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Sickle cell disease (SCD) comprises inherited red blood cell disorders due to a mutation in the ß-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 ß-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.
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Abstract To date, hydroxyurea is the only effective and safe drug that significantly reduces morbidity and mortality of individuals with Sickle cell disease. Twenty years of real-life experience has demonstrated that hydroxyurea reduces pain attacks, vaso-occlusive events, including acute chest syndrome, the number and duration of hospitalizations and the need for transfusion. The therapeutic success of hydroxyurea is directly linked to access to the drug, the dose used and adherence to treatment which, in part, is correlated to the availability of hydroxyurea. This consensus aims to reduce the number of mandatory exams needed to access the drug, prioritizing the requesting physician's report, without affecting patient safety.
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To date, hydroxyurea is the only effective and safe drug that significantly reduces morbidity and mortality of individuals with Sickle cell disease. Twenty years of real-life experience has demonstrated that hydroxyurea reduces pain attacks, vaso-occlusive events, including acute chest syndrome, the number and duration of hospitalizations and the need for transfusion. The therapeutic success of hydroxyurea is directly linked to access to the drug, the dose used and adherence to treatment which, in part, is correlated to the availability of hydroxyurea. This consensus aims to reduce the number of mandatory exams needed to access the drug, prioritizing the requesting physician's report, without affecting patient safety.
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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.
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Dor , Qualidade de Vida , Criança , Adolescente , Humanos , Brasil , Reprodutibilidade dos Testes , Psicometria/métodos , Inquéritos e QuestionáriosRESUMO
Implementation of HCT programs is a high priority in Brazil, given the growing survival rates for children with SCD. Our data highlights a well-connected community of healthcare workers, but also reveals that the current level of HCT activities for SCD in Brazil is low. This underscores the urgent need for transition intervention. The key facilitators for successful HCT implementation in Brazil are strong leadership and a motivated workforce. However, community participation and finances are weak points that require implementation strategies during program implementation. Compared to the US, both Brazilian institutions scored significantly lower on all components needed for transition, emphasizing the need for intervention. This project is the first to evaluate the readiness for HCT implementation in a low- and middle-income country. Designing a context-specific HCT program that suits low-resource settings will improve outcomes for individuals with SCD in the country. (AU)
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The polymerization of hemoglobin under deoxygenation is the main pathophysiological event in sickle cell diseases, described more than 70 years ago. The last two decades have seen a major increase in knowledge about the cascade of events that follow the polymerization of hemoglobin and the ensuing sickling of red blood cells. Several distinctive therapeutic targets have been discovered as a result, and a few drugs with innovative mechanisms of action are already on the market, while several others are the focus of ongoing trials. The aim of this narrative review is to describe some of the more recent data in the SCD literature regarding pathophysiology and novel treatments.
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Anemia Falciforme , Hemoglobina Falciforme , Humanos , Anemia Falciforme/tratamento farmacológico , Eritrócitos , Hemoglobinas , Eritrócitos AnormaisRESUMO
Sickle cell disease (SCD) is a group of hereditary chronic diseases with a substantial impact on quality of life and morbimortality. In Brazil, it is 1 of the most common hereditary diseases; however, there are sparse epidemiological data for the country. Using data from death certificates, we aimed to estimate the median age at death, years of life lost because of SCD, and the median survival. From 2015 to 2019, we identified 3320 records of deaths of individuals with SCD, from a total of 6 553 132 death records. Among individuals with SCD, the median age at death was 37 years less than that of the general population (SCD: aged 32.0 years at death, interquartile range [IQR], 19.0-46.0; general population: aged 69.0 years at death; IQR, 53.0-81.0). Results were consistent when stratified by sex or race. Over the 5 years evaluated, crude death rates varied from 0.30 to 0.34 per 100 000 inhabitants (mean 0.32 per 100 000 inhabitants). We estimated a prevalence of 60 017 individuals living with SCD (29.02 cases per 100 000) and an average incidence of 1362 cases yearly. The median estimated survival was 40 years for individuals with SCD and 80 years for the general population. SCD was associated with an increased risk of mortality in most age ranges. Among individuals with SCD aged between 1 and 9 years and between 10 and 39 years, the risk of death was 32 and 13 times higher, respectively. The most common causes of death were sepsis and respiratory failure. These results highlight the burden of SCD in Brazil and the necessity of improved care for this population.
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Anemia Falciforme , Qualidade de Vida , Humanos , Lactente , Pré-Escolar , Criança , Brasil/epidemiologia , Anemia Falciforme/complicações , Incidência , PrevalênciaRESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: In total, 1144 patients, median age 17 years (range 0-70), 903 (78.9%) with HbSS/HbSß0-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/HbSß0-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/HbSß0-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. DISCUSSION: 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/HbSß0-thalassemia but is dependent on adherence level.
