Chest最新文献

Background: Adaptation of the right ventricle is a key determinant of outcomes in pulmonary arterial hypertension (PAH). Despite a compelling rationale to develop targeted therapies for the right ventricle in PAH, no such treatments exist. H₂-receptor antagonism is a potential myocardial-focused paradigm in heart failure.

Research question: Do H₂-receptor antagonists improve outcomes in participants with PAH?

Study design and methods: We conducted a 24-week, single-center, 1:1 randomized, double-blind, placebo-controlled trial of the H₂-receptor antagonist famotidine in patients with a diagnosis of PAH. The primary outcome was change in six-minute walk distance (6MWD) at 24 weeks. Secondary endpoints included B-type natriuretic peptide levels, NYHA functional class, right ventricular parameters, health-related quality of life, and escalation in PAH-focused care.

Results: From May 2019 to July 2023, 80 participants were randomized with 79 receiving study drug. There was no significant difference in the primary outcome of 6MWD at 24 weeks, with an increase of 4.7 meters seen in the placebo arm versus a decrease of 17.0 meters in the famotidine arm (p = 0.24). There were also no differences in secondary endpoints at 24 weeks. Study drug was well tolerated, and safety profiles were similar between arms. Adherence and study conduct was good overall. Participants with methamphetamine-associated PAH were similar in all aspects to the study participants more broadly.

Interpretation: The results of this trial do not support the routine use of famotidine 20 mg daily as an adjunct therapy for the treatment of PAH. The REHAB-PH trial argues against the practice of avoiding participants with methamphetamine-associated PAH in randomized clinical trials of novel therapies.

Clinical trials registration: The trial was registered at clinicaltrials.gov (NCT03554291).

Background: Central airway obstruction (CAO), seen in a variety of malignant and nonmalignant airway disorders, is associated with a poor prognosis. The management of CAO is dependent on provider training and local resources, which may make the clinical approach and outcomes highly variable. We reviewed the current literature and provided evidence-based recommendations for the management of CAO.

Methods: A multidisciplinary expert panel developed key questions using the Patient, Intervention, Comparator, and Outcomes format and conducted a systematic literature search using MEDLINE (PubMed) and the Cochrane Library. The panel screened references for inclusion and used vetted evaluation tools to assess the quality of included studies and extract data, and graded the level of evidence supporting each recommendation. A modified Delphi technique was used to reach consensus on recommendations.

Results: A total of 9,688 abstracts were reviewed, 150 full-text articles were assessed, and 31 studies were included in the analysis. One good practice statement and 10 graded recommendations were developed. The overall certainty of evidence was very low.

Conclusions: Therapeutic bronchoscopy can improve the symptoms, quality of life, and survival of patients with malignant and nonmalignant CAO. Multi-modality therapeutic options, including rigid bronchoscopy with general anesthesia, tumor/tissue debridement, ablation, dilation, and stent placement, should be utilized when appropriate. Therapeutic options and outcomes are dependent on the underlying etiology of CAO. A multidisciplinary approach and shared decision-making with the patient are strongly encouraged.

Background: Complex pleural space infections often require treatment with multiple doses of intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease, with treatment failure frequently necessitating surgery. Pleural infections are rich in neutrophils, and neutrophil elastase degrades plasminogen, the target substrate of tPA, that is required to generate fibrinolysis. We hypothesized that pleural fluid from patients with pleural space infection would show high elastase activity, evidence of inflammatory plasminogen degradation, and low fibrinolytic potential in response to tPA that could be rescued with plasminogen supplementation.

Research question: Does neutrophil elastase degradation of plasminogen contribute to intrapleural fibrinolytic failure?

Study design and methods: We obtained infected pleural fluid and circulating plasma from hospitalized adults (n = 10) with institutional review board approval from a randomized trial evaluating intrapleural fibrinolytics vs surgery for initial management of pleural space infection. Samples were collected before the intervention and on days 1, 2, and 3 after the intervention. Activity assays, enzyme-linked immunosorbent assays, and Western blot analysis were performed, and turbidimetric measurements of fibrinolysis were obtained from pleural fluid with and without exogenous plasminogen supplementation. Results are reported as median (interquartile range) or number (percentage) as appropriate, with an α value of .05.

Results: Pleural fluid elastase activity was more than fourfold higher (P = .02) and plasminogen antigen levels were more than threefold lower (P = .04) than their corresponding plasma values. Pleural fluid Western blot analysis demonstrated abundant plasminogen degradation fragments consistent with elastase degradation patterns. We found that plasminogen activator inhibitor 1 (PAI-1), the native tPA inhibitor, showed high antigen levels before the intervention, but the overwhelming majority of this PAI-1 (82%) was not active (P = .003), and all PAI-1 activity was lost by day 2 after the intervention in patients receiving intrapleural tPA and deoxyribonuclease. Finally, using turbidity clot lysis assays, we found that the pleural fluid of 9 of 10 patients was unable to generate a significant fibrinolytic response when challenged with tPA and that plasminogen supplementation rescued fibrinolysis in all patients.

Interpretation: Our findings suggest that inflammatory plasminogen deficiency, not high PAI-1 activity, is a significant contributor to intrapleural fibrinolytic failure.

Trial registry: ClinicalTrials.gov; No.: NCT03583931; URL: www.

Clinicaltrials: gov.

Background: Obesity-associated asthma results in increased morbidity and mortality. We report 1-year asthma outcomes with a weight management regimen, the Counterweight-Plus Programme (CWP), compared with usual care (UC) in a single-center, randomized controlled trial in patients with difficult-to-treat asthma and obesity.

Research question: Can use of the CWP result in improved asthma control and quality of life compared with UC at 1 year in patients with difficult-to-treat asthma and obesity?

Study design and methods: Adults with difficult-to-treat asthma and BMI ≥ 30 kg/m² were randomized (1:1 CWP:UC) to treatment. The CWP, with dietitian support, included a 12-week total diet replacement phase (850 kcal/d low-energy formula), and then subsequent food reintroduction and maintenance phases up to 1 year. Outcomes include results of the six-item Asthma Control Questionnaire (ACQ-6) and Asthma Quality of Life Questionnaire (AQLQ), as well as health care usage. A minimal clinically important difference (MCID) is 0.5 for ACQ-6 and AQLQ.

Results: Of 36 patients recruited, 29 attended visits at 52 weeks (13 CWP and 16 UC). The CWP resulted in greater weight change (median, -14 kg [interquartile range (IQR), -15 to -9 kg]) compared with UC (median, 2 kg [IQR, -7 to 8 kg]; P = .015) at 52 weeks. A greater proportion achieved MCID with the CWP vs UC in AQLQ (71% vs 6%, respectively; P < .001). No between-group differences were observed in ACQ-6. Median exacerbation frequency was reduced over 52 weeks with the CWP from 4 (IQR, 2 to 5) to 0 (IQR, 0 to 2) (P < .001), although no between-group difference was observed. Seventy percent of the CWP group lost ≥ 10% body weight and had improvement in ACQ-6 (mean difference, -1.1; 95% CI, -1.9 to -0.3; P = .018) and AQLQ (mean difference, 1.2; 95% CI, 0.4, 2.1; P = .011) across 52 weeks.

Interpretation: In this study, the use of a dietitian-supported weight management program resulted in sustained weight loss and is a potential treatment for obesity in asthma. The CWP resulted in a higher proportion achieving MCID improvements in AQLQ compared with UC. Within-group differences in AQLQ and exacerbation frequency suggest potential with the CWP. These encouraging signals justify a larger sample study to further assess asthma-related outcomes.