Sickle Cell Disease

2015 ◽  
Author(s):  
Caroline Freiermuth ◽  
Idan Cudykier
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Cells ◽  
Genetic Basis ◽  
Globin Gene ◽  
The United States ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
The Past ◽  
Pain Medications

Sickle cell disease affects between 70,000 and 90,000 individuals in the United States, the majority of whom are of African-American descent. The genetic basis of the disease is an abnormality in the β-globin gene, which causes the red blood cells to change to a “sickle” shape due to low oxygenation. The life span of patients with this disease has improved over the past few decades, although morbidity remains high. This review covers the pathophysiology of sickle cell disease and the stabilization and assessment, diagnosis and treatment, maintenance and preventive therapies, and cure of patients with sickle cell disease. Figures show hemoglobin electrophoresis; age at death for individuals with sickle cell disease in the years 1979, 1989, 1999, and 2006; sickled cells blocking blood flow; acute chest syndrome; dactylitis; and avascular necrosis. Tables list important trials, topics in need of further research, common complications, most common intravenous pain medications, and indications for transfusion. This review contains 6 highly rendered figures, 5 tables, 97 references, and a list of educational resources.

Newborn Screening for Sickle Cell Disease and Other Hemoglobinopathies

PEDIATRICS ◽  
1989 ◽  
Vol 83 (5) ◽  
pp. 813-814
Author(s):  
DORIS WETHERS ◽  
HOWARD PEARSON ◽  
MARILYN GASTON
Keyword(s):  
Sickle Cell Disease ◽  
Early Diagnosis ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Case Fatality ◽  
The United States ◽  
Early Mortality ◽  
Cell Disease ◽  
Newborn Period ◽  
The Past

Hemoglobinopathies represent one of the major health problems in the United States and constitute the most common genetic disorders in some populations. Sickle cell disease (SS, SC, S-β-thalassemia) alone affects about one in 400 American black newborns, as well as persons of African, Mediterranean, Asian, Caribbean, Middle Eastern, and South and Central American origins. For the past 20 years, the medical profession has known that children with sickle cell anemia have an increased susceptibility to severe bacterial infection, particularly due to Streptococcus pneumoniae. The risk of major infection and death posed by this organism is greatest in the first 3 years of life and can occur as early as 3 months of age. In fact, this infection may be the first clinical manifestation of disease. The infection can be fulminant, progressing from the onset of fever to death in a matter of hours, and the case fatality rate is reported as high as 30%. In addition, acute splenic sequestration, another acute catastrophic event, contributes to early mortality in children with sickle cell anemia and may occur as early as 5 months of age. It has been proposed that early diagnosis to identify infants with major sickle hemoglobinopathies, who have a high risk of early mortality and morbidity, is essential to institute appropriate ongoing care and effective measures of prophylaxis and intervention. Early diagnosis of hemoglobinopathies should be in the newborn period. Even though the technology to screen infants in the newborn period has been available for the past 15 to 20 years, screening has not received widespread acceptance.

scholarly journals Potential role of LSD1 inhibitors in the treatment of sickle cell disease: a review of preclinical animal model data

2018 ◽  
Vol 315 (4) ◽  
pp. R840-R847 ◽  
Author(s):  
Angela Rivers ◽  
Ramasamy Jagadeeswaran ◽  
Donald Lavelle
Keyword(s):  
Reactive Oxygen Species ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Reactive Oxygen ◽  
Organ Damage ◽  
The United States ◽  
Oxygen Species ◽  
Cell Disease ◽  
Hematopoietic Stem

