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Chronic obstructive pulmonary disease (COPD) is a major public health problem in the Americas (a region of the world comprising North, Central, and South America), though there is substantial variation in disease prevalence, morbidity and mortality between and within nations. Across the Americas, COPD disproportionately affects vulnerable populations including minoritized populations and impoverished persons, who are more likely to be exposed to risk factors such as tobacco use, air pollution, infections such as tuberculosis, and biomass smoke but less likely to have adequate healthcare access. Management of COPD can be challenging across the Americas, with some barriers being specific to certain countries and others shared across the U.S., Canada, and Latin America. Because most cases of COPD are undiagnosed due to suboptimal access to healthcare and pulmonary function testing, and thus cannot be treated, increased access to spirometry would have a substantial impact on disease management across the Americas. For individuals who are diagnosed, access to medications and other interventions is quite variable across and within nations, even in those with universal healthcare systems, such as Canada and Brazil. This emphasizes the importance of collaborative treatment guidelines, which should be adapted for the healthcare systems and policies of each nation or region, as appropriate. To have a positive impact on COPD management in the Americas, we propose actionable items, including the need for all our respiratory societies to engage key stakeholders (e.g., patient-led organizations, professional societies, and governmental and non-governmental agencies) while advocating for campaigns and policies to ensure clean air for all, eliminate tobacco use and enhance coverage for treatment of nicotine dependence, and improve access to early case-finding, diagnosis and treatment for all patients, including underserved and vulnerable populations.
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BACKGROUND: Knowledge of the frequency of rare SERPINA1 mutations could help in the management of alpha1 antitrypsin deficiency (AATD). The present study aims to assess the frequencies of rare and null alleles and their respiratory and hepatic pathogenicity. METHODS: This is a secondary analysis of a study that evaluated the viability of the Progenika diagnostic genotyping system in six different countries by analyzing 30,827 samples from cases of suspected AATD. Allele-specific genotyping was carried out with the Progenika A1AT Genotyping Test which analyses 14 mutations in buccal swabs or dried blood spots samples. SERPINA1 gene sequencing was performed for serum AAT-genotype discrepancies or by request of the clinician. Only cases with rare mutations were included in this analysis. RESULTS: There were 818 cases (2.6%) carrying a rare allele, excluding newly identified mutations. All were heterozygous except for 20 that were homozygous. The most frequent alleles were the M-like alleles, PI*Mmalton and PI*Mheerlen. Of the 14 mutations included in the Progenika panel, there were no cases detected of PI*Siiyama, PI*Q0granite falls and PI*Q0west. Other alleles not included in the 14-mutation panel and identified by gene sequencing included PI*Mwürzburg, PI*Zbristol, and PI*Zwrexham, and the null alleles PI*Q0porto, PI*Q0madrid, PI*Q0brescia, and PI*Q0kayseri. CONCLUSIONS: The Progenika diagnostic network has allowed the identification of several rare alleles, some unexpected and not included in the initial diagnostic panel. This establishes a new perspective on the distribution of these alleles in different countries. These findings may help prioritize allele selection for routine testing and highlights the need for further research into their pathogenetic role.
