Browsing by Author "Ferreira, J."
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- Comparative efficacy and safety of pharmacological interventions for sickle cell disease in children and adolescents: a network meta-analysisPublication . Tonin, Fernanda; Ginete, Catarina; Ferreira, J.; Delgadinho, Mariana; Fernandez-Llimos, Fernando; Brito, MiguelBackground: Sickle cell disease (SCD), an inherited hemoglobinopathy characterized by anemia, severe pain, acute chest syndrome (ACS), and vaso-occlusive crisis (VOC), has an important impact on morbidity and mortality worldwide, especially in the pediatric population (over 50% die before age of 5). Although few treatment options are available, new disease-modifying therapies, intended to prevent or reduce SCD-related complications are under development. Previous systematic reviews are limited to adult patients or focused only on gathering data on a few therapies. Aims: Our aim was to synthetize the evidence on the efficacy and safety profiles of pharmacological interventions for managing SCD in children and adolescents. Methods: A systematic review with searches in PubMed, Scopus, and Web of Science was performed (May-2022). The protocol is registered at PROSPERO CRD42022328471. We included randomized controlled trials comparing any disease-modifying agent used to treat SCD complications in patients under 18 years old. The outcomes of interest included: VOC, ACS, transfusions, hospital admission, discontinuation, and serious adverse events. Data were pooled by means of Bayesian network meta-analyses with the surface under the cumulative ranking curve analyses (SUCRA). Results were reported as odds ratio (OR) with 95% credibility intervals (CrI). Additionally, stochastic multicriteria acceptability analyses (SMAA) were performed. The methodological quality of the trials and certainty of evidence were evaluated through RoB 2.0 tool and the GRADE approach, respectively. Results: Overall, 17 randomized controlled trials (n=1,972 patients) published between 1982-2022, conducted mostly in Africa (41%) and North America (35%) were included for analyses. Around one-third of the trials were restricted to homozygous patients for the SCD allele (SS HMZ); yet when reported, patients with heterozygous S-C combination represented less than 30% of the population. Males accounted for 49.0% of the cases, with ages varying from 1 to 19 years old. Almost all trials (n=15, 88.2%) directly compared active drugs with placebo. The evaluated interventions were: hydroxyurea [n=6 trials], L-arginine [n=3], antiplatelets [n=2], immunotherapy/monoclonal antibodies [n=2], sulfates [n=2], docosahexaenoic acid [n=1], niprisan [n=1] (Figure 1). SUCRA and SMAA revealed that immunotherapy/monoclonal antibodies and hydroxyurea 20 mg/kg are potentially more effective against ACS (17% and 24% probabilities, respectively), VOC (around 29% and 20%, respectively) and needing of transfusions (around 25%), while L-arginine (100-200 mg/kg) and placebo were more associated with these events. Although therapies were overall considered safe, antiplatelet and sulfates may lead to more discontinuations and severe adverse events (uncertainty evidence). Results were similar between age subgroups (<10 years vs. 10-19 years). Summary - Conclusion: The available evidence on the effect of drugs on managing SCD in children and adolescents is still insufficient and weak. No clear definition and reporting criteria for some outcomes exist. Hydroxyurea 20 mg/kg/day may remain the standard of care for these patients, however, long-term, well-designed trials comparing new immunotherapy/monoclonal antibodies should be performed. The use of monotherapies with L-arginine, antiplatelets, or sulfates should be avoided given the poor benefit-risk ratio for this population.
- Genetic variability and disease severity in a cohort of Angolan sickle cell disease patientsPublication . Brito, Miguel; Ferreira, J.; Capriello, I.; Ginete, Catarina; Delgadinho, Mariana; Sebastião, Cruz; Mendes, M.; Quinto, F.; Mavunza, F.; Vasconcelos, J.; Cogle, A.Purpose: Sickle Cell Anaemia (SCA) is an inherited autosomal and lethal blood disorder caused by a mutation in the HBB gene that promotes haemoglobin (Hb) polymerization and consequent sickling of red blood cells (RBCs) in hypoxia. Regardless of being a monogenic disease, SCA has a remarkably high clinical heterogeneity in its phenotypic expression. Several factors have been shown to modulate the clinical manifestations of SCA, namely genetic markers such as α-thalassaemia and β-globin cluster haplotypes, that can modulate biological parameters like the degree of haemolytic anaemia or the levels of foetal haemoglobin (HbF).