Sickle cell disease (SCD) is caused by a mutation of the β-globin gene (Ingram VM. Nature 180: 326–328, 1957), which triggers the polymerization of deoxygenated sickle hemoglobin (HbS). Approximately 100,000 SCD patients in the United States and millions worldwide (Piel FB, et al. PLoS Med 10: e1001484, 2013) suffer from chronic hemolytic anemia, painful crises, multisystem organ damage, and reduced life expectancy (Rees DC, et al. Lancet 376: 2018–2031, 2010; Serjeant GR. Cold Spring Harb Perspect Med 3: a011783, 2013). Hematopoietic stem cell transplantation can be curative, but the majority of patients do not have a suitable donor (Talano JA, Cairo MS. Eur J Haematol 94: 391–399, 2015). Advanced gene-editing technologies also offer the possibility of a cure (Goodman MA, Malik P. Ther Adv Hematol 7: 302–315, 2016; Lettre G, Bauer DE. Lancet 387: 2554–2564, 2016), but the likelihood that these strategies can be mobilized to treat the large numbers of patients residing in developing countries is remote. A pharmacological treatment to increase fetal hemoglobin (HbF) as a therapy for SCD has been a long-sought goal, because increased levels of HbF (α2γ2) inhibit the polymerization of HbS (Poillin WN, et al. Proc Natl Acad Sci USA 90: 5039–5043, 1993; Sunshine HR, et al. J Mol Biol 133: 435–467, 1979) and are associated with reduced symptoms and increased lifespan of SCD patients (Platt OS, et al. N Engl J Med 330: 1639–1644, 1994; Platt OS, et al. N Engl J Med 325: 11–16, 1991). Only two drugs, hydroxyurea and l-glutamine, are approved by the US Food and Drug Administration for treatment of SCD. Hydroxyurea is ineffective at HbF induction in ~50% of patients (Charache S, et al. N Engl J Med 332: 1317–1322, 1995). While polymerization of HbS has been traditionally considered the driving force in the hemolysis of SCD, the excessive reactive oxygen species generated from red blood cells, with further amplification by intravascular hemolysis, also are a major contributor to SCD pathology. This review highlights a new class of drugs, lysine-specific demethylase (LSD1) inhibitors, that induce HbF and reduce reactive oxygen species.

scholarly journals Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease [see comments]

Blood ◽  
1995 ◽  
Vol 86 (2) ◽  
pp. 776-783 ◽  
Author(s):  
FM Gill ◽  
LA Sleeper ◽  
SJ Weiner ◽  
AK Brown ◽  
R Bellevue ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Clinical Course ◽  
The United States ◽  
Beta Thalassemia ◽  
Acute Chest Syndrome ◽  
Cooperative Study ◽  
Cell Disease ◽  
Splenic Sequestration ◽  
Clinical Events

Within the Cooperative Study of Sickle Cell Disease, 694 infants with confirmed sickle cell disease were enrolled at less than 6 months of age. Information about the nature and frequency of complications was collected prospectively over a 10-year period. Painful crises and acute chest syndrome were the most common sickle cell-related events in homozygous sickle cell anemia (SS), hemoglobin SC disease (SC), and S beta thalassemia patients (overall incidence in SS patients of 32.4 and 24.5 cases per 100 person-years, respectively). Bacteremia occurred most frequently in SS children under 4 years of age and in SC patients less than 2 years of age. The mortality rate was low in this cohort compared with that found in previous reports. Twenty children, all with Hb SS, died (1.1 deaths per 100 person-years among SS patients). Infection, most commonly with Streptococcus pneumoniae and Hemophilus influenzae, caused 11 deaths. Two children died of splenic sequestration, 1 of cerebrovascular accident, and 6 of unclear causes. Two patients underwent cholecystectomies, and 17 underwent splenectomies after one or more splenic sequestration crises. The experience of this cohort should reflect closely the true clinical course of those children with Hb SS and Hb SC disease who are observed in sickle cell centers in the United States.

Abnormal Pulmonary Function in Adults with Sickle Cell Disease: Association of Decreased DLCO with Systemic Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 316-316 ◽  
Author(s):  
Elizabeth S. Klings ◽  
Diego F. Wyszynski ◽  
Vikki G. Nolan ◽  
Martin H. Steinberg
Keyword(s):  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Sickle Cell ◽  
Pulmonary Function Tests ◽  
Systemic Disease ◽  
The United States ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Restrictive Physiology ◽  
Abnormal Pulmonary Function

