Therapeutic Advances in Respiratory Disease最新文献

Background: Non-idiopathic pulmonary fibrosis interstitial lung diseases (non-IPF ILDs) comprise a broad spectrum of pathologies with varying degrees of inflammation and fibrosis. Progressive fibrosing ILD is associated with significant mortality and limited treatment options. Standard regimens employ multimodal immunosuppression, most commonly prolonged courses of oral corticosteroids (OCS), that are associated with a high risk of adverse effects and limited proven efficacy.

Objectives: This study investigates the safety, tolerability, and effectiveness of monthly intravenous pulse methylprednisolone (PMP) for the treatment of patients with progressive non-IPF ILD.

Design: Retrospective single-center cohort study of patients at an academic tertiary referral center for ILD between October 2019 and September 2022.

Methods: All non-IPF ILD patients who received intravenous PMP (1000 mg daily for three consecutive days/month) between October 2019 and September 2022 were included. The decision to treat was based on a multidisciplinary consensus diagnosis following ATS/ERS/JRS/ALAT guidelines and confirmed or at high risk for ILD progression. Treatment continuation was contingent upon pulmonary function test (PFT) improvement (assessed approximately every 3 months), tolerable adverse events, and shared decision making with patients. Effectiveness was measured by a change in forced vital capacity (FVC) and diffusion limit of carbon monoxide (DLCO), with improvement being defined as an absolute increase in either FVC >5% or DLCO >10% from baseline.

Results: Thirty-three patients received PMP at our center. One patient died of an acute exacerbation of ILD. Of the 32 patients included for analysis, 17 (53%) exhibited improved lung function with PMP between PFTs, which was maintained for a median follow-up of 209 days. The regimen was generally well-tolerated, with the most common adverse effects being insomnia and restlessness on infusion days. Advanced disease, indicated by lower FVC, traction bronchiectasis, and oxygen dependence, predicted poor response.

Conclusions: PMP may offer a safer, better-tolerated, and more effective treatment for progressive non-IPF ILD than prolonged OCS. Notably, a third of fibrotic hypersensitivity pneumonitis patients showed improved FVC after 3 months of PMP, defying expectations of steroid non-responsiveness. However, further well-designed controlled prospective clinical trials are needed to confirm our findings and establish long-term safety.

Background: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease marked by airway inflammation and obstruction. Ensifentrine is a novel inhaled PDE3 and PDE4 inhibitor with both bronchodilator and anti-inflammatory effects.

Objectives: Comprehensively review the available evidence on ensifentrine and its potential role in COPD management.

Design: Systematic review and meta-analysis with trial sequential analysis of randomized clinical trials.

Data sources and methods: We systematically searched PubMed, Scopus, ScienceDirect, Cochrane Library, and Medline for clinical trials published between 2018 and August 2024 that evaluated the safety and efficacy of ensifentrine in patients with COPD. We assessed study quality using the RoB 2 tool and conducted the meta-analysis with the "meta" package in R (version 4.3.2), using the mean difference with a 95% confidence interval to evaluate changes in outcomes.

Results: Five studies met the predefined inclusion criteria with 2519 participants. At week 12, the pooled analysis indicated that forced expiratory volume in 1 s (FEV₁) and trough FEV₁ were significantly increased in the ensifentrine group (mean difference (MD): 91.32; 95% CI: 69.63 to 113.01) and (MD: 40.90; 95% CI: 19.65 to 62.15), respectively. At week 24, the pooled analysis indicated that the evaluating respiratory symptoms total score was significantly decreased in the ensifentrine group (MD: -0.81; 95% CI: -1.36 to -0.27), transition dyspnea index score was significantly increased in the ensifentrine group (MD: 0.96; 95% CI: 0.62 to 1.29), no significant difference was observed in rescue medication use (MD: -0.30; 95% CI: -0.60 to 0.00), and no significant difference was observed in St. George's Respiratory Questionnaire total score (MD: -1.46; 95% CI: -3.22 to 0.30). Based on subgroup analysis, higher doses were associated with more favorable results.

Conclusion: In conclusion, owing to its dual effects, ensifentrine has a significant impact on improving pulmonary function and quality of life with minimal side effects. Promising results are expected if implied by synergizing with other drugs, however, more studies are needed to study the long-term effect on disease progression.

