Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations.

BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterised by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, forced expiratory volume in 1 s (FEV1)) were collected from 19 countries using the European Reference Network's ERN-LUNG international PCD Registry. Genetic data were evaluated according to American College of Medical Genetics and Genomics guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. RESULTS: The study included 1236 individuals carrying 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%, range 47-100%) and laterality defects (mean 42%, range 28-69%) varied widely among countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). Median FEV1 z-scores were significantly lower in CCNO (-3.26), CCDC39 (-2.49) and CCDC40 (-2.96) variant groups, while the FEV1 z-score reductions were significantly milder in DNAH11 (-0.83) and ODAD1 (-0.85) variant groups compared to the whole PCD cohort. CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of the genetic epidemiology of PCD and indicates that the genetic variant can predict diagnostic and phenotypic features such as the course of lung function.

Rate of severe exacerbations, healthcare resource utilisation and clinical outcomes in patients with COPD in low-income and middle-income countries: results from the EXACOS International Study.

INTRODUCTION: The EXAcerbations of Chronic obstructive lung disease (COPD) and their OutcomeS (EXACOS) International Study aimed to quantify the rate of severe exacerbations and examine healthcare resource utilisation (HCRU) and clinical outcomes in patients with COPD from low-income and middle-income countries. METHODS: EXACOS International was an observational, cross-sectional study with retrospective data collection from medical records for a period of up to 5 years. Data were collected from 12 countries: Argentina, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Guatemala, Hong Kong, Mexico, Panama, Russia and Taiwan. The study population comprised patients ≥40 years of age with COPD. Outcomes/variables included the prevalence of severe exacerbations, the annual rate of severe exacerbations and time between severe exacerbations; change in lung function over time (measured by the forced expiratory volume in 1 s (FEV1)); peripheral blood eosinophil counts (BECs) and the prevalence of comorbidities; treatment patterns; and HCRU. RESULTS: In total, 1702 patients were included in the study. The study population had a mean age of 69.7 years, with 69.4% males, and a mean body mass index of 26.4 kg/m2. The mean annual prevalence of severe exacerbations was 20.1%, and 48.4% of patients experienced ≥1 severe exacerbation during the 5-year study period. As the number of severe exacerbations increased, the interval between successive exacerbations decreased. A statistically significant decrease in mean (SD) FEV1 from baseline to post-baseline was observed in patients with ≥1 severe exacerbation (1.23 (0.51) to 1.13 (0.52) L; p=0.0000). Mean BEC was 0.198 x109 cells/L, with 64.7% of patients having a BEC ≥0.1 x109 cells/L and 21.3% having a BEC ≥0.3 x109 cells/L. The most common comorbidity was hypertension (58.3%). An increasing number of severe exacerbations per year was associated with greater HCRU. DISCUSSION: The findings presented here indicate that effective treatment strategies to prevent severe exacerbations in patients with COPD remain a significant unmet need in low-income and middle-income countries.

A BEAT-PCD consensus statement: a core outcome set for pulmonary disease interventions in primary ciliary dyskinesia.

Background: Consistent use of reliable and clinically appropriate outcome measures is a priority for clinical trials, with clear definitions to allow comparability. We aimed to develop a core outcome set (COS) for pulmonary disease interventions in primary ciliary dyskinesia (PCD). Methods: A multidisciplinary international PCD expert panel was set up. A list of outcomes was created based on published literature. Using a modified three-round e-Delphi technique, the panel was asked to decide on relevant end-points related to pulmonary disease interventions and how they should be reported. First, inclusion of an outcome in the COS was determined. Second, the minimum information that should be reported per outcome. The third round finalised statements. Consensus was defined as ≥80% agreement among experts. Results: During the first round, experts reached consensus on four out of 24 outcomes to be included in the COS. Five additional outcomes were discussed in subsequent rounds for their use in different subsettings. Consensus on standardised methods of reporting for the COS was reached. Spirometry, health-related quality-of-life scores, microbiology and exacerbations were included in the final COS. Conclusion: This expert consensus resulted in a COS for clinical trials on pulmonary health among people with PCD.

Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of treatment with the combination of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators-elexacaftor+tezacaftor+ivacaftor (ETI)-on important clinical endpoints in individuals with cystic fibrosis. METHODS: This was a systematic review and meta-analysis of randomized clinical trials that compared the use of ETI in individuals with CF and at least one F508del allele with that of placebo or with an active comparator such as other combinations of CFTR modulators, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) methodology. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We retrieved 54 studies in the primary search. Of these, 6 met the inclusion criteria and were analyzed (1,127 patients; 577 and 550 in the intervention and control groups, respectively). The meta-analysis revealed that the use of ETI increased FEV1% [risk difference (RD), +10.47%; 95% CI, 6.88-14.06], reduced the number of acute pulmonary exacerbations (RD, -0.16; 95% CI, -0.28 to -0.04), and improved quality of life (RD, +14.93; 95% CI, 9.98-19.89) and BMI (RD, +1.07 kg/m2; 95% CI, 0.90-1.25). Adverse events did not differ between groups (RD, -0.03; 95% CI, -0.08 to 0.01), and none of the studies reported deaths. CONCLUSIONS: Our findings demonstrate that ETI treatment substantially improves clinically significant, patient-centered outcomes.

Outcomes of Endoscopic Sinus Surgery for Chronic Rhinosinusitis in Adults with Primary Ciliary Dyskinesia

Abstract Introduction Primary ciliary dyskinesia (PCD) is a rare inherited disease associated with impairment of mucociliary transport and, consequently, with a high incidence of chronic rhinosinusitis. For patients with chronic rhinosinusitis who remain symptomatic despite medical treatment, endoscopic sinus surgery is a safe and effective therapeutic option. However, to date, no studies have been found evaluating the effect of surgery on the quality of life associated with the effect on olfaction and nasal endoscopy findings of patients with primary ciliary dyskinesia and chronic rhinosinusitis. Objective To describe the effect of endoscopic sinus surgery on the quality of life, on olfaction, and on nasal endoscopy findings of adults with PCD and chronic rhinosinusitis. Methods Four patients who underwent endoscopic sinus surgery were included. The Sinonasal Outcome Test-22 (SNOT-22) score, the Nasal Obstruction Symptom Evaluation (NOSE) questionnaire, and the Lund-Kennedy score were collected preoperatively and at 3 and 6 months postoperatively. The olfaction as assessed with the University of Pennsylvania Smell Identification Test (UPSIT), which was administered preoperatively and 3 months postoperatively. Results A total of 4 patients with a mean age of 39.3 years old (3 men and 1 woman) completed the study. All patients showed clinically significant improvement in the SNOT-22, NOSE, and Lund-Kennedy scores at 3 months postoperatively, and this improvement was sustained throughout the follow-up period. However, olfaction did not improve after surgery. Conclusion The endoscopic sinus surgery treatment of chronic rhinosinusitis in adults with PCD was associated with improvement in quality of life and endoscopic findings. However, no improvement in olfaction was demonstrated. Studies with a larger number of patients and control groups should help confirm these findings.

Outcomes of Endoscopic Sinus Surgery for Chronic Rhinosinusitis in Adults with Primary Ciliary Dyskinesia.

Introduction Primary ciliary dyskinesia (PCD) is a rare inherited disease associated with impairment of mucociliary transport and, consequently, with a high incidence of chronic rhinosinusitis. For patients with chronic rhinosinusitis who remain symptomatic despite medical treatment, endoscopic sinus surgery is a safe and effective therapeutic option. However, to date, no studies have been found evaluating the effect of surgery on the quality of life associated with the effect on olfaction and nasal endoscopy findings of patients with primary ciliary dyskinesia and chronic rhinosinusitis. Objective To describe the effect of endoscopic sinus surgery on the quality of life, on olfaction, and on nasal endoscopy findings of adults with PCD and chronic rhinosinusitis. Methods Four patients who underwent endoscopic sinus surgery were included. The Sinonasal Outcome Test-22 (SNOT-22) score, the Nasal Obstruction Symptom Evaluation (NOSE) questionnaire, and the Lund-Kennedy score were collected preoperatively and at 3 and 6 months postoperatively. The olfaction as assessed with the University of Pennsylvania Smell Identification Test (UPSIT), which was administered preoperatively and 3 months postoperatively. Results A total of 4 patients with a mean age of 39.3 years old (3 men and 1 woman) completed the study. All patients showed clinically significant improvement in the SNOT-22, NOSE, and Lund-Kennedy scores at 3 months postoperatively, and this improvement was sustained throughout the follow-up period. However, olfaction did not improve after surgery. Conclusion The endoscopic sinus surgery treatment of chronic rhinosinusitis in adults with PCD was associated with improvement in quality of life and endoscopic findings. However, no improvement in olfaction was demonstrated. Studies with a larger number of patients and control groups should help confirm these findings.