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Anemia Falciforme , Adolescente , Adulto , Idoso , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/epidemiologia , Criança , Pré-Escolar , Custos e Análise de Custo , Serviço Hospitalar de Emergência , Hospitalização , Humanos , Hidroxiureia/uso terapêutico , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Adulto JovemRESUMO
Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and lifethreatening disease characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. Paroxysmal nocturnal hemoglobinuria results from the expansion of a clone of hematopoietic cells that due to an inactivating mutation of the X-linked gene PIG-A are deficient in glycosylphosphatidylinositol-linked proteins. Early diagnosis, using flow cytometry performed on peripheral blood, the gold standard test to confirm the diagnosis of paroxysmal nocturnal hemoglobinuria, is essential for improved patient management and prognosis. The traditional therapy for paroxysmal nocturnal hemoglobinuria includes blood transfusion, anti-thrombosis prophylaxis or allogeneic bone marrow transplantation. The treatment that has recently become available is the complement blockade by the anti-C5 monoclonal antibody eculizumab. In this consensus, we are aiming to review the diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients, as well as the early recognition of its systemic complications. These procedures express the opinions of experts and have been based on the best available evidence and international guidelines, with the purpose of increasing benefits and reducing harm to patients.
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Humanos , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/epidemiologia , Hemoglobinúria Paroxística/diagnóstico por imagem , Consenso , Anticorpos MonoclonaisRESUMO
Abstract Introduction: Sickle cell anemia (SCA) is a Mendelian disorder with a heterogeneous clinical course. The reasons for this phenotypic diversity are not entirely established, but it is known that high fetal hemoglobin levels lead to a milder course of the disease. Additionally, genetic variants in the intergenic region HBS1L-MYB promote high levels of fetal hemoglobin into adulthood. Objective: In the present study, we investigated the HMIP1 C-839A (rs9376092) polymorphism, located at the HBS1L-MYB intergenic region block 1, in SCA patients. Method: We analyzed 299 SCA patients followed in two reference centers in Brazil. The HMIP1 C-839A (rs9376092) genotypes were determined by allele specific polymerase chain reactions. Clinical and laboratory data were obtained from patient interviews and medical records. Results: The median fetal hemoglobin levels were higher in patients with the HMIP1 C-839A (rs9376092) AA genotype (CC = 6.4%, CA = 5.6% and AA = 8.6%), but this difference did not reach significance (p = 0.194). No association between HMIP1 C-839A (rs9376092) genotypes and other clinical and laboratorial features was detected (p > 0.05). Conclusion: In summary, our data could not support the previously related association between the HMIP1 C-893A (rs9376092) polymorphism and differential fetal hemoglobin levels.
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Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Hemoglobina Fetal , Anemia Falciforme , Polimorfismo GenéticoRESUMO
Importance: 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. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: 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-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: 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). Main Outcomes and Measures: 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. Results: 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%). Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.
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Anemia Falciforme/tratamento farmacológico , Dor/tratamento farmacológico , Poloxâmero/uso terapêutico , Vasodilatadores/uso terapêutico , Adolescente , Adulto , Analgésicos Opioides/uso terapêutico , Anemia Falciforme/complicações , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Dor/etiologia , Placebos/efeitos adversos , Placebos/uso terapêutico , Poloxâmero/efeitos adversos , Vasodilatadores/efeitos adversos , Adulto JovemRESUMO
Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and life-threatening disease characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. Paroxysmal nocturnal hemoglobinuria results from the expansion of a clone of hematopoietic cells that due to an inactivating mutation of the X-linked gene PIG-A are deficient in glycosylphosphatidylinositol-linked proteins. Early diagnosis, using flow cytometry performed on peripheral blood, the gold standard test to confirm the diagnosis of paroxysmal nocturnal hemoglobinuria, is essential for improved patient management and prognosis. The traditional therapy for paroxysmal nocturnal hemoglobinuria includes blood transfusion, anti-thrombosis prophylaxis or allogeneic bone marrow transplantation. The treatment that has recently become available is the complement blockade by the anti-C5 monoclonal antibody eculizumab. In this consensus, we are aiming to review the diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients, as well as the early recognition of its systemic complications. These procedures express the opinions of experts and have been based on the best available evidence and international guidelines, with the purpose of increasing benefits and reducing harm to patients.