Abstract Pulmonary complications of sickle cell disease (SCD), including acute chest syndrome, pulmonary hypertension (PH) and pulmonary fibrosis, are common. Dyspnea and hypoxemia are equally common in this population. It is likely that pulmonary function tests (PFT) are abnormal in the SCD population, however, no extensive study has been reported to date. Moreover, the relationship between abnormal pulmonary function and other manifestations of SCD, such as PH, is unclear. We hypothesized that abnormalities of pulmonary function, particularly a low diffusion capacity for carbon monoxide (DLCO), may be associated with other complications of SCD. The Cooperative Study of Sickle Cell Disease (CSSCD) enrolled and followed more than 4,000 SCD patients who had visited one of 23 participating clinical centers across the United States between 1978 and 1998. Data were collected on many complications of the disease, and standardized collection of PFTs were part of the protocol. From the more than 1300 CSSCD patients who had the results of PFTs recorded, 310 adults (age≥ 20 years of age) homozygous for the Hb S gene without coincident α thalassemia and with sufficient data were identified. Predicted values for FEV1, FVC, FEV1/FVC, TLC, RV and DLCO were calculated using algorithms that accounted for gender, age, and height in the African American population (using STATA, version 9); data are presented as percent predicted. Based on criteria established by the American Thoracic Society, subjects were sub-classified into 7 groups: obstructive physiology; restrictive physiology; mixed obstructive/restrictive disease; low lung volumes with normal spirometry (LLV); LLV with a low DLCO, isolated low DLCO, or normal. The association of blood counts and serum chemistries between patients with low DLCO compared with those with a normal DLCO was assessed by multivariate linear regression (using SAS software version 8.2). Normal PFTs were present in only 31 of 310 (10 %) SCD patients. Overall, the adult SCD population was characterized by decreased total lung capacities (70.2 + 14.7% predicted) and DLCO (64.5 + 19.9 % predicted adjusted for hemoglobin concentration). The most common PFT patterns observed were restrictive physiology (35.8%), LLV with normal spirometry (34.2% of patients), and an isolated low DLCO (12.9%). The presence of a low DLCO was associated with an elevated platelet count (p=0.05), hepatic dysfunction [elevated ALT (p=0.07) with elevated AST (p=0.01)] and renal dysfunction [elevated BUN and creatinine (p=0.05, 0.07)]. Restrictive disease is marginally associated with a decrease in hematocrit (p=0.07) and Hb F levels (p=0.07). Pulmonary function is abnormal in 90% of adult SCD patients. Common abnormalities include restrictive physiology, LLV with normal spirometry and a decreased DLCO. The presence of a decreased DLCO may be a marker of more severe systemic disease that includes impaired renal and hepatic function and possibly complications of hemolytic anemia such as PH.

Microparticles As Biomarkers Of Osteonecrosis Of The Hip In Sickle Cell Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2226-2226
Author(s):  
Anne M Marsh ◽  
Raymond Schiffelers ◽  
Ginny Gildengorin ◽  
Frans A Kuypers ◽  
Carolyn Hoppe
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Vascular Occlusion ◽  
Predictive Biomarker ◽  
Acute Chest Syndrome ◽  
Mobility Limitations ◽  
Cell Disease ◽  
The Past ◽  
D Dimer

