Therapeutic Advances in Respiratory Disease最新文献

Background: Research into safe and effective treatments for alpha-1 antitrypsin deficiency (AATD) has been ongoing for more than four decades. There is still a high medical need for better treatment options: Safe, effective, and convenient therapies that target both the lungs and other AATD organ manifestations are eagerly awaited by patients.

Objectives: The purpose of this study is to provide a quantitative clinical-regulatory insight into the current status of the Food and Drug Administration (FDA) and European Medicines Agency (EMA) orphan drug approvals and designations for compounds intended to treat AATD.

Design: A cross-sectional approach was applied, involving a one-time comprehensive search of relevant databases.

Methods: The primary endpoint of this study was to determine the number and nature of FDA and EMA-approved orphan drugs. The secondary endpoint was the registration of compounds with orphan drug designation status. All database searches were performed since the inception of the FDA database in 1983 and the EMA database in 2000, as well as for all compounds listed in the FDA and EMA drug label databases up to 20 January 2025. The search terms 'antitrypsin' and 'proteinase' were used.

Results: In 1987, the FDA approved the first human alpha1-proteinase inhibitor, representing the only approved active substance (5%) out of 20 with orphan drug designation in the FDA for the treatment of AATD. Conversely, the EMA has granted orphan drug designation to nine active substances, though none of these have yet been approved. However, there are several new active substances that have been granted orphan drug designation: oral neutrophil elastase inhibitor (FDA 2021, EMA 2025), IgG4 Fc-bound recombinant human AAT (FDA 2022), HSV vector therapy (FDA 2023), and A1AT modulator/protein folding stabiliser (FDA 2023, EMA 2024). Furthermore, the development of RNA interference therapeutics has progressed in the United States and Europe.

Conclusion: The development of new therapies may offer expanded treatment options for patients with AATD in the future. In addition to pulmonary manifestations, extrapulmonary manifestations could also be treated in the future.

Corynebacterium jeikeium is an uncommon but increasingly recognized cause of invasive infection, usually affecting immunocompromised patients. Empyema due to C. jeikeium has not been previously reported in an immunocompetent adult. We describe the first case and review the existing literature on non-diphtherial Corynebacterium-related empyema to highlight diagnostic and therapeutic challenges. A 26-year-old previously healthy man presented with 5 days of pleuritic chest pain, fever, and productive cough. Chest computed tomography revealed a large, loculated left pleural effusion with an air-fluid level. Initial thoracentesis yielded frank pus, confirming empyema, but the patient declined immediate drainage and was started on intravenous cefoperazone/sulbactam and moxifloxacin. His condition worsened, prompting repeat thoracentesis and catheter drainage. Culture of pleural fluid grew C. jeikeium, leading to a switch to intravenous vancomycin and meropenem. The patient improved rapidly, with defervescence, normalization of inflammatory markers, and complete radiographic resolution. He remained well at the 3-month follow-up. A literature review identified only four previous cases of non-diphtherial Corynebacterium-related empyema, all in patients with significant comorbidities. This case demonstrates that C. jeikeium can cause empyema even in immunocompetent hosts. Early microbiological diagnosis, timely pleural drainage, and appropriate antimicrobial therapy, particularly vancomycin, are critical for successful outcomes. Increased awareness and case reporting will help refine management strategies for this rare but clinically relevant pathogen.

Background: Subglottic cysts (SGCs) are a rare disease with a high misdiagnosis rate.

Objectives: We aim to improve the diagnostic and management ability of pediatricians for SGCs by analyzing the clinical characteristics of confirmed cases.

Design: Observational, retrospective cohort studyMethods:We enrolled children diagnosed with SGCs admitted to the Children's Hospital of Chongqing Medical University between January 2010 and December 2022. Clinical characteristics data were collected and analyzed retrospectively. Patients were regularly followed up for 1 year post-treatment or discharge.

Results: Eleven children were included in this retrospective study. There were nine (9/11, 81.8%) males and two (2/11, 18.2%) females, and the median age was 15 months. Eight (72.7%) were premature. Seven (63.6%) patients had a history of intubation. The common manifestations were stridor (72.7%), wet cough (72.7%), shortness of breath (72.7%), and dyspnea (54.5%). The average diagnosis time was 7 months. The most common comorbidity was laryngopharyngeal reflux disease (LPRD, 45.5%), followed by laryngomalacia (27.3%), bronchopulmonary dysplasia (27.3%), bronchial stenosis (18.2%), and adenoid hypertrophy ( 18.2%). The obstruction degree of SGCs was "3" (51%-75% occlusion) or higher in eight (72.7%) patients. Two (18.2%) patients experienced recurrence after initial cyst aspiration and subsequently underwent successful laryngoscopy marsupialization. Ultimately, eight (72.7%) patients achieved complete recovery after endoscopic marsupialization.

