Sickle cell disease (SCD) is an inherited hemolytic anemia whose pathophysiology is driven by polymerization of the hemoglobin S (Hb S), leading to hemolysis and vaso-occlusive events. Inflammation ...is a fundamental component in these processes and a continuous inflammatory stimulus can lead to tissue damages. Thus, pro-resolving pathways emerge in order to restore the homeostasis. For example there is the annexin A1 (ANXA1), an endogenous anti-inflammatory protein involved in reducing neutrophil-endothelial interactions, accelerating neutrophil apoptosis and stimulating macrophage efferocytosis. We investigated the expression of ANXA1 in plasma of SCD patients and its relation with anemic, hemolytic and inflammatory parameters of the disease. Three SCD genotypes were considered: the homozygous inheritance for Hb S (Hb SS) and the association between Hb S and the hemoglobin variants D-Punjab (Hb SD) and C (Hb SC). ANXA1 and proinflammatory cytokines were quantified by ELISA in plasma of SCD patients and control individuals without hemoglobinopathies. Hematological and biochemical parameters were analyzed by flow cytometry and spectrophotometer. The plasma levels of ANXA1 were about three-fold lesser in SCD patients compared to the control group, and within the SCD genotypes the most elevated levels were found in Hb SS individuals (approximately three-fold higher). Proinflammatory cytokines were higher in SCD groups than in the control individuals. Anemic and hemolytic markers were higher in Hb SS and Hb SD genotypes compared to Hb SC patients. White blood cells and platelets count were higher in Hb SS genotype and were positively correlated to ANXA1 levels. We found that ANXA1 is down-regulated and differentially expressed within the SCD genotypes. Its expression seems to depend on the inflammatory, hemolytic and vaso-occlusive characteristics of the diseased. These data may lead to new biological targets for therapeutic intervention in SCD.
Summary
Although evidence is accumulating that hydroxycarbamide decreases mortality among adults with sickle cell disease (SCD), there are no published data regarding the effect of hydroxycarbamide ...on mortality among children. The Paediatric Hydroxycarbamide Program was established to treat children with SCD aged 3–18 years if they met disease severity criteria. Mortality data and clinical/laboratorial effects of hydroxycarbamide were retrospectively collected for the first 9 years of the Program. Mortality among those who received hydroxycarbamide was compared to that of untreated children. Among 1760 subjects, 267 received hydroxycarbamide at a median dose of 20·8 mg/kg/d (range 10–32) for a median of 2 years (range 0·1–6·5). Survival among hydroxycarbamide‐treated children was significantly greater than that among untreated ones (99·5% vs. 94·5%, P = 0·01), due primarily to fewer deaths from acute chest syndrome and infection. Hydroxycarbamide therapy was significantly associated with increases in haemoglobin concentration, fetal haemoglobin, mean corpuscular volume, and reduction in platelet counts, reticulocytes and neutrophils. Toxicity was minimal and predominantly mild reversible neutropenia. Significantly fewer hospitalizations and emergency room visits, and shorter admissions were observed among hydroxycarbamide‐treated subjects, when compared to the 12‐month period prior to treatment initiation. Hydroxycarbamide therapy reduces disease severity and is probably associated with decreased mortality among children with SCD.
Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; ...treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea.
To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes.
Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-β0 thalassemia, or S-β+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included.
A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194).
Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup.
Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 45.4% female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h 95% CI, -7.8 to 15.7; geometric mean ratio, 1.2 95% CI, 1.0-1.5; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h 95% CI, 1.7-32.0; geometric mean ratio, 1.4 95% CI, 1.1-1.8; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%).
Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes.
ClinicalTrials.gov Identifier: NCT01737814.
Introduction
Despite the high prevalence of sickle cell disease (SCD) in Brazil, no studies have described the validation of an SCD‐specific health‐related quality‐of‐life (HRQoL) instrument in ...children. We validated PedsQL 3.0 Sickle Cell Disease Module (PedsQL‐SCD) for Brazilian Portuguese, and cross‐validated it with PedsQL 4.0 Generic Core Scale (PedsQL‐GCS) in children with SCD.
Methods
PedsQL‐SCD was translated and culturally adapted using forward and reverse translations. PedsQL‐SCD and PedsQL‐GCS were tested in children and adolescents with SCD aged 2–18 years and their caregivers. Validity was assessed using the Pearson and intraclass correlation coefficients, and reliability measured with Cronbach's alpha.
Results
PedsQL‐SCD was validated in 206 children with SCD (median age 14 years, range: 8–18) and 201 caregivers. Among patients and caregivers, the mean total score for PedsQL‐SCD was 65.7 and 64.1, respectively. The mean total score for PedsQL‐GCS was 73.1 and 68.9 among patients and caregivers, respectively. The internal consistency for PedsQL‐SCD and PedsQL‐GCS was good; Cronbach's alpha coefficients ranged from .59–.93 to .64–.83 among patients and from .60–.95 to .65–.85 among caregivers, respectively. Most intercorrelations between PedsQL‐SCD and PedsQL‐GCS, for patients and caregivers, had medium to large effect sizes (range: .23–.63 and .27–.64, respectively). Pain and pain impact domains of PedsQL‐SCD and physical dimension of PedsQL‐GCS had the highest cross‐correlation (.63 and .6 for patients; .63 and .64 for caregivers, respectively), confirming convergent construct validity.