Abstract Introduction Sickle cell disease (SCD) is the most common cause of osteonecrosis of the femoral head (ONFH) in children. ONFH is a debilitating condition that is associated with mobility limitations, chronic pain, and an impaired quality of life. While the mechanisms that cause ONFH remain unknown, ischemia from recurrent microvascular occlusion is likely to play a role. Vascular occlusion may result directly from obstruction by sickled cells, or indirectly via complex interdependent pathways characterized by sustained endothelial activation, chronic inflammation, and coagulation. Microparticles (MP) are small, cell membrane-derived vesicles generated in response to cellular activation, injury or apoptosis. MPs have emerged as potential modulators of inflammation and thrombosis and have been found to be elevated in patients with ONFH in the general population. Objective This pilot study examined whether microparticle levels in patients with SCD who have ONFH differ from SCD patients without ONFH, as well as healthy African American (AA) controls. Methods Subjects were recruited at their baseline status and were excluded if they had been transfused within the past 30 days, hospitalized for a vaso-occlusive pain episode, acute chest syndrome, fever or surgery within the past 30 days, or had bony lesions of the femur or hip due to causes unrelated to SCD. For MP analysis, whole blood was collected in sodium citrate tubes and centrifuged for 15 minutes at 1500 x g at 20° C to generate platelet poor plasma. Aliquots of the plasma were immediately frozen and stored at -80° C until the time of MP analysis. 300 μl samples were diluted in PBS and centrifuged at 10000 x g for 1hr and the supernatant was centrifuged at 100,000 x g for 2 hr. The pellet was re-suspended in 1 mL of PBS and subjected to nanoparticle-tracking analysis to determine concentration and size. Additional laboratory biomarkers of inflammation and coagulation, including highly-sensitive C-reactive protein (hs-CRP), von Willebrand factor antigen (vWF Ag), tissue factor (TF), and D-dimer were analyzed for differences between groups. Analysis of variance was used to compare MP and biomarker levels between the three groups. The institutional review board at Children's Hospital & Research Center Oakland approved the study protocol and written informed consent was obtained from all participants. Results Characteristics of the 30 subjects enrolled are shown in Table I. Total microparticle levels in ONFH(+) patients were 2.3-fold higher than in ONFH(-) patients, and 2.5-fold higher than in AA controls (Figure 1). Mean MP levels for ONFH(+) patients, ONFH(-) patients, and AA controls were 4.55 x 1010, 1.99 x 1010, and 1.85 x 1010, respectively. Microparticle levels in ONFH(-) SCD patients did not differ from AA controls. There were no statistically significant differences in hsCRP, vWF Ag, TF, or D-dimer levels between the ONFH(-) and ONFH(+) groups. Conclusions The results of this study demonstrate significantly elevated MP levels in individuals with SCD who have ONFH. Additional studies are needed to better understand the mechanistic effects of MPs on the development of ONFH and to determine whether MP levels may be useful as a predictive biomarker for early disease detection. This publication was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Beyond the Definitions of the Phenotypic Complications of Sickle Cell Disease: An Update on Management

2012 ◽  
Vol 2012 ◽  
pp. 1-55 ◽  
Author(s):  
Samir K. Ballas ◽  
Muge R. Kesen ◽  
Morton F. Goldberg ◽  
Gerard A. Lutty ◽  
Carlton Dampier ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Point Mutation ◽  
Sickle Cell ◽  
Globin Gene ◽  
Single Point ◽  
Acute Chest Syndrome ◽  
Single Point Mutation ◽  
Cell Disease ◽  
Exon 1 ◽  
Abnormal Hemoglobin

The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of theβglobin gene resulting in the substitution of glutamic acid by valine at position 6 of theβglobin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes.

Stem Cell Transplantation for Children with Sickle Cell Anemia: Factors Associated with Parent and Patient Interest

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1079-1079
Author(s):  
Roth Michael ◽  
Julie Krystal ◽  
Deepa Manwani ◽  
Catherine Driscoll ◽  
Rosanna J. Ricafort
Keyword(s):  
Stem Cell ◽  
Sickle Cell Disease ◽  
Life Span ◽  
Disease Severity ◽  
Sickle Cell ◽  
The United States ◽  
Life Goals ◽  
Acute Chest Syndrome ◽  
Cell Transplant ◽  
Cell Disease

