Therapeutic Advances in Respiratory Disease最新文献

Pulmonary arterial hypertension (PAH) is a rare but fatal disease characterized by progressive vascular remodeling, which results in increased pulmonary vascular resistance and elevated pulmonary arterial pressure. These changes are detrimental to the right ventricle (RV). If not treated, it can eventually lead to maladaptive RV structural changes, right heart failure, and death. Late diagnosis at an advanced stage remains a significant issue that limits the effectiveness of existing treatments. PAH pathophysiology is mediated by several molecular pathways that act on different cell types, including endothelial cells, smooth muscle cells, and fibroblasts. These cells exhibit cancer-like properties, including increased proliferation, resistance to apoptosis, and metabolic reprogramming. This review provides new insights into clinical and diagnostic research on PAH. Herein, we discuss classification systems, their relevance and significance in PAH, innovative imaging techniques, and genetic testing to identify hereditary risk factors. The potential of artificial intelligence to improve disease detection and management is also discussed in the context of diagnostic workflows. Overall, we aim to provide new insights in this review and emphasize the critical need for early diagnosis, personalized treatment strategies, and continued innovation in PAH care to improve patient outcomes and quality of life.

Background: Bronchoscopic lung volume reduction (BLVR) can be an effective treatment for highly selected patients with severe emphysema but only half of carefully selected patients derive clinical benefit. Two commercially available platforms exist to help determine candidacy for BLVR via quantitative analysis of computed tomography (CT) scans.

Objectives: To determine if the two commercially available quantitative platforms identified the same patient population that may benefit from BLVR.

Design: A multicenter, retrospective cohort study.

Methods: Consecutive patients referred for BLVR between January 1, 2022 and March 31, 2023 at three medical centers in the United States with the same CT scan submitted for quantitative analysis to two commercially available platforms to determine BLVR candidacy were analyzed. The primary outcome of interest was whether quantitative analysis provided different recommendations for individual patients. The recommendation to proceed with BLVR was based on a prespecified algorithm using criteria established in clinical trials for each quantitative platform, respectively.

Results: A total of 83 patients referred for BLVR across three centers were included; patients were a median 67 years old, had a median post bronchodilator FEV1 of 30% predicted (IQR: 25, 38), a median residual volume of 220% predicted (IQR: 185, 268), and 29 (34.9%) received endobronchial valves. A total of 26 patients (31.3%) received different recommendations from the two quantitative platforms.

Conclusion: In this cohort of patients evaluated for BLVR across multiple medical centers, nearly a third of patients received different recommendations based on the platform utilized for valve assessment. This suggests that the selection process for BLVR may warrant refinement.

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory condition associated with increased morbidity and mortality, particularly during respiratory infections such as influenza. The interaction between COPD and influenza is multifaceted, involving compromised immune responses, chronic inflammation, and impaired lung function. Influenza infection can exacerbate COPD, leading to acute exacerbations, hospitalizations, and higher mortality. This review examines the pathophysiological mechanisms underlying the exacerbation of COPD by influenza, evaluates its impact on patient outcomes, and explores the role of comorbidities in shaping disease severity. We also assess the effectiveness of influenza vaccination in preventing severe outcomes and discuss strategies to improve vaccination uptake among COPD patients. Current evidence highlights the importance of tailored prevention and management approaches, as well as the need for further research into biomarkers and optimal therapeutic strategies to mitigate the burden of influenza on COPD populations.

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.

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: 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.

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.

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.