Therapeutic Advances in Respiratory Disease最新文献

Background: Bronchiectasis exacerbations are a significant contributor to morbidity and mortality. While environmental factors, such as viral infections, are well-established triggers for exacerbations, the role of intrinsic factors, particularly chronic bacterial infections, remains incompletely understood.

Objectives: In this context, we sought to investigate the impact of chronic bacterial infections using the COVID-19 pandemic as a natural experiment, providing a unique opportunity to assess the effects of reduced external infections.

Design: A retrospective observational cohort study was conducted involving patients with non-cystic fibrosis bronchiectasis.

Methods: Data were collected via telephone interviews and medical record reviews, comparing exacerbation rates before (2019) and during (2020) the pandemic. The difference in exacerbation rates between 2020 and 2019 (delta exacerbations) served as the dependent variable in a multiple regression model.

Results: Sixty-three patients were included in the analysis. Those without chronic bacterial infections showed a significant reduction in exacerbations during the pandemic: mean (SD) was 1.06 (1.3) versus 1.61 (1.3), respectively (p-value = 0.006). In contrast, no such reduction was observed in patients with chronic bacterial infections. Notably, chronic infection with Pseudomonas aeruginosa emerged as an independent predictor of sustained or increased exacerbations in 2020 (positive delta exacerbations), despite the implementation of social distancing measures.

Conclusion: While social distancing effectively reduced bronchiectasis exacerbations in patients without chronic bacterial infections, those with Pseudomonas aeruginosa infections remained vulnerable to exacerbations, underscoring the importance of intrinsic disease/host factors. These findings highlight the need for targeted management strategies addressing chronic infections in patients with bronchiectasis.

Background: Respiratory diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease, and non-CF bronchiectasis are significant global health burdens. Current treatments aim to improve mucus clearance but do not fully address these diseases, highlighting the need for novel treatments. This study presents the results from phase I and phase IIb trials of GDC-6988, an inhaled, selective, and potent TMEM16A potentiator, in healthy volunteers.

Objectives: To assess the safety and tolerability of orally inhaled GDC-6988 (nebulized and as a dry powder inhaler) in healthy subjects compared with placebo.

Design: The phase I trial was a first-in-human, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and repeat doses of nebulized GDC-6988.

Methods: The study consisted of three parts: Part A with six cohorts (doses from 1.5 mg to 150 mg) using a single ascending dose (SAD) design; Part B with three cohorts (22.5 mg BID for 7 days, 75 mg BID for 14 days, and 45 mg BID for 14 days) using a multiple ascending dose (MAD) design; and Part C assessing the effect of salbutamol pretreatment on the highest dose tested in Part B (75 mg). The phase Ib study was a double-blind, randomized, placebo-controlled, single-center, multiple-dose escalation study evaluating the safety and PK of GDC-6988 DPI formulation, with and without salbutamol pretreatment. Three cohorts with doses of 11.2 mg, 28 mg, and 42 mg BID were tested. A bridging cohort compared PK in two capsule strengths of GDC-6988.

Results: In the phase I study, 76 healthy subjects received GDC-6988 or placebo; in the phase Ib study, 41 subjects were enrolled (31 in MAD cohorts, 10 in the bridging cohort). GDC-6988 was safe and generally well tolerated, with no serious, severe, or grade ⩾3 adverse events observed at any dose level. Mild-to-moderate dose-dependent FEV₁ declines were observed in both studies, but were mitigated by salbutamol pretreatment. In both trials, plasma PK concentrations of GDC-6988 were low, as expected.

Conclusion: Inhaled GDC-6988 was safe and well tolerated across all dose levels. The plasma PK of GDC-6988 was low and generally dose-proportional with a relatively short half-life.

Trial registration: Phase I: ClinicalTrials.gov Identifier NCT04488705; Phase Ib: ISRCTN30841680.

Nontuberculous mycobacteria (NTM) are ubiquitous, opportunistic pathogens that can cause lung disease in people with non-cystic fibrosis bronchiectasis (NCFB) and cystic fibrosis (CF). The incidence of NTM pulmonary infections and lung disease has continued to increase worldwide over the last decade among both groups. Notably, women with NCFB NTM pulmonary disease (NTM-PD) bear a disproportionate burden with NTM rates increasing in this population as well as having consistently higher incidence of NTM-PD compared to men. In contrast, among people with CF, an overall increased risk among women has not been observed. In the United States, the majority of people with CF are taking highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators, and these numbers are increasing worldwide. The long-term impact of CFTR modulator medications on NTM infections is not entirely understood. Guidelines for the screening, diagnosis, and management of NTM-PD exist for people with NCFB and CF, but do not consider unique implications relevant to women. This review highlights aspects of NTM-PD among women with NCFB and CF, including the epidemiology of NTM infection, special considerations for treatment, and unmet research needs relevant to women with NTM-PD.