Abstract Abstract 1079 BACKGROUND: Sickle cell disease (SCD) is the most common inherited blood disorder in the United States affecting more than 70,000 children and adults. SCD is associated with significant morbidity and mortality with a mean life expectancy of approximately 45 years in patients with more severe Hb SS. Allogeneic hematopoietic stem cell transplant (HSCT) is the only curative treatment for sickle cell disease. Currently hematologists consider HSCT only for patients with a history of multiple pain crises, stroke, renal disease and/or multiple episodes of acute chest syndrome. However, factors that influence patients' and parents' interest in HSCT for SCD are not known. METHODS: We designed and administered a 40 question survey to assess the interest in HSCT as a cure for SCD in parents and adolescents with HbSS or HbSBetaThalassemia0. The survey tool assessed factors that may influence interest in HSCT including demographic data, disease severity, views on prognosis and Health Related Quality of Life (PedsQL4.0). All participants were given a handout on the risks and benefits of a HSCT prior to completing the survey. Participants' who responded they definitely or probably would undergo HSCT if recommended by their hematologist were categorized as “likely would undergo HSCT” while participants who responded they would maybe, probably not, or definitely would not undergo HSCT were categorized as “less likely would undergo HSCT”. RESULTS: Ninety parents and 42 adolescents completed the survey, with only 1 parent refusing to participate. Forty six percent (39/85) of parents would likely have their child undergo HSCT and 34% (14/41) of adolescents would likely undergo HSCT if it was recommended by their hematologist. Adolescents with better social function and better overall emotional function were more likely to undergo transplant (50% (10/20) vs. 19% (4/21), p=0.04) (53% (9/17) vs. 21% (5/24), p=0.03), respectively. Parents of children age>7 who believe their child's life span will be shortened secondary to SCD were more likely to undergo transplant (100% (3/3) vs. 35% (15/43), p=0.03). In addition, parents of children who have received an exchange transfusion were more likely to undergo transplant (62% (18/29) vs. 38% (20/53), p=0.04). Disease severity represented by the number of pain crises, episodes of acute chest, or presence of a stroke were not associated with increased parent or adolescent interest in HSCT. In addition, 50% (11/22) of parents of children who would not qualify for HSCT based on current disease severity criteria would likely undergo HSCT. In this cohort, parents who believed their child's disease would not get better were more likely to go forward with transplant (100% (5/5) vs. 31% (5/16), p=0.007). The majority of parents believe their child's sickle cell disease will get better (63% (55/87)), will not likely prevent their child from achieving life goals (83% (71/86)), and will not shorten their child's lifespan (88% (74/84)). Forty six percent (19/41) of adolescents believe their sickle cell disease will get better, 74% (31/42) believe it will not prevent them from achieving life goals, and 64% (27/42) believe sickle cell disease will not shorten their lifespan. CONCLUSIONS: There is a strong interest in HSCT in our patient cohort that was not pre-selected based on disease severity. Parents had an interest in HSCT based on both disease severity and perception of prognosis, while adolescents' interest in HSCT was directly related to higher psychosocial functioning. The current standard inclusion criteria for HSCT for children with SCD exclude a number of children whose parents are interested in HSCT. The finding of perception of a normal life span in the majority of patients and parents is troubling and suggests a need for more thorough education regarding the long term sequelae of SCD and the role for HSCT as a cure. Disclosures: No relevant conflicts of interest to declare.

Preclinical Studies for Sickle Cell Disease Gene Therapy Using Bone Marrow CD34+ Cells Modified with a βAS3-Globin Lentiviral Vector

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3119-3119
Author(s):  
Fabrizia Urbinati ◽  
Zulema Romero Garcia ◽  
Sabine Geiger ◽  
Rafael Ruiz de Assin ◽  
Gabriela Kuftinec ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Cells ◽  
Globin Gene ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Cd34 Cells