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INTRODUCTION: Sickle cell anemia (SCA) is a Mendelian disorder with a heterogeneous clinical course. The reasons for this phenotypic diversity are not entirely established, but it is known that high fetal hemoglobin levels lead to a milder course of the disease. Additionally, genetic variants in the intergenic region HBS1L-MYB promote high levels of fetal hemoglobin into adulthood. OBJECTIVE: In the present study, we investigated the HMIP1 C-839A (rs9376092) polymorphism, located at the HBS1L-MYB intergenic region block 1, in SCA patients. METHOD: We analyzed 299 SCA patients followed in two reference centers in Brazil. The HMIP1 C-839A (rs9376092) genotypes were determined by allele specific polymerase chain reactions. Clinical and laboratory data were obtained from patient interviews and medical records. RESULTS: The median fetal hemoglobin levels were higher in patients with the HMIP1 C-839A (rs9376092) AA genotype (CC=6.4%, CA=5.6% and AA=8.6%), but this difference did not reach significance (p=0.194). No association between HMIP1 C-839A (rs9376092) genotypes and other clinical and laboratorial features was detected (p>0.05). CONCLUSION: In summary, our data could not support the previously related association between the HMIP1 C-893A (rs9376092) polymorphism and differential fetal hemoglobin levels.
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The clinical picture of patients with sickle cell anemia (SCA) is associated with several complications some of which could be fatal. The objective of this study is to analyze the causes of death and the effect of sex and age on survival of Brazilian patients with SCA. Data of patients with SCA who were seen and followed at HEMORIO for 15 years were retrospectively collected and analyzed. Statistical modeling was performed using survival analysis in the presence of competing risks estimating the covariate effects on a sub-distribution hazard function. Eight models were implemented, one for each cause of death. The cause-specific cumulative incidence function was also estimated. Males were most vulnerable for death from chronic organ damage (p = 0.0005) while females were most vulnerable for infection (p=0.03). Age was significantly associated (p ≤ 0.05) with death due to acute chest syndrome (ACS), infection, and death during crisis. The lower survival was related to death from infection, followed by death due to ACS. The independent variables age and sex were significantly associated with ACS, infection, chronic organ damage and death during crisis. These data could help Brazilian authorities strengthen public policies to protect this vulnerable population.
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ß-S globin haplotype (ßS haplotype) characterization in sickle cell anemia (SCA) patients is important because it assists individualized treatment. However, the patient with atypical haplotypes do not present detailed studies such as clinical and laboratory data. To understand the phenotypic expression of atypical haplotype patients in relation to typical haplotype ones, it may be necessary to assess the main clinical and laboratorial parameters and investigate transcription factors, as possible genetic modulators that can contribute to the improvement of the SCA patients' clinical condition. The study group was composed of 600 SCA Brazilian patients of both genders ranging in age from 1 to 68 years. The atypical haplotypes were the third most frequent (5.7%) with 11 patterns numerically ranked according to occurrence. We verified that patients with atypical 1 haplotype in combination with Bantu haplotype presented milder clinical outcomes in relation to Bantu/Bantu and Benin/Benin patients, according to improved values of hemoglobin and hematocrit. In clinical severity, we did not observe significant statistical differences between typical and atypical haplotype patients, and this result can be explained with reference to the action of transcription factors in ß-globin cluster. Thus, we presented the atypical haplotype relationship with SCA pathophysiology, reinforcing the hypothesis that individual genetic factors may be responsible for phenotypic diversity of the disease.
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Anemia Falciforme/classificação , Anemia Falciforme/genética , Hemoglobina Falciforme/genética , Polimorfismo Genético , Globinas beta/genética , Adolescente , Adulto , Idoso , Anemia Falciforme/patologia , Brasil , Criança , Pré-Escolar , Feminino , Haplótipos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Família Multigênica , Índice de Gravidade de Doença , Adulto JovemRESUMO
Approximately 3500 children with sickle cell disease (SCD) are born in Brazil each year, but the burden of SCD morbidity is not fully characterised. A large, multi-centre cohort was established to characterise clinical outcomes in the Brazilian SCD population and create the infrastructure to perform genotype-phenotype association studies. Eligible patients were randomly selected from participating sites and recruited at routine visits. A biorepository of blood samples was created and comprehensive demographic and clinical outcome data were entered in a centralized electronic database. Peripheral blood genome-wide single nucleotide polymorphism (SNP) genotyping was performed using a customized Transfusion Medicine (TM) Array. A total of 2795 participants at six Brazilian sites were enrolled between 2013 and 2015. The cohort included slight predominance of children <18 years (55·9%) and females (53·0%). Haemoglobin (Hb) SS was the most common SCD genotype (70·7%), followed by HbSC (23%), Sß0 (3·0%) and Sß+ (2·9%). SNP data from the TM Array were analysed to evaluate the genetic ancestry of the cohort and revealed significant admixture among the population. Demographics and clinical complications, stratified by age and SCD genotype, are summarized and future studies in this cohort are discussed.