Trial registration: The study protocol was published via PROSPERO: International Prospective Register of Systematic Reviews (#CRD42024570799).

Background: Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disorder caused by SLC34A2 variants, characterized by diffuse alveolar calcium phosphate deposits. While the SLC34A2 mutation spectrum has been well-documented, the distinct variant landscape in Chinese patients remains unclear.

Objectives: This study aims to report three newly identified PAM cases and describe the SLC34A2 mutation spectrum of Chinese PAM patients through a systematic review.

Design: We documented the diagnosis and treatment processes and genetic variations of three PAM cases for reporting. Furthermore, we searched academic websites for published PAM cases with SLC34A2 variants and extracted clinical and genetic data for analysis.

Methods: We employed whole-exome sequencing to identify genetic mutations of these three patients. We systematically searched PubMed, Web of Science, China National Knowledge Infrastructure, and Cochrane Library for published PAM cases with SLC34A2 mutations. Clinical and genetic data were extracted into an Excel database and analyzed using SPSS 23.0 software (IBM, Armonk, NY, USA).

Results: Among the three cases we reported, two homozygous mutations in SLC34A2-c.910A>T (p.Lys304*) in exon 8 and c.575C>A (p.Thr192Lys) in exon 6 were identified. Analysis of 27 Chinese and 49 non-Chinese PAM patients revealed similar clinical manifestations, but a strikingly distinct genetic spectrum. Compound heterozygous mutations predominated in Chinese patients, while only two cases of compound heterozygous mutations were found in non-Chinese patients. Deletion/insertion mutations are the most common in non-Chinese patients (19/47, 40.4%), whereas nonsense mutations are the most frequent in Chinese patients (12/20, 60%). Further analysis of the reported SLC34A2 mutation sites in Chinese PAM patients showed hotspot regions in exons 5, 6, and 8, with c.910A>T in exon 8 being a unique gene screening target in Chinese patients.

Conclusion: This study delineates a distinct spectrum of SLC34A2 mutations in Chinese PAM patients, highlighting the importance of ethnicity-specific genetic screening in PAM diagnosis.

Background: Patients with chronic obstructive pulmonary disease (COPD) who survive sepsis remain immunocompromised and are at increased risk of subsequent viral infections, including influenza and respiratory syncytial virus (RSV).

Objective: This study aimed to address the 1-year risk of viral infections after sepsis in patients with COPD through the use of a federated database, TriNetX.

Design: A propensity score-matched (PSM) retrospective cohort study.

Methods: We used data of 903,683 COPD patients and identified 113,589 who experienced sepsis. The risk of distinct viral infections, including herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), RSV and influenza, within 1 year post-sepsis was analyzed, with the employment of PSM to minimize confounding. The effect of vaccination was also assessed to determine its protective efficacy.

Results: A total of 98,883 COPD patients with sepsis and 1:1 matched COPD without sepsis were eligible for analyses. COPD patients with sepsis had consistently higher risk for viral infections within 1 year after the sepsis compared with COPD patients without sepsis. The hazard ratios (HRs) were as follows: HSV 1.936 (95% CI: 1.775-2.112), VZV 3.050 (2.489-3.737), CMV 2.101 (1.832-2.410), RSV 3.297 (3.158-3.443), and Influenza 3.197 (3.071-3.328). Sensitivity analysis demonstrated the consistently elevated risks across sepsis with varying severities. We further explored the protective effect of vaccinations among patients with COPD and found the significant protective effect of VZV glycoprotein E (HR 0.724, 95% CI: 0.595-0.882), RSV prefusion F protein-based vaccine (HR 0.676, 95% CI: 0.563-0.812) and influenza vaccine (HR 0.709, 95% CI: 0.649-0.776).

Conclusion: COPD patients recovering from sepsis remain at increased risk of viral infections, highlighting the importance of targeted preventive strategies, including vaccination.