Brazilian guidelines for the pharmacological treatment of the pulmonary symptoms of cystic fibrosis. Official document of the Sociedade Brasileira de Pneumologia e Tisiologia (SBPT, Brazilian Thoracic Association).

Cystic fibrosis (CF) is a genetic disease that results in dysfunction of the CF transmembrane conductance regulator (CFTR) protein, which is a chloride and bicarbonate channel expressed in the apical portion of epithelial cells of various organs. Dysfunction of that protein results in diverse clinical manifestations, primarily involving the respiratory and gastrointestinal systems, impairing quality of life and reducing life expectancy. Although CF is still an incurable pathology, the therapeutic and prognostic perspectives are now totally different and much more favorable. The purpose of these guidelines is to define evidence-based recommendations regarding the use of pharmacological agents in the treatment of the pulmonary symptoms of CF in Brazil. Questions in the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) format were employed to address aspects related to the use of modulators of this protein (ivacaftor, lumacaftor+ivacaftor, and tezacaftor+ivacaftor), use of dornase alfa, eradication therapy and chronic suppression of Pseudomonas aeruginosa, and eradication of methicillin-resistant Staphylococcus aureus and Burkholderia cepacia complex. To formulate the PICO questions, a group of Brazilian specialists was assembled and a systematic review was carried out on the themes, with meta-analysis when applicable. The results obtained were analyzed in terms of the strength of the evidence compiled, the recommendations being devised by employing the GRADE approach. We believe that these guidelines represent a major advance to be incorporated into the approach to patients with CF, mainly aiming to favor the management of the disease, and could become an auxiliary tool in the definition of public policies related to CF.

Brazilian guidelines for the pharmacological treatment of the pulmonary symptoms of cystic fibrosis. Official document of the Sociedade Brasileira de Pneumologia e Tisiologia (SBPT, Brazilian Thoracic Association)

A fibrose cística (FC) é uma doença genética que resulta em disfunção da proteína reguladora de condutância transmembrana da FC (CFTR), que é um canal de cloro e bicarbonato expresso na porção apical de células epiteliais de diversos órgãos. A disfunção dessa proteína resulta em manifestações clínicas diversas, envolvendo primariamente os sistemas respiratório e gastrointestinal com redução da qualidade e expectativa de vida. A FC ainda é uma patologia incurável, porém o horizonte terapêutico e prognóstico é hoje totalmente distinto e muito mais favorável. O objetivo destas diretrizes foi definir recomendações brasileiras baseadas em evidências em relação ao emprego de agentes farmacológicos no tratamento pulmonar da FC. As perguntas PICO (acrônimo baseado em perguntas referentes aos Pacientes de interesse, Intervenção a ser estudada, Comparação da intervenção e Outcome [desfecho] de interesse) abordaram aspectos relativos ao uso de moduladores de CFTR (ivacaftor, lumacaftor + ivacaftor e tezacaftor + ivacaftor), uso de dornase alfa, terapia de erradicação e supressão crônica de Pseudomonas aeruginosa, e erradicação de Staphylococcus aureus resistente a meticilina e do complexo Burkholderia cepacia. Para a formulação das perguntas, um grupo de especialistas brasileiros foi reunido e realizou-se uma revisão sistemática sobre os temas, com meta-análise quando aplicável. Os resultados encontrados foram analisados quanto à força das evidências compiladas, sendo concebidas recomendações seguindo a metodologia GRADE. Os autores acreditam que o presente documento represente um importante avanço a ser incorporado na abordagem de pacientes com FC, objetivando principalmente favorecer seu manejo, podendo se tornar uma ferramenta auxiliar na definição de políticas públicas relacionadas à FC.