Conclusion: SGCs should be considered in the differential diagnosis of children, especially those with a history of prematurity and/or perinatal intubation, who present with stridor, wet cough, and respiratory distress. Endoscopic evaluation is crucial for both definitive diagnosis and guiding effective treatment.

The population of adults with cystic fibrosis (CF) exceeds that of the pediatric CF population, and life expectancy for people with CF (PwCF) continues to improve, resulting in an adult CF population with chronic extrapulmonary comorbid conditions, including CF-related diabetes (CFRD), a common complication affecting roughly 50% of PwCF, as well as mental health disorders, including depression and generalized anxiety. These comorbidities have been strongly associated with increased risk of progressive lung disease, impaired quality of life, and increased risk of acute exacerbations requiring healthcare utilization. These risks disproportionately affect PwCF who are from ethnic minorities and are often genetically ineligible for novel treatments. Social determinants of health (SDOH) are related to and contribute to health disparities in PwCF. To reduce the impact of SDOH on health-related disparities in this population, PwCF needs greater awareness of associated factors to develop interventions that can improve care. This narrative review critically synthesizes the available literature on the complex intersections of social determinants of health, mental health, and concomitant CFRD that affect health outcomes for PwCF.

Background: Chronic obstructive pulmonary disease (COPD) is a leading global health burden, with high prevalence of comorbidities (e.g., hypertension and diabetes) that further increase healthcare utilization and mortality. Integrated care is proposed as a potential management strategy for COPD patients with comorbidities, but its overall effects remain unclear due to inconsistent evidence from prior studies.

Objectives: To systematically evaluate the effects of integrated care on key health outcomes in patients with COPD and at least one comorbidity.

Design: Systematic review and meta-analysis.

Data sources and methods: Databases including MEDLINE, EMBASE, CENTRAL, CINAHL, and ClinicalTrial.gov were searched. Eligible studies were randomized controlled trials (RCTs) evaluating integrated care in patients with COPD and comorbidities. Two independent reviewers conducted study screening, data extraction, and quality assessment. Effects of integrated care were assessed using a random-effects model.

Results: Seven RCTs from high-income countries were included. Common integrated care components were health education, self-management support, and (in two studies) telemonitoring. Meta-analysis showed that integrated care significantly reduced the number of COPD exacerbations and all-cause hospitalizations. No significant effects were observed for all-cause emergency visits or CAT scores.

Conclusion: Integrated care effectively reduces COPD exacerbations and all-cause hospitalizations in patients with COPD and comorbidities, supporting its clinical value. However, high heterogeneity across studies, limited generalizability to non-high-income countries (e.g., China), and lack of impact on patient-reported outcomes (CAT scores) highlight the need for further localized research.

Trial registration: Registered with PROSPERO, Registration ID: CRD420251170533.

Background: Therapeutic advancements utilizing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) have revolutionized the treatment of people with cystic fibrosis (pwCF). Elexacaftor-Tezacaftor-Ivacaftor (ETI) is a highly effective modulator therapy and has been shown to improve health outcomes in people with CF (PwCF). Due to these therapeutic advancements, many pwCF are getting older, but little is known regarding the safety and efficacy of ETI in pwCF at a more advanced age.

Objectives: We aimed to determine the effect of ETI on clinical outcomes in older pwCF.

Design: This study was a single-center, retrospective analysis of pwCF who received open-label ETI following FDA approval and were over the age of 40 at the time of ETI initiation.

Methods: Data were obtained from the electronic medical record from a large CF center in the United States of America between November 2019 and January 2021, including body mass index (BMI), lung function as % predicted FEV₁ before ETI initiation, and approximately 3 months and one a follow-up visit within 9-15 months post-ETI initiation. The exacerbation frequency over 12 months was recorded before and after ETI initiation.

Results: Forty-two patients met the inclusion criteria. Mean age at time of ETI initiation was 47.9, 23 patients (54.8%) were male, and 11 (26.2%) were homozygous for the F508del mutation. Linear mixed effects models suggest a monthly increase of 0.24 (95% CI 0.08-0.41, p = 0.003) for ppFEV1 and 0.03 (95% CI 0.002-0.06, p = 0.036) for BMI post-ETI, resulting in a 2.96 (95% CI 0.98-4.95) increase in ppFEV1 and 0.39 (95% CI 0.03-0.76) increase in BMI approximately 1-year post-ETI. In addition, a significant decline in pulmonary exacerbations was seen in the year following ETI initiation (1.5 ± 1.3 exacerbations/year prior vs 0.5 ± 0.7 exacerbations/year post; p < 0.0001).