- Preliminary findings from the follow-up of pregnant sickle cell disease patients in Luanda, AngolaPublication . Brito, Miguel; Ginete, Catarina; Ferreira, J.; Delgadinho, Mariana; Sebastião, Cruz; Mateus, A.; Mendes, M.; Quinto, F.; Simão, F.; Fernandes, F.; Vasconcelos, J.Background: In Angola, the prevalence of Sickle Cell Disease (SCD) is almost 2%, and the carriers reach 21% of the population. Although its presentation tends to be very heterogeneous, chronic hemolytic anemia, frequent painful crises, and extensive organ damage are common features of these patients. Pregnancy in SCD patients is associated with an increase in severe outcomes, namely, a high risk of eclampsia and pre-eclampsia, stroke, and even death. Therefore, it is crucial to maintain continuous medical surveillance during pregnancy, especially in women with previous strokes. Moreover, health services in low- and middle-income countries are generally not prepared to follow these patients. Aims: We aim to present the preliminary findings from the cohort study conducted at the Lucrecia Paim Maternity Hospital (Luanda, Angola), which aims to determine pregnancy complications in SCD women, especially those responsible for maternal death, and, by supporting the obstetric consultations in this hospital, contribute to the reduction of mortality and morbidity rates. Methods: Pregnancy monitoring includes analysis of clinical history and incidents (number of hospitalizations, blood transfusions, strokes, and other clinical complications), hematological and biochemical analysis, transcranial Doppler to assess cerebral hemodynamics and genetic analysis (confirmation of the diagnosis, genotyping of four SNPs in the β-cluster to assess the haplotype, and evaluation of the presence of the 3.7kb deletion of the α-globin gene). Results: To date, 61 women are being followed in the obstetric consultations, with ages from 18 to 40 years old (mean 26.1±5.4). There are no records of previous strokes, although 83.9% of the patients have been previously transfused (47 out of 56), 98.2% have been hospitalized (55 out of 56) due to SCD complications and 19.6% (10 out of 54) had at least one miscarriage. At the first appointment, total hemoglobin values ranged from 4.70 to 10.40 g/dL (n=52, mean 7.18±1.30), erythrocytes from 1.46 to 5.42 x1012/L (n=52, mean 2.46±0,72), white blood cells count from 1.67 to 61.88 x109/L (n=51, mean 12.20±8.69), platelets from 24.2 to 710.0 x109/L (n=52, mean 272.2±155.9), and lactate dehydrogenase (LDH) from 263.3 to 2836.7 (n=50, mean 708.1±450.46). The CAR/CAR haplotype, which is usually associated with a more severe prognosis, is the most prevalent in this population (57.7%, 30 out of 52), followed by the CAR/SEN haplotype (25.0%, 13 out of 52). In this population, 17.3% (9 out of 52) are homozygous for the 3.7kb α-thalassemia deletion and 44.2% (23 out of 52) are carriers. This deletion influences hematological and clinical aspects of sickle cell disease patients, resulting in less severe phenotypes. TCD time-averaged mean of the maximum velocity (TAMMx) at the middle cerebral arteries ranged between 41 to 132 cm/s (n=61, mean 84cm/s), and peak systolic velocity (PSV) from 61 to 180 cm/s (mean 129 cm/s). At the basilar artery level, TAMMx obtained were between 29 to 102 cm/s (n=60, mean 52 cm/s) and PSV ranged from 43 to 141 cm/s (mean 78 cm/s). Summary - Conclusion: The main goal of this project is to study pregnancy-related complications and outcomes by giving support to an Angolan cohort of SCD pregnant women. We also intend to obtain TCD reference values of cerebral blood flow velocities in pregnant women with SCD as a risk predictor of vascular events as there are no values in the literature for this specific population.