACS rates. A higher WBC or history of ACS in a child without one of those symptoms may suggest the need for a CXR. Prospective validation of these criteria is needed. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
PMID: 27404765 [PubMed – as supplied by publisher]
J Natl Med Assoc. 2016 May;108(2):113-8. doi: 10.1016/j.jnma.2016.04.004. Epub 2016 Jun 9. Physicians’ Perception of Sickle-cell Disease Pain. Lucchesi F1, Figueiredo MS1, Mastandrea EB1, Levenson JL2, Smith WR2, Jacinto AF3, Citero Vde A4.
The aim of this study was to evaluate the physician’s perception of pain experienced by patients with sickle-cell disease (SCD). Pain experiences reported by patients were compared with physicians’ perception of the patient’s pain, and the treatment decision-making process was evaluated. Fifty-two patient-physician pairs were assessed. Before the clinic visit, the patients completed a 3-item on pain experienced 24 h prior to the visit and the PHQ-9. After the patient visit, the physicians completed a questionnaire assessing their perception of the patient’s pain and a questionnaire on the factors taken into consideration when evaluating the patient’s pain experience. The physicians rated the patients’ pain as more intense than did the patients themselves; and there was agreement between pain intensity measurements (p < 0.05). The physicians’ perception was influenced by the pain intensity reported by the patient, results of blood count at the time of the patient visit, and medication availability in the public health services. However, these factors were not predictive of the patient’s pain intensity perceived by the physician. Patients’ depressive symptoms were not predictive factor of the physicians’ perception. Biochemical, genetic and symptomatic characteristics of SCD influenced the physicians’ perception of the patient’s pain experience, while psychosocial aspects did not.
Copyright © 2016 National Medical Association. Published by Elsevier Inc. All rights reserved.
PMID: 27372471 [PubMed – in process]
J Pediatr Psychol. 2016 Jun 30. pii: jsw061. Daily Pain, Physical Activity, and Home Fluid Intake in Pediatric Sickle Cell Disease. Karlson CW1, Baker AM2, Bromberg MH3, David Elkin T4, Majumdar S5, Palermo TM6.
OBJECTIVES : This study examined the temporal relationship between physical activity, fluid intake, and daily pain in children with sickle cell disease (SCD) with frequent pain. METHODS : A total of 30 African American children (M age = 13.9; 53% female; 76.3% type SS) who reported pain more than or equal to once every 2 weeks and their parents completed measures of pain and anxiety/depressive symptoms. Children then completed a daily pain diary and wore a physical activity Actiwatch for 14 days at home. RESULTS : Contrary to physiological theory-based hypotheses, lower physical activity was associated with greater pain during the same day and the next day. Less pain was associated with greater physical activity the next day. There was no relationship between self-reported home fluid intake and daily pain (p’s < .05). CONCLUSIONS : Results lend support for a complex bidirectional relationship between physical activity and daily pain in pediatric SCD, and identify physical activity as a target for future research.
© The Author 2016. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: email@example.com.
PMID: 27370016 [PubMed – as supplied by publisher]
Lancet. 2016 Jun 18;387(10037):2565-74. doi: 10.1016/S0140-6736(16)00647-4. Cardiovascular complications and risk of death in sickle-cell disease. Gladwin MT1.
In sickle-cell disease, a point mutation in the β-globin chain causes haemoglobin to polymerise within erythrocytes during deoxygenation, altering red blood cell rheology and causing haemolysis. Improvements in health infrastructure, preventive care, and clinical treatments have reduced the morbidity and mortality of sickle-cell disease in developed countries. However, as these patients live longer, the chronic effects of sustained haemolytic anaemia and episodic vaso-occlusive events drive the development of end-organ complications. Cardiopulmonary organ dysfunction and chronic kidney injury have a large effect on morbidity and premature mortality, and typically accelerate in the second decade of life. These processes culminate in the development of pulmonary hypertension, left ventricular diastolic heart disease, dysrhythmia, and sudden death. In this Series paper, we review the mechanisms, clinical features, and epidemiology of major cardiovascular complications in patients with sickle-cell disease and discuss how screening and intervention could reduce their incidence.
Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID: 27353687 [PubMed – in process]
Lancet. 2016 Jun 18;387(10037):2554-64. doi: 10.1016/S0140-6736(15)01341-0. Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies. Lettre G1, Bauer DE2.
1Montreal Heart Institute, Montreal, QC, Canada; Université de Montréal, Montreal, QC, Canada. Electronic address: firstname.lastname@example.org.
2Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School and Harvard Stem Cell Institute, Boston, MA, USA. Electronic address: email@example.com.
Sickle-cell disease affects millions of individuals worldwide, but the global incidence is concentrated in Africa. The burden of sickle-cell disease is expected to continue to rise over the coming decades, adding to stress on the health infrastructures of many countries. Although the molecular cause of sickle-cell disease has been known for more than half a century, treatment options remain greatly limited. Allogeneic haemopoietic stem-cell transplantation is the only existing cure but is limited to specialised clinical centres and remains inaccessible for most patients. Induction of fetal haemoglobin production is a promising strategy for the treatment of sickle-cell disease. In this Series paper, we review scientific breakthroughs in epidemiology, genetics, and molecular biology that have brought reactivation of fetal haemoglobin to the forefront of sickle-cell disease research. Improved knowledge of the regulation of fetal haemoglobin production in human beings and the development of genome editing technology now support the design of innovative therapies for sickle-cell disease that are based on fetal haemoglobin.
Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID: 27353686 [PubMed – in process]
Lancet. 2016 Jun 18;387(10037):2545-53. doi: 10.1016/S0140-6736(16)00145-8. The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia. DeBaun MR1, Strunk RC2.
Acute chest syndrome is a frequent cause of acute lung disease in children with sickle-cell disease. Asthma is common in children with sickle-cell disease and is associated with increased incidence of vaso-occlusive pain events, acute chest syndrome episodes, and earlier death. Risk factors for asthma exacerbation and an acute chest syndrome episode are similar, and both can present with shortness of breath, chest pain, cough, and wheezing. Despite overlapping risk factors and symptoms, an acute exacerbation of asthma or an episode of acute chest syndrome are two distinct entities that need disease-specific management strategies. Although understanding has increased about asthma as a comorbidity in sickle-cell disease and its effects on morbidity, substantial gaps remain in knowledge about best management.
Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID: 27353685 [PubMed – in process]
Pediatr Nurs. 2016 May-Jun;42(3):113-9, 144. Depression, Anxiety, and Quality of Life In Children and Adolescents With Sickle Cell Disease. Graves JK, Hodge C, Jacob E.
The relationships among depression, anxiety, and quality of life were tested, as were the effects of age, gender, and pain frequency on these variables in children (n = 44) and adolescents (n = 31) with sickle cell disease. Participants completed the Revised Child Anxiety and Depression Scale (ROADS) and the Pediatric Quality of Life (PedQL Generic Model). The mean and standard deviation for summary RCADS scores for the majority of participants were below the clinical thresholds of T < 65, indicating low risk for depression (n = 65; 89.3%) and anxiety (n = 70; 93.3%). The subscale scores for the different dimensions of QOL health were a) psychosocial (73.3 ± 15.9), b) emotional (75.0 ± 20.7), c) social (80.8 ± 19.1), d) school functioning (64.0 ≥ 19.8), and e) physical (77.4 ± 17.4). Significant negative correlations were found between mean total quality of life scores and symptoms of a) general anxiety (r = -0.51, p < 0.0001), b) depression (r = -0.66, p < 0.0001), c) obsessive compulsive (r = -0.53, p < 0.0001), d) panic (r = -0.60, p < 0.0001), and e) social phobia (r = -0.57, p < 0.0001). Age and gender did not have significant effects on risk for depression and anxiety or poor QOL. Pain frequency also did not have significant effects on the risk for depression and anxiety. Findings suggest that health care providers need to screen for anxiety and depression, and make referrals for early interventions to improve quality of life and promote school function in youth with sickle cell disease.