Cystic fibrosis (CF) is a genetic disease that results in dysfunction of the CF transmembrane conductance regulator (CFTR) protein, which is a chloride and bicarbonate channel expressed in the apical portion of epithelial cells of various organs. Dysfunction of that protein results in diverse clinical manifestations, primarily involving the respiratory and gastrointestinal systems, impairing quality of life and reducing life expectancy. Although CF is still an incurable pathology, the therapeutic and prognostic perspectives are now totally different and much more favorable. The purpose of these guidelines is to define evidence-based recommendations regarding the use of pharmacological agents in the treatment of the pulmonary symptoms of CF in Brazil. Questions in the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) format were employed to address aspects related to the use of modulators of this protein (ivacaftor, lumacaftor+ivacaftor, and tezacaftor+ivacaftor), use of dornase alfa, eradication therapy and chronic suppression of Pseudomonas aeruginosa, and eradication of methicillin-resistant Staphylococcus aureus and Burkholderia cepacia complex. To formulate the PICO questions, a group of Brazilian specialists was assembled and a systematic review was carried out on the themes, with meta-analysis when applicable. The results obtained were analyzed in terms of the strength of the evidence compiled, the recommendations being devised by employing the GRADE approach. We believe that these guidelines represent a major advance to be incorporated into the approach to patients with CF, mainly aiming to favor the management of the disease, and could become an auxiliary tool in the definition of public policies related to CF.

Computed Tomography Evaluation of the Paranasal Sinuses in Adults with Primary Ciliary Dyskinesia

Abstract Introduction Primary ciliary dyskinesia is a rare inherited disease that results in a malfunction of mucociliary clearance and sinonasal complaints. Aplasia/hypoplasia of the frontal and sphenoid sinuses has been described as more frequent in this population. However, to date, no studies have provided a detailed description of computed tomography findings in adult patients with a diagnosis of this condition. Objective To describe the computed tomography (CT) findings of adult patients with primary ciliary dyskinesia. Methods Retrospective observational study of adult patients with primary ciliary dyskinesia who underwent CT. Results Twenty-one adults were included in the study. Aplasia occurred in 38.1% of frontal sinuses and in 14.3% of sphenoid sinuses. Likewise, hypoplasia occurred in 47.6% of the frontal sinuses, in 54.8% of the sphenoid sinuses and in 40.5% of the maxillary sinuses. Furthermore, trabecular loss was identified in 61.9% ethmoidal sinuses. The mean Lund-Mackay score was 13.5. In addition, 9.5% of the patients had concha bullosa, 47.6% had marked bilateral inferior turbinate hypertrophy, 38.1% had marked middle turbinate hypertrophy, and 47.6% had marked septal deviation. Finally, we identified images suggestive of fungus ball, mucocele, osteoma, a possible antrochoanal polyp, and frontal bone erosions. Conclusion The present study provides a detailed description of CT findings in patients with primary ciliary dyskinesia. We also describe abnormalities that must be identified for safer surgical planning and that suggest a diagnosis of primary ciliary dyskinesia if found in patients with a consistent clinical picture.

Computed Tomography Evaluation of the Paranasal Sinuses in Adults with Primary Ciliary Dyskinesia.

Introduction Primary ciliary dyskinesia is a rare inherited disease that results in a malfunction of mucociliary clearance and sinonasal complaints. Aplasia/hypoplasia of the frontal and sphenoid sinuses has been described as more frequent in this population. However, to date, no studies have provided a detailed description of computed tomography findings in adult patients with a diagnosis of this condition. Objective To describe the computed tomography (CT) findings of adult patients with primary ciliary dyskinesia. Methods Retrospective observational study of adult patients with primary ciliary dyskinesia who underwent CT. Results Twenty-one adults were included in the study. Aplasia occurred in 38.1% of frontal sinuses and in 14.3% of sphenoid sinuses. Likewise, hypoplasia occurred in 47.6% of the frontal sinuses, in 54.8% of the sphenoid sinuses and in 40.5% of the maxillary sinuses. Furthermore, trabecular loss was identified in 61.9% ethmoidal sinuses. The mean Lund-Mackay score was 13.5. In addition, 9.5% of the patients had concha bullosa, 47.6% had marked bilateral inferior turbinate hypertrophy, 38.1% had marked middle turbinate hypertrophy, and 47.6% had marked septal deviation. Finally, we identified images suggestive of fungus ball, mucocele, osteoma, a possible antrochoanal polyp, and frontal bone erosions. Conclusion The present study provides a detailed description of CT findings in patients with primary ciliary dyskinesia. We also describe abnormalities that must be identified for safer surgical planning and that suggest a diagnosis of primary ciliary dyskinesia if found in patients with a consistent clinical picture.

