American journal of respiratory and critical care medicine最新文献

Rationale: Obesity hypoventilation syndrome (OHS) is treated with non-invasive ventilation (NIV) that is titrated during polysomnography. Auto-adjusted NIV could obviate the need for polysomnographic titration, thereby reducing costs and delays in care. However, non-inferiority long-term clinical trials comparing auto-adjusted NIV with manually-adjusted NIV are lacking.

Objective: To determine the comparative effectiveness of automatic vs manual NIV modality in OHS.

Methods: In this multicenter, blinded, parallel group, non-inferiority and cost-effectiveness trial, we randomly assigned treatment-naïve ambulatory patients with OHS to auto-adjusted NIV (volume-targeted pressure support with auto-EPAP) or manually-adjusted NIV (bilevel PAP ST mode).

Measurements: The primary outcome was change in daytime PaCO2 at 12 months, with the non-inferiority premise set at -2 mmHg. Secondary outcomes included symptoms, quality of life, and healthcare resource utilization. Intention-to-treat and per-protocol analyses were performed.

Main results: 205 ambulatory patients with OHS were randomized, 107 to auto-adjusted NIV and 89 to manually-adjusted NIV. The mean [95% CI] improvement in PaCO2 was -9.2 [-9.7;-8.7] mmHg in the auto-adjusted group and -8.7 [-9.1;-8.3] mmHg in the manually-adjusted group, with mean adjusted difference of 0.15 mmHg between groups ([low confidence limit -1.4]; non-inferiority P = 0.01). Cost-effectiveness was favorable to auto-adjusted group with a saving of 15287€(95% CI: -2370; -6854) per patient. There were no significant differences in other secondary outcomes.

Conclusions: In ambulatory patients with OHS, auto-adjusted NIV had a non-inferior long-term effectiveness compared to manually-adjusted NIV while being more cost-effective. Auto-adjusted NIV may be preferred in clinical practice given its lower complexity and cost.

Rationale: Depemokimab is the first ultra-long-acting biologic with high interleukin-5 binding affinity, high potency, and an extended half-life enabling twice-yearly dosing.

Objectives: Investigate the efficacy and safety of switching to depemokimab in participants with severe asthma already managed with and responsive to short-acting biologic therapies targeting interleukin-5 or its receptor.

Methods: NIMBLE (NCT04718389) was a multicenter, randomized, double-blind, double-dummy, parallel-group, Phase 3A non-inferiority study. Participants were ≥12 years old with asthma and documented clinical benefit on mepolizumab 100 mg subcutaneously every 4 weeks or benralizumab 30 mg subcutaneously every 8 weeks for ≥12 months. Participants were randomized 1:1 to depemokimab 100 mg subcutaneously every 26 weeks or maintained on their prior biologic (mepolizumab or benralizumab). The primary endpoint was annualized rate of clinically significant exacerbations over 52 weeks, with predefined non-inferiority margin set at 1.28. Safety endpoints included adverse events.

Measurements and main results: Annualized rates (95% confidence intervals) of clinically significant exacerbations over 52 weeks were 0.57 (0.50 to 0.64) with depemokimab (n = 848) and 0.49 (0.43 to 0.55) with active comparator (n = 839); rate ratio (95% confidence interval) was 1.16 [0.98 to 1.38]). Since the upper bound of the 95% confidence interval exceeded 1.28, non-inferiority was not met. Most participants in both treatment arms experienced no clinically significant exacerbations. Health-related quality of life, asthma control, and lung function outcomes were stable throughout the study. Adverse events were comparable between treatment groups.

Conclusions: While statistical non-inferiority was not met, exacerbation rates were low and symptom control/lung function were maintained in both groups. This first randomized, controlled switch trial in severe asthma suggests that participants with severe asthma on mepolizumab or benralizumab may safely switch to twice-yearly depemokimab.

Rationale: Emerging research highlights cellular abnormalities in Chronic Obstructive Pulmonary Disease (COPD), focusing on alveolar type 2 (AT2) cells, which are key to lung tissue repair and normal cellular differentiation. Lipofibroblasts (LipoFBs), stromal fibroblasts containing lipid droplets, are closely associated with AT2 cells and support their function.

Objectives: We present a comprehensive investigation into the therapeutic potential of extracellular vesicles (EVs) derived from LipoFBs (LipoFB-EVs) in COPD treatment.

Methods: LipoFBs were induced from lung fibroblasts using Metformin or Rosiglitazone in vitro, and their EVs were isolated via ultracentrifugation for analysis.

Main results: They effectively mitigate key COPD pathologies such as cellular senescence and inflammatory responses in lung epithelial cells. This is achieved by reducing reactive oxygen species (ROS) levels and modulating DNA damage response pathways. Moreover, LipoFB-EVs demonstrate anti-fibrotic properties by inhibiting TGF-β-induced myofibroblast differentiation, surpassing conventional anti-fibrotic drugs. They also aid in restoring impaired AT2 stem cells, which are crucial for lung homeostasis, by enhancing their viability, colony-forming ability, and proliferation. Furthermore, we identify the presence of L-type amino acid transporter 1 (LAT1) within LipoFB-EVs, which mediates amino acid uptake, particularly leucine transport, and contributes to the restoration of AT2 cell dysfunction. Importantly, the administration of LipoFB-EVs in murine models of COPD resulted in significant improvements in airway inflammation, remodeling, obstruction, cellular senescence, and alveolar emphysema induced by both short- and long-term CS exposure.

Conclusions: Our findings highlight the therapeutic potential of LipoFB-EVs as a novel regenerative therapy for COPD, offering promising avenues for future clinical interventions.