PMID: 27468512 [PubMed – in process]
Am J Hematol. 2016 Jul 28. doi: 10.1002/ajh.24498. Patterns of Opioid Use in Sickle Cell Disease. Han J1,2, Saraf SL2, Zhang X2, Gowhari M2, Molokie RE2,3, Hassan J2, Alhandalous C2, Jain S2,Younge J1, Abbasi T3, Machado RF4, Gordeuk VR2.
Pain, the hallmark complication of sickle cell disease (SCD), is largely managed with opioid analgesics in the United States, but comprehensive data regarding the long-term use of opioids in this patient population is lacking. The pain medication prescription records from a cohort of 203 SCD patients were analyzed. Twenty-five percent were not prescribed opioid medications while 47% took only short-acting opioids, 1% took only long-acting opioids, and 27% took a combination of short-acting and long-acting opioids. The median (interquartile range) daily opioid dose was 6.1 mg (1.7-26.3 mg) of oral morphine equivalents, which is lower than the published opioid use among patients with other pain syndromes. The dose of opioids correlated with the number of admissions due to vaso-occlusive crisis (VOC) (r=0.53, p<0.001). When the patients were grouped into quartiles based on daily dose opioid use, a logistic regression model showed that history of avascular necrosis (AVN) (OR 2.87, 95% CI: 1.37-6.02, p=0.005), 25-OHD levels (OR 0.59, 95% CI: 0.38-0.93, p=0.024) and total bilirubin concentration (OR 0.64, 95% CI: 0.42-0.99, p=0.043) were independently associated with opioid use quartiles. In conclusion, doses and types of opioid medications used by adult SCD patients vary widely. Our findings implicate AVN and lower vitamin D levels as factors associated with higher opioid use. They also suggest an association of higher bilirubin levels, possibly suggesting higher hemolytic rate, with lower opioid use. This article is protected by copyright. All rights reserved.
© 2016 Wiley Periodicals, Inc.
PMID: 27466799 [PubMed – as supplied by publisher]
Community Pract. 2016 Jun;89(6):44-7. Supported or stigmatised? The impact of sickle cell disease on families. Keane B, Defoe L.
Caring for a child with a chronic medical condition can be stressful for parents and likely to have an impact on family dynamics. In a low-prevalence region, services to support parents of children with sickle cell disease (SCD) are limited and consequently parents can feel isolated. We explored this issue in a service evaluation, using semi-structured questionnaires to interview twelve families who had a child with SCD. Our analysis outlines the impact that this condition has on family life and the importance that cultural values and perspectives have in learning to deal with the issues involved. We conclude that families would benefit from greater multidisciplinary support on a regular basis.
PMID: 27443031 [PubMed – in process]
BMC Health Serv Res. 2016 Jul 26;16(1):304. doi: 10.1186/s12913-016-1572-6. Newborn screening and prophylactic interventions for sickle cell disease in 47 countries in sub-Saharan Africa: a cost-effectiveness analysis. Kuznik A1,2,3, Habib AG3, Munube D4, Lamorde M5.
Sickle cell disease (SCD) constitutes a major public health problem in sub-Saharan Africa (SSA). Newborn screening and early subsequent clinical intervention can reduce early mortality and increase life expectancy, but have not been widely implemented in SSA. This analysis assesses the cost-effectiveness of a newborn screening and prophylactic intervention (NSPI) package for SCD in 47 SSA countries.
A lifetime Markov model with annual cycles was built with infants either being screened using isoelectric focusing (IEF) or not screened. Confirmed positive cases received interventions including insecticide-treated mosquito bed nets, folic acid supplementation, prophylactic antimalarial and penicillin therapy, and vaccinations against bacterial infections. Estimates for the local incidence of SCD, the life expectancy of untreated children, the SCD disability weight, and the cost of screening laboratory tests were based on published sources. Among treated infants, the annual probability of mortality until 30 years of age was derived from a pediatric hospital-based cohort. The outcome of interest included a country-specific cost per Disability Adjusted Life Year (DALY) averted.