Brazilian guidelines for the pharmacological treatment of the pulmonary symptoms of cystic fibrosis. Official document of the Sociedade Brasileira de Pneumologia e Tisiologia (SBPT, Brazilian Thoracic Association) / Diretrizes brasileiras para o tratamento farmacológico pulmonar na fibrose cística. Documento oficial da Sociedade Brasileira de Pneumologia e Tisiologia

ABSTRACT Cystic fibrosis (CF) is a genetic disease that results in dysfunction of the CF transmembrane conductance regulator (CFTR) protein, which is a chloride and bicarbonate channel expressed in the apical portion of epithelial cells of various organs. Dysfunction of that protein results in diverse clinical manifestations, primarily involving the respiratory and gastrointestinal systems, impairing quality of life and reducing life expectancy. Although CF is still an incurable pathology, the therapeutic and prognostic perspectives are now totally different and much more favorable. The purpose of these guidelines is to define evidence-based recommendations regarding the use of pharmacological agents in the treatment of the pulmonary symptoms of CF in Brazil. Questions in the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) format were employed to address aspects related to the use of modulators of this protein (ivacaftor, lumacaftor+ivacaftor, and tezacaftor+ivacaftor), use of dornase alfa, eradication therapy and chronic suppression of Pseudomonas aeruginosa, and eradication of methicillin-resistant Staphylococcus aureus and Burkholderia cepacia complex. To formulate the PICO questions, a group of Brazilian specialists was assembled and a systematic review was carried out on the themes, with meta-analysis when applicable. The results obtained were analyzed in terms of the strength of the evidence compiled, the recommendations being devised by employing the GRADE approach. We believe that these guidelines represent a major advance to be incorporated into the approach to patients with CF, mainly aiming to favor the management of the disease, and could become an auxiliary tool in the definition of public policies related to CF.

RESUMO A fibrose cística (FC) é uma doença genética que resulta em disfunção da proteína reguladora de condutância transmembrana da FC (CFTR), que é um canal de cloro e bicarbonato expresso na porção apical de células epiteliais de diversos órgãos. A disfunção dessa proteína resulta em manifestações clínicas diversas, envolvendo primariamente os sistemas respiratório e gastrointestinal com redução da qualidade e expectativa de vida. A FC ainda é uma patologia incurável, porém o horizonte terapêutico e prognóstico é hoje totalmente distinto e muito mais favorável. O objetivo destas diretrizes foi definir recomendações brasileiras baseadas em evidências em relação ao emprego de agentes farmacológicos no tratamento pulmonar da FC. As perguntas PICO (acrônimo baseado em perguntas referentes aos Pacientes de interesse, Intervenção a ser estudada, Comparação da intervenção e Outcome [desfecho] de interesse) abordaram aspectos relativos ao uso de moduladores de CFTR (ivacaftor, lumacaftor + ivacaftor e tezacaftor + ivacaftor), uso de dornase alfa, terapia de erradicação e supressão crônica de Pseudomonas aeruginosa, e erradicação de Staphylococcus aureus resistente a meticilina e do complexo Burkholderia cepacia. Para a formulação das perguntas, um grupo de especialistas brasileiros foi reunido e realizou-se uma revisão sistemática sobre os temas, com meta-análise quando aplicável. Os resultados encontrados foram analisados quanto à força das evidências compiladas, sendo concebidas recomendações seguindo a metodologia GRADE. Os autores acreditam que o presente documento represente um importante avanço a ser incorporado na abordagem de pacientes com FC, objetivando principalmente favorecer seu manejo, podendo se tornar uma ferramenta auxiliar na definição de políticas públicas relacionadas à FC.

Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis / Uso de elexacaftor + tezacaftor + ivacaftor em indivíduos com fibrose cística com pelo menos um alelo F508del: revisão sistemática e meta-análise