Background: Quantitative computed tomography has emerged as a crucial tool for assessing the severity of emphysema in chronic obstructive pulmonary disease (COPD) patients. Vascular endothelial growth factor (VEGF) levels are significantly elevated in patients with chronic bronchitis but reduced in those with emphysema. Chronic inflammation is a key factor in the pathogenesis and progression of COPD, with cytokines such as Interleukin-1 beta playing a significant role.

Objective: This study aimed to evaluate the characteristics of emphysema in patients with COPD using quantitative computed tomography (QCT) and to investigate the relationship between the extent of emphysema, clinical phenotypes, lung function, and plasma concentrations of VEGF and IL-1β in COPD patients.

Design: A prospective cross-sectional study was conducted on 30 male patients with stable COPD at Military Hospital 175.

Methods: The emphysema index (EI) was quantified using QCT of the chest and categorized into levels from 0 to 4. Data on acute exacerbation frequency, CAT scores, mMRC, pulmonary function indices, arterial blood gas measurements, and plasma concentrations of VEGF and IL-1β were collected and analyzed to determine their relationship with EI.

Results: The study found an average EI of 12.8% ± 11.64%, with 96.7% of patients exhibiting a bronchitis-dominant phenotype. The severity of airflow obstruction, PaCO₂ levels, mMRC scores, and the number of exacerbations per year increased with the degree of emphysema. Conversely, FEV1% and the FEV1/FVC ratio significantly decreased with increasing emphysema severity. Plasma VEGF concentration was inversely correlated with the EI. In GOLD 3 and 4 stages, plasma VEGF levels decreased in proportion to emphysema severity, indicating that more advanced emphysema was associated with a more rapid decline in VEGF concentrations. Notably, when emphysema exceeded 25%, a significant reduction in both VEGF and IL-1β concentrations was observed.

Conclusion: The EI determined by QCT is a valuable tool for identifying COPD phenotypes and assessing disease severity. It can also provide insights into the prognosis regarding the risk of exacerbations, clinical symptom burden, and lung function decline. The significant inverse correlation between plasma VEGF concentration and EI indicates that decreased VEGF levels may be a crucial factor in the pathogenesis of emphysema, suggesting a potential target for research on "treatable" factors in COPD management.

Trial registration: The study was approved by an independent ethics committee (Ethics Committee of Military Hospital 175, No. 003/QĐ-IRB-VN01.055) and conducted in accordance with the Declaration of Helsinki and Guidelines for Good Clinical Practice.

Background: Asthma is a chronic condition with a high health and social burden in children. Although many well-studied effective therapies are available, because of suboptimal adherence and inhalation technique, asthma in children remains frequently uncontrolled. It is often assumed that adherence and technique are highly correlated items, but this assumption has not been thoroughly validated.

Objective: This trial evaluates the correlation between adherence and inhalation technique and the association of patient-related factors with these two important parameters.

Design: Observational phase I of the IMproving Adherence by Guiding INhalation via Electronic monitoring (IMAGINE) study, a three-phased Randomized Controlled Trial (RCT) in children with uncontrolled asthma.

Methods: The observational phase I of the IMAGINE study was designed to determine the correlation between adherence and inhalation technique in pediatric subjects with uncontrolled asthma. During this observational study phase, adherence and inhalation technique were measured with a smart add-on device called Respiro^© (Amiko, London). Patient-related factors were assessed either at baseline (e.g. characteristics of the patient), or during the study period (e.g. number of emergency room (ER) visits and daily salbutamol intake).

Results: Of the 34 enrolled subjects, 6-18 years old, suffering from moderate to severe uncontrolled asthma, 32 successfully completed phase I. No significant correlation between adherence and inhalation technique was observed (r = -0.21; p = 0.234). Twenty-one percent of children had both good adherence and good inhalation technique. Children with good adherence had more often ⩾1 ER visits during follow-up, while poor inhalation technique was associated with younger age and lower height at baseline, and a higher daily salbutamol dosage intake and ⩾1 ER admission during follow-up.

