Therapeutic Advances in Respiratory Disease最新文献

The interstitial lung diseases (ILDs) are a heterogeneous and complex group of diseases. The treatable trait (TT) model represents a shift in ILD management, away from traditional diagnostic labels towards a more individualised, trait-focused approach. This review explores the application of the TT paradigm to ILD, identifying key traits across the aetiological, pulmonary, extrapulmonary and behavioural domains. By addressing these traits, the TT model offers a framework to improve outcomes in ILD through multidisciplinary management with a precision medicine focus. Further research is necessary to evaluate the overall impact of this TT model on ILD care.

Background: Pulmonary fibrosis is a severe, progressive form of interstitial lung disease associated with increased morbidity and mortality. Pulmonary hypertension often accompanies severe pulmonary fibrosis and is also associated with worse outcomes. Antifibrotic therapy and pulmonary vasodilator therapy have demonstrated clinical benefits in pulmonary fibrosis and pulmonary hypertension, respectively. However, the benefit of combined antifibrotic and pulmonary vasodilator therapy in patients with both pulmonary fibrosis and pulmonary hypertension is less established.

Objectives: We aimed to determine the effectiveness of a combination pulmonary vasodilator and antifibrotic therapy with regard to transplant-free survival and six-minute walk distance improvement in patients with pulmonary fibrosis and pulmonary hypertension.

Design: This was a retrospective cohort study of patients with pulmonary fibrosis (idiopathic pulmonary fibrosis, combined pulmonary fibrosis and emphysema, and other fibrotic interstitial lung disease) and pulmonary hypertension diagnosed via right heart catheterization. Patients received antifibrotic therapy with or without pulmonary vasodilator therapy.

Methods: Patients who received combination antifibrotic therapy and pulmonary vasodilator therapy were compared to those prescribed antifibrotic therapy alone. Transplant-free survival and change in six-minute walk distance were compared between the two groups. Multivariable Cox regression was performed to determine predictors of transplant-free survival.

Results: Patients who received antifibrotic and pulmonary vasodilator therapy had significantly improved transplant-free survival (log rank p = 0.001). Treatment with antifibrotic and pulmonary vasodilator therapy was significantly and independently associated with reduced risk of death or lung transplantation (HR 0.24, 95% CI 0.06-0.93, p = 0.04). These patients had worse pulmonary hemodynamics than those receiving antifibrotic therapy alone.

Conclusion: We found a potential survival benefit when pulmonary vasodilator therapy was given in combination with antifibrotic therapy in patients with pulmonary fibrosis and pulmonary hypertension. This may be reflective of a pulmonary vascular phenotype among those with pulmonary fibrosis and pulmonary hypertension. Further trials are needed to better elucidate which patients benefit from combination therapy.

SummaryWhat is this summary about?● This is a plain language summary of two articles originally published in The New England Journal of Medicine and The Lancet Respiratory Medicine. These articles presented the results of GALATHEA and TERRANOVA, two clinical studies that took place across 41 countries. ○ GALATHEA and TERRANOVA measured how patients' COPD changed from before their first benralizumab (10, 30, or 100 mg) injection, to after 56 weeks of treatment. ○ In both studies, benralizumab was compared with placebo. ○ To see whether benralizumab treatment would benefit any particular patients included in these studies, researchers carried out an additional analysis following the main studies of GALATHEA and TERRANOVA.

Alpha 1 antitrypsin deficiency (AATD) is a genetic disorder that alters the functionality and/or serum levels of alpha 1 antitrypsin (AAT). Dysfunctional forms of AAT, or low levels of serum AAT, predispose affected individuals to pulmonary complications. When AATD-associated lung disease develops, the most common pulmonary pathology is emphysema. The development of emphysema and decline in lung function varies by AATD genotype and is accelerated by risk factors, such as smoking. To improve the understanding and treatment of AATD, emerging knowledge and unresolved questions need to be discussed. Here we focus on developments in the areas of disease pathogenesis, biomarkers, and clinical endpoints for trials in AATD, as well as barriers to treatment. The clinical impact of AATD on lung function is highly variable and highlights the complexity of AATD pathogenesis, in which multiple underlying processes are involved. Reduced levels of functional AAT disrupt the protease-antiprotease homeostasis, leading to a loss of neutrophil elastase inhibition and the breakdown of elastin within the lung interstitium. Inflammatory processes also play a critical role in the development of AATD-associated lung disease, which is not yet fully understood. Biomarkers associated with the disease and its complications may have an important role in helping to address AATD underdiagnosis and evaluating response to treatment. To improve access to treatment, the problem of underdiagnosis needs to be addressed and the provision of therapeutic options needs to become uniform. Patients should also be empowered to play a key role in the self-management of the disease. Advancing our understanding of the disease will ultimately improve the life expectancy and quality of life for patients affected by AATD.

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.

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.