Abstract Abstract 3119 BACKGROUND: Sickle cell disease (SCD) affects approximately 80, 000 Americans, and causes significant neurologic, pulmonary, and renal injury, as well as severe acute and chronic pain that adversely impacts quality of life. Because SCD results from abnormalities in red blood cells, which in turn are produced from adult hematopoietic stem cells, hematopoietic stem cell transplant (HSCT) from a healthy (allogeneic) donor can benefit patients with SCD, by providing a source for life-long production of normal red blood cells. However, allogeneic HSCT is limited by the availability of well-matched donors and by immunological complications of graft rejection and graft-versus-host disease. Thus, despite major improvements in clinical care, SCD continues to cause significant morbidity and early mortality. HYPOTHESIS: We hypothesize that autologous stem cell gene therapy for SCD has the potential to treat this illness without the need for immune suppression of current allogeneic HSCT approaches. Previous studies have demonstrated that addition of a β-globin gene, modified to have the anti-sickling properties of fetal (γ-) globin (βAS3), to bone marrow (BM) stem cells in murine models of SCD normalizes RBC physiology and prevents the manifestations of sickle cell disease (Levassuer Blood 102 :4312–9, 2003). The present work seeks to provide pre-clinical evidence of efficacy for SCD gene therapy using human BM CD34+ cells modified with the bAS3 lentiviral (LV) vector. RESULTS: The βAS3 globin expression cassette was inserted into the pCCL LV vector backbone to confer tat-independence for packaging. The FB (FII/BEAD-A) composite enhancer-blocking insulator was inserted into the 3' LTR (Ramezani, Stem Cells 26 :32–766, 2008). Assessments were performed transducing human BM CD34+ cells from healthy or SCD donors with βAS3 LV vectors. Efficient (1–3 vector copies/cell) and stable gene transmission were determined by qPCR and Southern Blot. CFU assays demonstrated that βAS3 gene modified SCD CD34+ cells are fully capable of maintaining their hematopoietic potential. To demonstrate the effectiveness of the erythroid-specific bAS3 gene in the context of human HSPC (Hematopoietic Stem and Progenitor Cells), we optimized an in vitro model of erythroid differentiation of huBM CD34+ cells. We successfully obtained an expansion up to 700 fold with >80% fully mature enucleated RBC derived from CD34+ cells obtained from healthy or SCD BM donors. We then assessed the expression of the βAS3 globin gene by isoelectric focusing: an average of 18% HbAS3 over the total globin present (HbS, HbA2) per Vector Copy Number (VCN) was detected in RBC derived from SCD BM CD34+. A qRT-PCR assay able to discriminate HbAS3 vs. HbA RNA, was also established, confirming the quantitative expression results obtained by isoelectric focusing. Finally, we show morphologic correction of in vitro differentiated RBC obtained from SCD BM CD34+ cells after βAS3 LV transduction; upon induction of deoxygenation, cells derived from SCD patients showed the typical sickle shape whereas significantly reduced numbers were detected in βAS3 gene modified cells. Studies to investigate risks of insertional oncogenesis from gene modification of CD34+ cells by βAS3 LV vectors are ongoing as are in vivo studies to demonstrate the efficacy of βAS3 LV vector in the NSG mouse model. CONCLUSIONS: This work provides initial evidence for the efficacy of the modification of human SCD BM CD34+ cells with βAS3 LV vector for gene therapy of sickle cell disease. This work was supported by the California Institute for Regenerative Medicine Disease Team Award (DR1-01452). Disclosures: No relevant conflicts of interest to declare.

PedsQL™ Sickle Cell Disease Module: Feasibility, Reliability and Validity

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 476-476
Author(s):  
Julie A. Panepinto ◽  
Cristiane B. Bendo ◽  
Sylvia Torres ◽  
Timothy McCavit ◽  
Christina J. Bemrich-Stolz ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Construct Validity ◽  
Sickle Cell ◽  
Severe Disease ◽  
The United States ◽  
Self Report ◽  
Measurement Properties ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Parent Proxy