Bronchiectasis is a chronic disease characterised by permanent dilatation of the bronchi, which leads to the development of chronic airways inflammation and clinical sequelae such as cough, sputum production, and recurrent infections. The clinical syndrome is typically associated with reduced quality of life and greater healthcare utilisation. Prevalence data for bronchiectasis remain limited in many parts of the world, and the available studies report heterogeneous results with overall prevalence rates reported between 52.5 and 1248.7 per 100,000. Over the past 25 years, the prevalence has steadily increased, likely due to increased awareness and improved diagnostic techniques. Bronchiectasis is most prevalent in older age groups, and it is more commonly found in females. It is associated with multiple comorbidities, including chronic obstructive pulmonary disease, chronic rhinosinusitis, asthma, hypertension, cardiovascular disease and symptoms of anxiety and depression. First Nations populations experience a disproportionately high burden of disease. Bronchiectasis is more common in First Nations patients living in rural or remote communities and in those with socioeconomic disadvantage. It is associated with a lower age at diagnosis than the general population, more frequently associated with higher smoking rates and childhood respiratory tract infections, including a higher prevalence of human T-cell lymphotropic virus 1 in Australian Indigenous populations. These factors contribute to more extensive bronchiectasis on imaging, higher exacerbation rates and greater mortality. The introduction of lung cancer screening programmes is likely to increase the incidental detection of asymptomatic bronchiectasis patients, whose consequences are likely to burden healthcare systems. It would be beneficial to determine risk factors for those likely to develop clinically significant disease and, therefore, to prioritise referrals for further assessment.

Background: Interstitial lung disease (ILD) leads to progressive lung function decline and significant respiratory symptoms. Although antifibrotic agents preserve lung function and reduce mortality in ILD, their impact on health-related quality of life (HRQoL) remains unclear.

Objectives: We aimed to evaluate whether antifibrotic agents improve HRQoL and their effectiveness in treating HRQoL-related symptoms in patients with ILD.

Design: Systematic review and meta-analysis.

Data sources and methods: A literature search was conducted using MEDLINE, EMBASE, and the Cochrane Library from inception to August 25, 2025. The search included terms related to ILD, antifibrotic agents, and measures of HRQoL. HRQoL outcomes were assessed using the St. George's Respiratory Questionnaire (SGRQ), including total and domain scores. Data were pooled using a random-effects model, with outcomes reported as mean differences (MD) or relative risks (RR) and heterogeneity evaluated using the I² statistic.

Results: A total of 13 randomized controlled trials were included. Antifibrotic agents showed significant improvement in SGRQ scores, particularly in the symptom (MD: -2.59, 95% confidence interval [CI]: -4.56 to -0.61; I² = 32%) and activity (MD: -2.88, 95% CI: -4.82 to -0.94; I² = 34%) domains. Antifibrotics reduced the rate of cough (RR: 0.77, 95% CI: 0.64-0.94; I² = 0%) and dyspnea (RR: 0.71, 95% CI: 0.56 to 0.89; I² = 0%). However, fatigue was frequently observed in patients treated with antifibrotics (RR: 1.48, 95% CI: 1.20-1.83; I² = 0%) compared with the non-antifibrotic group. Most trials were judged to have low-to-moderate risk of bias, and the certainty of evidence was rated very low for total SGRQ scores but low to moderate for domain-specific outcomes and symptoms.

Conclusion: Antifibrotic agents may improve HRQoL and reduce dyspnea and cough in patients with ILD, but the certainty of evidence is low, and they may increase fatigue, requiring careful monitoring.Trial registration:The study protocol was registered in PROSPERO (CRD42023450917).

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT), as a rare and highly malignant neoplasm associated with a high mortality risk, is easily confused with SMARCA4-deficient nonsmall-cell lung cancer (NSCLC). To date, no standard and effective protocol for thoracic SMARCA4-UT has been established. Immunotherapy has demonstrated efficacy in advanced NSCLC, achieving unprecedented survival benefits. However, immune-related adverse events (irAEs) remain a significant clinical challenge. Here, we reported the first case of thoracic SMARCA4-UT with immune-related cystitis and hypothyroidism, in which the patient benefited from first-line immune checkpoint inhibitor (ICI)-based combination therapy, achieving a remarkable overall survival of over 100 weeks. Furthermore, we performed a review and analysis of the diagnosis, differential diagnosis, immunotherapy, and prognosis of thoracic SMARCA4-UT, proposing that first-line therapy combining immunotherapy with platinum-based chemotherapy (induction and maintenance phases) with or without radiotherapy, may improve the prognosis of such patients. Additionally, we hypothesized a potential role of macrophages in the pathogenesis of immune-related cystitis for the first time and detailed the clinicopathological characteristics and evidence-based management of this irAE.