ABSTRACT Objective: To evaluate the effect of treatment with the combination of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators-elexacaftor+tezacaftor+ivacaftor (ETI)-on important clinical endpoints in individuals with cystic fibrosis. Methods: This was a systematic review and meta-analysis of randomized clinical trials that compared the use of ETI in individuals with CF and at least one F508del allele with that of placebo or with an active comparator such as other combinations of CFTR modulators, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) methodology. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: We retrieved 54 studies in the primary search. Of these, 6 met the inclusion criteria and were analyzed (1,127 patients; 577 and 550 in the intervention and control groups, respectively). The meta-analysis revealed that the use of ETI increased FEV1% [risk difference (RD), +10.47%; 95% CI, 6.88-14.06], reduced the number of acute pulmonary exacerbations (RD, −0.16; 95% CI, −0.28 to −0.04), and improved quality of life (RD, +14.93; 95% CI, 9.98-19.89) and BMI (RD, +1.07 kg/m2; 95% CI, 0.90-1.25). Adverse events did not differ between groups (RD, −0.03; 95% CI, −0.08 to 0.01), and none of the studies reported deaths. Conclusions: Our findings demonstrate that ETI treatment substantially improves clinically significant, patient-centered outcomes.

RESUMO Objetivo: Avaliar o efeito do tratamento com a combinação de três moduladores da proteína cystic fibrosis transmembrane conductance regulator (CFTR, reguladora de condutância transmembrana em fibrose cística) - elexacaftor + tezacaftor + ivacaftor (ETI) - sobre desfechos clínicos importantes em indivíduos com fibrose cística. Métodos: Revisão sistemática e meta-análise de ensaios clínicos randomizados que compararam o uso de ETI em indivíduos com fibrose cística com pelo menos um alelo F508del com o uso de placebo ou de um comparador ativo como outras combinações de moduladores da CFTR. O estudo foi realizado seguindo as recomendações Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) e a metodologia Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO). Foram realizadas buscas nos seguintes bancos de dados: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials e ClinicalTrials.gov, desde a sua criação até 26 de dezembro de 2022. O risco de viés foi avaliado por meio da ferramenta de risco de viés da Cochrane, e a qualidade das evidências foi determinada com base no sistema Grading of Recommendations Assessment, Development and Evaluation (GRADE). Resultados: Foram identificados 54 estudos na busca primária. Destes, 6 preencheram os critérios de inclusão e foram analisados (1.127 pacientes: 577 pacientes intervenção e 550 pacientes controle). A meta-análise revelou que o uso de ETI aumentou o VEF1 em porcentagem do previsto [diferença de risco (DR): +10,47%; IC95%: 6,88-14,06], reduziu o número de exacerbações pulmonares agudas (DR: −0,16; IC95%: −0,28 a −0,04) e melhorou a qualidade de vida (DR: +14,93; IC95%: 9,98-19,89) e o IMC (DR: +1,07 kg/m2; IC95%: 0,90-1,25). Os eventos adversos não diferiram entre os grupos (DR: −0,03; IC95%: −0,08 a 0,01), e nenhum dos estudos relatou óbitos. Conclusões: Nossos achados demonstram que o tratamento com ETI melhora substancialmente os desfechos clinicamente significativos centrados no paciente.

Prevalence of the eosinophilic phenotype among severe asthma patients in Brazil: the BRAEOS study.

OBJECTIVE: To assess the prevalence of the eosinophilic and allergic phenotypes of severe asthma in Brazil, as well as to investigate the clinical characteristics of severe asthma patients in the country. METHODS: This was a cross-sectional study of adult patients diagnosed with severe asthma and managed at specialized centers in Brazil. The study was conducted in 2019. RESULTS: A total of 385 patients were included in the study. Of those, 154 had a blood eosinophil count > 300 cells/mm3 and 231 had a blood eosinophil count of ≤ 300 cells/mm3. The median age was 54.0 years, and most of the patients were female, with a BMI of 29.0 kg/m2 and a history of allergy (81.6%). The prevalence of patients with a blood eosinophil count > 300 cells/mm3 was 40.0% (95% CI: 35.1-44.9), and that of those with a blood eosinophil count > 300 cells/mm3 and a history of allergy was 31.9% (95% CI: 27.3-36.6). Age and BMI showed positive associations with a blood eosinophil count > 300 cells/mm3 (OR = 0.97, p < 0.0001; and OR = 0.96, p = 0.0233, respectively), whereas the time elapsed since the onset of asthma symptoms showed an increased association with a blood eosinophil count > 300 cells/mm3 (OR = 1.02, p = 0.0011). CONCLUSIONS: This study allowed us to characterize the population of severe asthma patients in Brazil, showing the prevalence of the eosinophilic phenotype (in 40% of the sample). Our results reveal the relevance of the eosinophilic phenotype of severe asthma at a national level, contributing to increased effectiveness in managing the disease and implementing public health strategies.