Conclusion: Our findings demonstrated no correlation between therapy adherence and inhalation technique, suggesting that these should be regarded as distinct and frequent pitfalls of inhaled medication use.We observed that inhalation technique was significantly associated with ER visits, rescue medication use, age, and height, while good adherence correlated with ER visits. Recognizing these factors allows pediatricians to identify risk profiles for poor inhalation technique and poor adherence, enabling more targeted and personalized interventions.Trial registration: NL-OMON25807.

Background: Chest computed tomography (CT) may provide evidence to forecast unexpected recurrence and metastasis following radical surgery for stage I synchronous multiple primary lung cancer (SMPLC).

Objective: This study aims to develop and validate a novel CT-based multi-parametric decision tree algorithm (CT-DTA) model capable of accurate risk assessment.

Design: A multicenter retrospective cohort study.

Methods: There were 209 patients with pathological stage I SMPLC from three tertiary centers included. We initially screened all of the CT-derived imaging parameters in the training cohort (130 patients from Center A) and then selected those showing statistical significance to construct a DTA model. The discriminative strength of the CT-DTA model for postoperative recurrence and metastasis was then validated in the validation cohort (79 patients from Centers B and C). Moreover, the performance of the CT-DTA model was further evaluated across different subgroups of the entire cohort.

Results: Five key imaging parameters measured on chest thin-section CT, including consolidation tumor ratio (CTR), long-axis diameter of the lesion, number of pure solid nodules, presence of spiculation and pleural indentation, constituted a CT-DTA model with nine leaf nodes, and CTR was the leading risk contributor of them. The CT-DTA model achieved a satisfactory predictive accuracy indicated by an area under the curve of more than 0.80 in both the training cohort and validation cohort. Meanwhile, this CT-DTA model was also exhaustively demonstrated to play as the only independent risk factor for postoperative recurrence and metastasis. Its promising predictive performance still remained stable across nearly all of the subgroups stratified by clinicopathological characteristics.

Conclusion: This CT-DTA model could serve as a noninvasive, user-friendly, and practicable risk prediction tool to aid treatment decision-making in operable stage I SMPLC.

Background: Complex pleural effusion and empyema (CPPE) is treated with intrapleural fibrinolytic therapy (IPFT) using tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) We present our single-center retrospective observational data using a simplified regimen of coadministering six divided doses of tPA and DNase over the course of 3 days.

Objective: To study the safety, utility, and clinical outcomes of IPFT.

Design: This is a single-center retrospective study of patients who received co-administration tPA/DNase for CPPE over a period of 5 years. The primary outcome was successful treatment without the need for surgery. Secondary outcomes were bleeding risk, post-procedural pain, treatment complications, and all-cause mortality at 30 days and 6 months. We have tested the clinical role RAPID score (Renal function measured as urea, Age, fluid Purulence, Infection source, Dietary status measured as albumin) to predict treatment success, and all-cause mortality at 6 months.

Results: A total of (n = 55) patients were included in the study. The mean age of the population studied was 67 (Interquartile range 57-74), including 47.3% male and 52.7% Female. 92.7% of the population studied was Caucasian. Comorbidities including chronic obstructive pulmonary disease, congestive heart failure, and Diabetes mellitus were present in 41.8%, 41.8%, and 43.6.% respectively. Patients were treated with tube thoracostomy with 14 French percutaneous pigtail catheters in 47 (85.5%) or 28-32 French chest tubes in 8 (14.5%) patients. Twenty-nine percent (16) of patients had acceptable clinical and radiographic improvement and did not require additional surgical or radiological intervention. Seventy-one percent (39) of patients required additional surgical drainage; video-assisted thoracoscopic surgery in 37, and open thoracotomy in 2 patients. The discriminating ability of the RAPID score for treatment success after IPFT was found to be poor (AUC: 0.601, 95% CI: 0.429-0.773, p = 0.24). All-cause mortality at 6 months was 23.6% (13) of patients. The predictive ability of the RAPID score for mortality at 6 months was found to be poor (AUC: 0.640, 95% CI: 0.478-0.802, p = 0.13). The optimal cutoff for the RAPID score for mortality was ⩾4, with 84.6% sensitivity and 46.3% specificity.

Conclusion: Results of our single-center study suggest that IPFT can be safely adopted by small and mid-sized clinical centers, as the risk of bleeding is low. The results of coadministering tPA and DNase are safe, and it reduces the need for surgical intervention in nearly one-third of patients.

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.