European Respiratory Journal最新文献

Persistent neutrophilic inflammation is a central feature in both the pathogenesis and progression of bronchiectasis. Neutrophils release neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), cathepsin G and proteinase 3. When chronically high levels of free NSP activity exceed those of protective antiproteases, structural lung destruction, mucosal-related defects, further susceptibility to infection and worsening of clinical outcomes can occur. Despite the defined role of prolonged, high levels of NSPs in bronchiectasis, no drug that controls neutrophilic inflammation is licensed for the treatment of bronchiectasis. Previous methods of suppressing neutrophilic inflammation (such as direct inhibition of NE) have not been successful; however, an emerging therapy designed to address neutrophil-mediated pathology, inhibition of the cysteine protease cathepsin C (CatC, also known as dipeptidyl peptidase 1), is a promising approach to ameliorate neutrophilic inflammation, since this may reduce the activity of all NSPs implicated in bronchiectasis pathogenesis, and not just NE. Current data suggest that CatC inhibition may effectively restore the protease-antiprotease balance in bronchiectasis and improve disease outcomes as a result. Clinical trials for CatC inhibitors in bronchiectasis have reported positive phase III results. In this narrative review, we discuss the role of high NSP activity in bronchiectasis, and how this feature drives the associated morbidity and mortality seen in bronchiectasis. This review discusses therapeutic approaches aimed at treating neutrophilic inflammation in the bronchiectasis lung, summarising clinical trial outcomes and highlighting the need for more treatment strategies that effectively address chronic neutrophilic inflammation in bronchiectasis.

Rationale: Adherence to Continuous Positive Airway Pressure (CPAP) for Obstructive Sleep Apnoea (OSA) continues to be low with high termination rates. Alternative therapies to CPAP are needed.

Objectives: To compare objective adherence to CPAP and Mandibular Advancement Splints (MAS) and to evaluate their effectiveness. Additionally, to identify treatment usage patterns and the clinical effectiveness of having both therapies.

Methods: This multi-center, double-randomized, three-phase trial (titration/cross-over/observation) was conducted at three Canadian universities. Eligible participants were treatment-naïve with mild to severe OSA.

Measurements and main results: Primary outcome was objectively measured adherence (hours/night) during cross-over phase. Secondary outcomes included efficacy during cross-over phase; adherence during observational phase; patient-centered outcomes, blood pressure and side-effects during cross-over and observational phases. Duration of cross-over and observational phases were 2.5 and 6 months respectively.Eighty-one participants were enrolled in the first randomization. Seventy-nine entered the adaptation/titration phase [mean age (sd); 52·3 (10·8) years, 58 males], 73 entered the cross-over phase (included in the intention-to-treat analysis) and 64 completed the observation phase. Mean objective adherence over 1-month, MAS showed higher adherence than CPAP, 6·0 versus 5·3 h/night (difference= 0·7 h/night, 95% CI: 0·3-1·2 h, p<0·001). Mean CPAP-MAS difference (95% CI) in efficacy of 10·4 (7·8-13) events/hour, p<0·001. During the observation phase 55% (35/64) of participants chose to alternate therapies. All treatments led to substantial improvement in patient-centered outcomes.

Conclusions: Despite the higher efficacy of CPAP and higher adherence to MAS, both demonstrate comparable clinical effectiveness on patient-centered outcomes. Having both CPAP and MAS can improve long-term management of OSA.