Therapeutic Advances in Respiratory Disease最新文献

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.

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening vascular disease characterized by increased pulmonary vascular resistance, leading to right ventricular failure and death. It has a higher prevalence in women than men, yet notable sex-based differences influence disease presentation, treatment response, and outcomes. This narrative review explores the distinct sex differences in PAH and their significant impact on prognosis. Data from major PAH clinical trials indicate that nearly 78.4% of participants are women. According to the REVEAL registry, the most common causes of PAH in women are connective tissue disease-associated PAH (CTD-PAH), idiopathic PAH (IPAH), and congenital heart disease-associated PAH (CHD-PAH). Women are often found to have better baseline right ventricular (RV) function and hemodynamics before treatment, as well as more favorable RV adaptation post-therapy. They also demonstrate a stronger response to endothelin receptor antagonists (ERA) and prostacyclins. Most notably, these factors contribute to better survival outcomes in women compared to men. In conclusion, significant sex-based differences exist in PAH, underscoring the need for personalized treatment approaches that consider sex-related factors. Future research should focus on optimizing therapeutic strategies to improve outcomes for both sexes.

Background: Palliative care is essential for managing advanced chronic illnesses (ACI) but remains underused.

Objectives: We aimed to evaluate the prevalence, associations, and outcomes of palliative care utilization (PCU) in patients with ACIs.

Design: A prospective observational questionnaire-based study.

Methods: The study included hospitalized patients with severe COPD (n = 53), advanced heart failure (HF; n = 56), or metastatic malignancy (n = 57). Participants were interviewed about their demographics, health status, PCU, and end-of-life decision-making.

Results: A total of 166 subjects were included (median age: 77 years; 41% females), with a 1-year median of 2 hospital admissions. Subjects with COPD and HF had low rates of PCU compared to those with malignancy (6% and 11% vs 39%, p < 0.01). PCU occurred exclusively in patients who had visited a specialist (cardiologist, pulmonologist, or oncologist) before study inclusion. Patients with PCU were more aware of advance directives (71% vs 38%), signed advanced orders (23% vs 3%), and shared their end-of-life decisions with others (71% vs 29%). These differences remained significant after adjustment for prior specialist visits. Independent associations with PCU were self-identifying as non-religious (adjusted OR 3.41, 95% CI 1.2-9.9), above high-school education (AOR 2.84, 95% CI 1.1-7.3), and chronic pain (aOR 2.81, 95% CI 1.11-7.14), while COPD showed the opposite (aOR 0.25, 95% CI 0.07-0.96).

Conclusion: Palliative care utilization is alarmingly low among patients with HF and COPD despite significant symptom burden. Specialists should advocate for PCU as their involvement could enhance end-of-life care planning, improve patient outcomes, and address current gaps in care.

Mesenchymal chondrosarcoma is a malignant tumor that arises from cartilage-forming cells and typically affects the bones, but in rare cases also the lungs. Due to its rarity, there is limited knowledge about the clinical presentation, diagnostic challenges, and treatment options for primary pulmonary chondrosarcoma. We conducted a comprehensive literature search through PubMed, EMBASE, Scopus, Clinical Trial Gov, and Google Scholar using search terms such as "primary pulmonary/lung chondrosarcoma." We also present our case study. In our case, the chondrosarcoma was discovered incidentally during a Computer Tomography (CT) scan. It was located in the middle lobe and was historically characterized as low-grade. After surgical removal, no recurrence was detected during follow-up examination. In the literature reviewed, the most common symptoms of primary pulmonary chondrosarcoma were cough and dyspnea. Radiologic features included well-defined margins, a central location, and calcifications. Histopathological examination revealed either hyaline or myxoid structures, with the myxoid type being more aggressive. Surgical resection is currently the preferred treatment method with a recurrence rate of approximately 21%.Primary pulmonary mesenchymal chondrosarcoma remains a rare and challenging diagnosis, typically presenting with non-specific symptoms. Surgical resection is the primary treatment method. Further research is needed to establish standardized diagnostic criteria and treatment protocols.

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.