Of 47 modeled countries in SSA, NSPI is almost certainly highly cost-effective in 24 countries (average cost per DALY averted: US$184); in 10 countries, it is cost-effective in the base case (average cost per DALY averted: US$285), but the results are subject to uncertainty; in the remaining 13, it is most likely not cost-effective. We observe a strong inverse relationship between the incidence rate of SCD and the cost per DALY averted. Newborn screening is estimated to be cost-effective as long as the incidence rate exceeds 0.2-0.3 %, although in some countries NSPI is cost-effective at incidence rates below this range. In total, NSPI could avert over 2.4 million disability adjusted life years (DALYs) annually across SSA.
Using IEF to screen all newborns for SCD plus administration of prophylactic interventions to affected children is cost-effective in the majority of countries in SSA.
PMCID: PMC4962462 Free PMC Article
PMID: 27461265 [PubMed – in process]
Sci Rep. 2016 Jul 27;6:30422. doi: 10.1038/srep30422. Novel HDAd/EBV Reprogramming Vector and Highly Efficient Ad/CRISPR-Cas Sickle Cell Disease Gene Correction. Li C1,2, Ding L1,2, Sun CW1,2, Wu LC1,2, Zhou D1,2, Pawlik KM1,2, Khodadadi-Jamayran A2, Westin E1,2, Goldman FD2,3, Townes TM1,2.
CRISPR/Cas enhanced correction of the sickle cell disease (SCD) genetic defect in patient-specific induced Pluripotent Stem Cells (iPSCs) provides a potential gene therapy for this debilitating disease. An advantage of this approach is that corrected iPSCs that are free of off-target modifications can be identified before differentiating the cells into hematopoietic progenitors for transplantation. In order for this approach to be practical, iPSC generation must be rapid and efficient. Therefore, we developed a novel helper-dependent adenovirus/Epstein-Barr virus (HDAd/EBV) hybrid reprogramming vector, rCLAE-R6, that delivers six reprogramming factors episomally. HDAd/EBV transduction of keratinocytes from SCD patients resulted in footprint-free iPSCs with high efficiency. Subsequently, the sickle mutation was corrected by delivering CRISPR/Cas9 with adenovirus followed by nucleoporation with a 70 nt single-stranded oligodeoxynucleotide (ssODN) correction template. Correction efficiencies of up to 67.9% (β(A)/[β(S)+β(A)]) were obtained. Whole-genome sequencing (WGS) of corrected iPSC lines demonstrated no CRISPR/Cas modifications in 1467 potential off-target sites and no modifications in tumor suppressor genes or other genes associated with pathologies. These results demonstrate that adenoviral delivery of reprogramming factors and CRISPR/Cas provides a rapid and efficient method of deriving gene-corrected, patient-specific iPSCs for therapeutic applications.
PMID: 27460639 [PubMed – in process]
Pain Res Manag. 2016;2016:3218186. doi: 10.1155/2016/3218186. Epub 2016 Mar 29. Patient Controlled Analgesia for Adults with Sickle Cell Disease Awaiting Admission from the Emergency Department. Santos J1, Jones S1, Wakefield D2, Grady J3, Andemariam B1.
Background. A treatment algorithm for sickle cell disease (SCD) pain in adults presenting to a single emergency department (ED) was developed prioritizing initiation of patient controlled analgesia (PCA) for patients awaiting hospitalization. Objectives. Evaluate the proportion of ED visits in which PCA was started in the ED. Methods. A two-year retrospective chart review of consecutive SCD pain ED visits was undertaken. Data abstracted included PCA initiation, low versus high utilizer status, pain scores, bolus opioid number, treatment times, and length of hospitalization. Results. 258 visits resulted in hospitalization. PCA was initiated in 230 (89%) visits of which 157 (68%) were initiated in the ED. Time to PCA initiation was longer when PCA was begun after hospitalization versus in the ED (8.6 versus 4.5 hours, p < 0.001). ED PCA initiation was associated with fewer opioid boluses following decision to admit and less time without analgesic treatment (all p < 0.05). Mean pain intensity (MPI) reduction did not differ between groups. Among visits where PCA was begun in the ED, low utilizers demonstrated greater MPI reduction than high utilizers (2.8 versus 2.0, p = 0.04). Conclusions. ED PCA initiation for SCD-related pain is possible and associated with more timely analgesic delivery.