Abstract Abstract 476 Background: Sickle cell disease (SCD) is an inherited chronic disease characterized by complications such as recurrent painful vaso-occlusive events that can require hospitalizations and contribute to early and increased mortality. Prior work using generic health-related quality of life (HRQL) instruments has demonstrated that patients with SCD experience significantly impaired HRQL in their baseline state of health that worsens during acute complications of the disease. To better understand differences in health status in children with SCD, we developed the PedsQL™ SCD Module to measure SCD-specific HRQL. The goal of this study was to determine the measurement properties for the child self- and parent-proxy reports for the newly developed PedsQL™ SCD Module. We hypothesized that the PedsQL™ SCD Module would be feasible and reliable and that children with more severe SCD would have worse HRQL than those with mild disease as measured by the PedsQL™ SCD Module. Methodology: This was a cross-sectional study conducted at 5 sites across the United States. Study participants were children with SCD ages 2–18 years who presented to clinic for a routine visit. HRQL was the main outcome measured with the newly developed 43-item PedsQL™ SCD Module which includes nine scales: Pain/Hurt (PH, 9 items), Pain Impact (PI, 10 items), Pain Management/Control (PMC, 2 items), Worry I (WO1, 5 items), Worry II (WO2, 2 items), Emotions (EM, 2 items), Treatment (TR, 7 items), Communication I (CO1, 3 items), Communication II (CO2, 3 items). Higher scores indicate better HRQL and lower SCD symptoms. Missing items were used to determine feasibility and Cronbach's alpha was used to determine reliability. HRQL of children with mild and severe disease were compared using an independent t-test to determine construct validity. Severe disease was defined as patients with 3 or more hospitalizations for pain in the 3 years prior, history of stroke and/or prior acute chest syndrome. Results: A total of 321 families (313 parents, 243 children ages 5–18 years) completed questionnaires. The average age of the children (46.7% boys) was 9.62 years (SD = 4.88). Feasibility was established, with 3% or less missing data for the module. The PedsQL™ SCD Module was reliable and distinguished between children with mild and severe SCD (Table 1). Conclusions: The PedsQL™ SCD Module performed well and demonstrated strong measurement properties in patients with SCD. Overall, both the parent-proxy report and child self-report differentiated between patients with severe and mild SCD supporting construct validity of the module. Although these are the first results using the PedsQL™ SCD Module, it has shown great potential as being a strong measure of HRQL for patients with SCD. Future studies incorporating the PedsQL™ SCD Module will benefit from the measure's disease-specific scales and overall ability to distinguish between mild and severe symptoms. Continually, these studies will help further define its' measurement properties and advance our knowledge of the HRQL in patients with SCD. Disclosures: Off Label Use: Hydroxyurea is approved for use in sickle cell disease in adults but not children. Varni:Mapi Research Trust: Dr. Varni holds the copyright and the trademark for the PedsQL™ and receives financial compensation from the Mapi Research Trust, which is a nonprofit research institute that charges distribution fees to for-profit companies that use the Pediatric Quality Other, PedsQL™, PedsQL™ Patents & Royalties.

scholarly journals Heme oxygenase-1 gene promoter polymorphism is associated with reduced incidence of acute chest syndrome among children with sickle cell disease

Blood ◽  
2012 ◽  
Vol 120 (18) ◽  
pp. 3822-3828 ◽  
Author(s):  
Christopher J. Bean ◽  
Sheree L. Boulet ◽  
Dorothy Ellingsen ◽  
Meredith E. Pyle ◽  
Emily A. Barron-Casella ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Heme Oxygenase ◽  
Sickle Cell ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Promoter Polymorphism ◽  
Adverse Outcomes ◽  
Acute Chest Syndrome ◽  
Heme Oxygenase 1 ◽  
Cell Disease

Abstract Sickle cell disease is a common hemolytic disorder with a broad range of complications, including vaso-occlusive episodes, acute chest syndrome (ACS), pain, and stroke. Heme oxygenase-1 (gene HMOX1; protein HO-1) is the inducible, rate-limiting enzyme in the catabolism of heme and might attenuate the severity of outcomes from vaso-occlusive and hemolytic crises. A (GT)n dinucleotide repeat located in the promoter region of the HMOX1 gene is highly polymorphic, with long repeat lengths linked to decreased activity and inducibility. We examined this polymorphism to test the hypothesis that short alleles are associated with a decreased risk of adverse outcomes (hospitalization for pain or ACS) among a cohort of 942 children with sickle cell disease. Allele lengths varied from 13 to 45 repeats and showed a trimodal distribution. Compared with children with longer allele lengths, children with 2 shorter alleles (4%; ≤ 25 repeats) had lower rates of hospitalization for ACS (incidence rate ratio 0.28, 95% confidence interval, 0.10-0.81), after adjusting for sex, age, asthma, percentage of fetal hemoglobin, and α-globin gene deletion. No relationship was identified between allele lengths and pain rate. We provide evidence that genetic variation in HMOX1 is associated with decreased rates of hospitalization for ACS, but not pain. This study is registered at www.clinicaltrials.gov as #NCT00072761.

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