Conclusion: Treatment with ETI in this unique cohort of pwCF was safe. Whereas ETI affected BMI in a subtle way, initiation of ETI was associated with stabilization of lung disease with a significant but moderate increase in lung function and a decline in the number of exacerbations in the follow-up period. Longer and larger studies will be needed to analyze the effect of ETI on an aging CF population.

Background: It has been shown that asthma is potentially linked to a higher risk of cardiovascular disease (CVD) and cardiovascular mortality (CVM).

Objectives: This study aims to systematically review and summarize epidemiological evidence on the relationship between asthma and these cardiovascular outcomes.

Design: Systematic review and meta-analysis.

Data sources and methods: This meta-analysis, registered with PROSPERO (CRD 42024576126), utilized data from PubMed, Embase, the Cochrane Library, and references from included studies. The search covered literature from the inception of these databases until July 17, 2024. We included observational studies examining the link between asthma and CVD and CVM. Bias risk was evaluated using the Newcastle-Ottawa Quality Assessment Scale (NOS). We calculated pooled relative risk (RR) with a 95% confidence interval (CI) using a random-effects model.

Results: A total of 29 studies encompassing 11,380,027 participants were included. The overall risk for CVD in asthma patients was 1.30 (95% CI: 1.20-1.42). Specific CVD risks were elevated for coronary heart disease (CHD, RR 1.35; 95% CI: 1.27-1.42), angina pectoris (AP, RR 1.48; 95% CI: 1.16-1.89), myocardial infarction (MI, RR 1.33; 95% CI: 1.25-1.41), and heart failure (HF, RR 1.53; 95% CI: 1.04-2.23). Asthma was also associated with a higher risk of CVM (RR 1.26; 95% CI: 1.05-1.51).

Conclusion: Asthma is associated with a higher risk of developing CVD, including specific types such as CHD, AP, MI, and HF. In addition, asthma patients face an increased risk of cardiovascular mortality compared to non-asthmatics.

Background: The role of preoperative conditioning on postoperative outcomes in thoracic surgery is of growing interest. There is a paucity of data on understanding compliance with a patient-led walking program and its impact on quality of life.

Objectives: To understand the feasibility of patient-driven data collection of daily steps via pedometers and to understand the impact of preoperative conditioning on quality of life.

Design: A prospective single-institution quality improvement study.

Methods: The study included patients who underwent thoracic surgery between 2020 and 2022 who were and were selected to receive a pedometer at their preoperative clinic appointment. A daily step goal was determined, and patients were instructed to record their daily steps. Quality of life was assessed at baseline and at presentation for surgery. Clinical data and postoperative outcomes were derived from the institutional Society of Thoracic Surgery General Thoracic Surgery Database.

Results: There were 167 patients provided with pedometers at their presurgical clinic appointment, of whom 43 returned pedometer data (utilization rate 26%). Of the 104 who underwent lung resection, 74 (44.3%) did not record step data, 15 had <6000 median daily steps, and 15 had >6000 median daily steps. Pre-intervention self-perceived outcomes were similar. Post-pedometer data demonstrated higher scores in the domains of general health (p = 0.016), quality of life (p = 0.03), general physical health (p = 0.002), physical performance (p = 0.03), social health (p = 0.009), social performance (p=0.01), and fatigue level (p = 0.01) for patients with higher median step counts. There were no significant differences in postoperative outcomes based on survival, length of stay (p = 0.77), or respiratory complications (p = 0.52).

Conclusion: A patient-led walking program using pedometers is feasible for a minority of patients. Higher recorded daily step counts are associated with improved self-perceived quality of life in patients prior to lung surgery.

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous lung condition characterised by chronic respiratory symptoms, fixed airway obstruction and persistent inflammation that leads to a progressive airflow limitation. Although COPD has traditionally been linked to neutrophilic inflammation, recent studies have identified a subset of patients - approximately 20%-40% - with elevated eosinophil levels in blood and sputum. Emerging evidence suggests that eosinophilic inflammation has a pivotal role in a subset of COPD patients and may influence disease progression, exacerbation frequency and therapeutic responses. This narrative review provides a comprehensive analysis of the role of eosinophils in COPD with particular attention to their role as biomarkers in blood and sputum. We evaluate the prevalence of eosinophilic inflammation in COPD exanimating different thresholds used in blood and in sputum to define it. In addition, we focus on eosinophilic COPD phenotype as a treatable trait, emphasising recent evidence that supports the effectiveness of biological target therapy.