PMCID: PMC4904609 Free PMC Article
PMID: 27445606 [PubMed – in process]
Duncan NA, Kronenberger WG, Hampton KC, Bloom EM, Rampersad AG, Roberson CP, Shapiro AD. A validated measure of adherence to antibiotic prophylaxis in children with sickle cell disease. Patient Preference and Adherence 2016;10:983-992.
Sickle Cell Conferences and Events
Sickle Cell Education Day 2016 – Children’s Healthcare of Atlanta, GA
“Learning to Live, Love, and Hope with Sickle Cell Disease”
Date: Saturday, September 24, 2016
Time: 9:00 a.m. to 3:00 p.m.
Parking: Courtyard by Marriott, Downtown Decatur
130 Clairemont Avenue
Decatur, GA 30030
Onsite parking is available for $8.
Complimentary parking will be available at the below address:
First Baptist Church of Decatur
308 Clairemont Ave.
Decatur, GA 30030
Registration for this program opens June 22, 2016. Please contact litisha [dot] m [dot] cooper [at] emory [dot] edu for additional information.
Sickle Cell Partners of the Carolinas presents, Sickle Cell Disease, “Let’s talk about it” day conference
www.sicklecellpartnersofthecarolinas.org Saturday September 10, 2016 9 am to 2 pm Friendship Missionary Baptist Church Conference Center 3400 Beatties Ford Road, Charlotte NC 28216 http://www.eventbrite.com/e/sickle-cell-diseaselets-talk-about-it-tickets-24651955663
The Indiana Hemophilia & Thrombosis Center is please to sponsor the annual Sickle Cell-abration Soiree: Celebrating Our Champions
To be held at the NCAA Hall of Champions located at 700 W Washington Street Indianapolis, IN on September 17, 2016 from 3:30-9:00 pm.
This year we will be recognizing the sickle cell champions around the state. The event will include education, dinner and entertainment for sickle cell patients and their families.
This year we are delighted to have Sonja Banks from the SCDAA as the guest speaker.
For more Information please contact Kisha Hampton at 317-871-0011 ext. 366.
2nd Annual Sickle Cell Disease Symposium: OPIOIDS: THE BIG ELEPHANT IN THE ROOM
Sickle Cell Disease (SCD) is an inherited blood disorder that affects 80,000 people in the US. Sickle red blood cells cause anemia, acute pain, debilitating chronic pain and may lead to a shortened lifespan. This educational program will focus on the
multidisciplinary approach to understanding and management of acute and chronic pain in adults living with SCD particularly in light of the current opioid overdose epidemic in the US.
WHEN: Saturday, September 24, 2016
7:00 am – 4:30 pm
The Harris Conference Center
3216 CPCC Harris Campus Dr.,
Charlotte, NC 28208
For more information or to register, please go to www.charlotteahec.org or contact
Tamara Smith-Tillman at 704-512-6534 or tamara.tillman@CarolinasHealthCare.org
WHEN: Saturday, September 24, 2016
7:00 am – 4:30 pm
The Harris Conference Center
3216 CPCC Harris Campus Dr.,
Charlotte, NC 28208
Call for Abstracts: Deadline July 31st, 2016
Charlotte AHEC has been authorized by the American Academy of Physician Assistants (AAPA) to designate AAPA Category 1 credits for activities designed primarily for its own learners and other learners who provide care to veterans.
44th SCDAA annual convention Baltimore, MD on September 27-October 1st, 2016
44th Annual Sickle Cell Convention. This year’s convention will be held in the great city of Baltimore, MD on September 27-October 1st, 2016 at the Hyatt Regency hotel.
SCDAA 44th Annual Convention Sept 27 – Oct 1 Baltimore MD
Listserv address to join or leave: http://listserv.cc.emory.edu/cgi-bin/wa?A0=sicklecell