Conclusion
PedsQL‐SCD is a valid, culturally appropriate measure to assess HRQoL in children with SCD in Brazil and is well‐correlated PedsQL‐GCS.
The costs associated with the treatment of sickle cell disease (SCD) are understudied in low and middle-income countries (LMIC). We evaluated the cost of treating SCD-related acute complications and ...the potential cost-savings of hydroxyurea in a specialized hematology center in Brazil.
The costs (US dollars) of emergency department (ED) and hospitalizations from SCD-related complications between 01.01.2018 and 06.30.2018 were ascertained using absorption and micro-costing approaches. The reasons for acute hospital visits were grouped as: 1) vaso-occlusive (VOC) pain, 2) infection, 3) anemia exacerbation, and 4) chronic organ damage complications. Hydroxyurea adherence was estimated by medication possession ratio (MPR) during the study period.
In total, 1144 patients, median age 17 years (range 0-70), 903 (78.9%) with HbSS/HbSβ
-thalassemia, 441 (38.5%) prescribed hydroxyurea, visited the ED, of whom 381 (33%) were admitted. VOC accounted for 64% of all ED visits and 60% of all admissions. Anemia exacerbation was the most expensive reason for ED visit ($321.87/visit), while chronic organ damage carried the highest admission cost ($2176.40/visit). Compared with other genotypes, individuals with HbSS/HbSβ
-thalassemia were admitted more often (79% versus 21%, p < 0.0001), and their admission costs were higher ($1677.18 versus $1224.47/visit, p = 0.0001). Antibiotics and analgesics accounted for 43% and 42% of the total ED costs, respectively, while housing accounted for 46% of the total admission costs. Costs of ED visits not resulting in admissions were lower among HbSS/HbSβ
-thalassemia individuals with hydroxyurea MPR ≥65% compared with visits by patients with MPR <65% ($98.16/visit versus $182.46/visit, p = 0.0007). No difference in admission costs were observed relative to hydroxyurea use.
In a LMIC hematology-specialized center, VOCs accounted for most acute visits from patients with SCD, but costs were highest due to anemia exacerbation. Analgesics, antibiotics, and housing drove most expenses. Hydroxyurea may reduce ED costs among individuals with HbSS/HbSβ
-thalassemia but is dependent on adherence level.
Sickle cell disease (SCD) comprises inherited red blood cell disorders due to a mutation in the β-globin gene (c20A > T, pGlu6Val) and is characterized by the presence of abnormal hemoglobin, ...hemoglobin S, hemolysis, and vaso-occlusion. This mutation, either in a homozygous configuration or in compound states with other β-globin mutations, leads to polymerization of hemoglobin S in deoxygenated conditions, causing modifications in red blood cell shape, particularly sickling. Vaso-occlusive crisis (VOC) is the hallmark of the disease, but other severe complications may arise from repeated bouts of VOCs. SCD is considered a global health problem, and its incidence has increased in some areas of the world, particularly the Americas and Africa. Management of the disease varies according to the region of the world, mainly due to local resources and socioeconomic status. This review aimed to describe more recent data on SCD regarding available treatment options, especially in Brazil. New treatment options are expected to be available to all patients, particularly crizanlizumab, which is already approved in the country.
Patients with Sickle cell disease (SCD) who receive regular transfusions are at risk for developing cardiac toxicity from iron overload. The aim of this study was to assess right and left cardiac ...volumes and function, late gadolinium enhancement (LGE) and iron deposits in patients with SCD using CMR, correlating these values with transfusion burden, ferritin and hemoglobin levels.
Thirty patients with SCD older than 20 years of age were studied in a 1.5 T scanner and compared to age- and sex-matched normal controls. Patients underwent analysis of biventricular volumes and function, LGE and T2* assessment of the liver and heart.
When compared to controls, patients with SCD presented higher left ventricular (LV) volumes with decreased ejection fraction (EF) with an increase in stroke volume (SV) and LV hypertrophy. The right ventricle (RV) also presented with a decreased EF and hypertrophy, with an increased end-systolic volume. Although twenty-six patients had increased liver iron concentrations (median liver iron concentration value was 11.83 ± 9.66 mg/g), only one patient demonstrated an abnormal heart T2* < 20 msec. Only four patients (13%) LGE, with only one patient with an ischemic pattern.
Abnormal heart iron levels and myocardial scars are not a common finding in SCD despite increased liver iron overload. The significantly different ventricular function seen in SCD compared to normal suggests the changes in RV and LV function may not be due to the anemia alone. Future studies are necessary to confirm this association.
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