Assuntos
Deficiência de alfa 1-Antitripsina , alfa 1-Antitripsina , Humanos , Alelos , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/genética , Genótipo , Mutação , HeterozigotoRESUMO
INTRODUCTION: Currently, strategies for improving alpha1 antitrypsin deficiency (AATD) diagnosis are needed. Here we report the performance of a multinational multiplex-based genotyping test on dried blood spots and buccal swabs sent by post or courier and with web registration for subjects with suspected AATD in Argentina, Brazil, Chile, Colombia, Spain, and Turkey. METHODS: This was an observational, cross-sectional analysis of samples from patients with suspected AATD from March 2018 to January 2022. Samples were coded on a web platform and sent by post or courier to the central laboratory in Northern Spain. Allele-specific genotyping for the 14 most common mutations was carried out with the A1AT Genotyping Test (Progenika-Grifols, Spain). SERPINA1 gene sequencing was performed if none of the mutations were found or one variant was detected in heterozygous status and the AAT serum level was < 60 mg/dl, or if requested by the clinician in charge. RESULTS: The study included 30,827 samples: 30,458 (94.7%) with final results after direct genotyping and 369 (1.1%) with additional gene sequencing. Only 0.3% of the samples were not processed due to their poor quality. The prevalence of the most frequent allele combinations was MS 14.7%, MZ 8.6%, SS 1.9%, SZ 1.9%, and ZZ 0.9%. Additionally, 70 cases with new mutations were identified. Family screening was conducted in 2.5% of the samples. Samples from patients with respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also presented AATD mutations. CONCLUSIONS: Our results confirm the viability of this diagnostic system for genotyping AATD conducted simultaneously in different countries. The system has proved satisfactory and can improve the timely diagnosis of AATD.
Assuntos
Doença Pulmonar Obstrutiva Crônica , Deficiência de alfa 1-Antitripsina , Alelos , Estudos Transversais , Estudos de Viabilidade , Genótipo , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/epidemiologia , Deficiência de alfa 1-Antitripsina/genéticaRESUMO
This document on COPD from the Latin American Chest Association (ALAT-2019) uses PICO methodology to analyze new evidence on inhaled medication and answer clinical questions. The following key points emerged from this analysis: 1) evidence is lacking on the comparison of short-acting vs. long-acting bronchodilators in patients with mild COPD; patients with moderate-to-severe COPD obtain greater benefit from long-acting bronchodilators; 2) the benefits of monotherapy with long-acting antimuscarinic agents (LAMA) and combined therapy with long-acting ß2-agonists and inhaled corticosteroids (LABA/ICS) are similar, although the latter is associated with a greater risk of pneumonia; 3) LABA/LAMA offer greater benefits in terms of lung function and risk of exacerbation than LABA/ICS (the latter involve an increased risk of pneumonia), 4) LAMA/LABA/ICS have greater therapeutic benefits than LABA/LAMA on the risk of moderate-severe exacerbations. With regard to the role of eosinophils in guiding the use of ICS, ICS withdrawal must be considered when the initial indication was wrong or no response is elicited, in patients with side effects such as pneumonia, and in patients with a low risk of exacerbation and an eosinophil blood count of <300 cells/µl. All this evidence, categorized according to the severity of the obstruction, symptoms, and risk of exacerbations, has been used to generate an algorithm for the use of inhaled medication in COPD.
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Agonistas de Receptores Adrenérgicos beta 2 , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Humanos , América Latina , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológicoRESUMO
Recent studies suggest that neoadjuvant chemoradiation can downstage locally advanced pancreatic tumors. There is limited evaluable data to support this approach. We review our experience with preoperative chemoradiation for surgically staged, locally advanced pancreatic cancer to determine whether patients are downstaged with multimodal therapy allowing for curative resection. A prospectively collected database from Memorial Sloan-Kettering Cancer Center was reviewed. Patients admitted between January 1993 and March 1999 with locally advanced pancreatic adenocarcinoma were identified (N = 163). Chemoradiation was administered to 87 (53.3%) of 163, and regimens varied from standard 5-fluorouracil/gemcitabine-based therapies to experimental protocols. Only three patients (3/87; 3.4%) had a sufficient clinical response on restaging to warrant reexploration. Of these, two thirds were unresectable on subsequent laparoscopy because of extensive vascular involvement or metastatic disease. Only one patient underwent a potentially curative resection, with a survival of 18 months despite negative margins and no nodal involvement. The overall median survival for all patients with locally advanced disease treated with chemoradiation was 11 months (6.5 months without multimodal therapy; P = 0.004). Although chemoradiation is associated with improved overall survival in locally advanced disease, it rarely leads to surgical "downstaging" allowing for potentially curative pancreatic resections. Novel multimodality approaches are required.