Background: Females with cystic fibrosis (fwCF) are at increased risk of urinary incontinence (UI), likely due to chronic coughing and elevated intra-abdominal pressure. Prevalence rates reported in the literature vary widely, and no large multicenter study has been carried out to date.

Objective: To estimate the prevalence and severity of UI in fwCF and to investigate clinical variables associated with UI.

Design: A multicenter, cross-sectional study conducted across 21 Italian CF centers.

Methods: UI prevalence and severity were assessed using two validated questionnaires. A multivariable fractional polynomial approach was used to select variables for inclusion in the final logistic regression model to identify relevant associations with UI.

Results: UI was present in 218/542 females (40.2%, 95% Confidence Interval (CI): 36.1-44.5). Among children and adolescents, the prevalence was 12/160 (7.5%, 95% CI: 4.1-13), whereas among adults it was 206/382 (53.9%, 95% CI: 48.8-59). FwCF with UI showed a BMI of 0.2 Z score higher (95% CI: 0.1-0.4) than fwCF without UI; however, the overall prevalence of UI in fwCF overweight was 41% (95% CI: 30.2-52.7) compared to 40.1% (95%CI: 35.6-44.7) in fwCF with normal weight. Age (interquartile range-odds ratio (IQR-OR) 4.19, 95% CI: 2.80-6.28), days of hospitalization (IQR-OR 1.72, 95% CI: 1.42-2.08), and physical activity (OR 0.66, 95% CI: 0.53-0.82) were the only factors statistically associated with UI.

Conclusion: UI affects mostly adult fwCF and is associated with older age and longer hospitalization. Physical activity of ⩾150 min per week was also associated with a reduced probability of UI.

Background: There is uncertainty regarding the optimal next imaging modality for identifying likely malignant pulmonary lesions in patients with abnormal chest radiography, with or without respiratory symptoms.

Objectives: We compared the diagnostic accuracy of chest contrast-enhanced computed tomography (CECT) and positron emission tomography or positron emission tomography-computed tomography (PET/PET-CT) for identifying malignant pulmonary lesions.

Design: Systematic review and meta-analysisData sources and methods:We searched the PubMed, Embase, Scopus, and Cochrane CENTRAL databases to identify head-to-head diagnostic accuracy studies comparing CECT and PET/PET-CT for their ability to differentiate between benign and malignant pulmonary lesions. The risk of bias of included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies - Comparative (QUADAS-C) tool. Meta-analysis was performed using the bivariate random effects model.

Results: We included eight studies, comprising a total of 873 subjects. The pooled sensitivity and specificity of CECT (850 lesions) were 0.93 (95% CI, 0.89-0.96; I² = 24.99%) and 0.54 (95% CI, 0.32-0.75; I² = 84.00%). The pooled sensitivity and specificity of PET/PET-CT (851 lesions) were 0.87 (95% CI, 0.78-0.93; I² = 65.15%) and 0.83 (95% CI, 0.63-0.94; I² = 73.23%). Compared to CECT, PET/PET-CT had a lower relative sensitivity (relative ratio [RR], 0.93; 95% CI, 0.89-0.97; p < 0.01) and a higher relative specificity (RR, 1.69; 95% CI, 1.18-2.41; p < 0.01). After excluding the study with the largest sample size, PET/PET-CT was not less sensitive than CECT (RR, 0.99; 95% CI, 0.94-1.04; p = 0.73). There was a high/unclear risk of bias and applicability concerns in the population domain in six out of eight studies.

Conclusions: Based on limited evidence with applicability concerns, CECT of the chest may have a higher sensitivity but lower specificity than PET/PET-CT for identifying malignant lesions among patients with suspected lung cancer.

Trial registration: The protocol for the systematic review was prospectively registered on PROSPERO (CRD42024590904).