IPF patients are limited by mechanical and not pulmonary-vascular factors – results of a derivation-validation cohort study

BACKGROUND: During cardiopulmonary exercise testing (CPET), Idiopathic Pulmonary Fibrosis (IPF) patients do not reach their direct maximum voluntary ventilation (MVV) and have deranged gas exchange. Their exercise limitation is therefore attributed to a pulmonary vascular mechanism. METHODS: We studied two cohorts (derivation and validation) of IPF patients with lung function testing and CPET. Maximal ventilation at exercise (VEpeak) was compared to direct MVV by Bland-Altman analysis. RESULTS: In the derivation cohort (n = 101), direct MVV over-estimated VEpeak by a factor of 1.51, driven by respiratory rate during MVV that was 1.99 times higher at rest as compared to VEpeak at exercise. The formula (FEV1 × 20.1) + 15.4 was shown to predict VEpeak (r2 = 0.56) in the derivation cohort. In the validation cohort of 78 patients, VEpeak was within a factor of 1.27 (6.8 l/min) of predicted according to the novel formula. According to the novel prediction formula the majority of patients (58%) in the entire cohort have VEpeak within 85% of their predicted MVV, which would indicate a mechanical respiratory limitation to exercise. CONCLUSION: Estimation of direct MVV performed at rest leads to significant over-estimation of the breathing reserve in IPF patients. This may lead to over-diagnosis of pulmonary vascular limitation in these patients. Expected maximal ventilation at exercise may be accurately predicted indirectly by an IPF-specific formula

Bronchoscopy for management and identification of etiology of right middle lobe syndrome: Analysis of 66 cases

Abstract Background Right middle lobe (RML) syndrome is a recurrent or chronic obstruction of the RML causing atelectasis of the right middle lobe due to mechanical and nonmechanical etiologies. The consequences of untreated RML syndrome range from chronic cough to post‐obstructive pneumonia and bronchiectasis. We report here our bronchoscopy experience in patients with RML syndrome. Methods We conducted a retrospective study of adult patients who underwent bronchoscopy for RML syndrome at Rabin Medical Center from 2008 through 2022. Demographic data and medical history, bronchoscopy findings and procedures, and follow‐up results were collected. Results A total of 66 patients (57.6% male, mean age 63 ± 13 years) underwent bronchoscopy for RML syndrome during the study period. Bronchoscopy revealed a mechanical etiology in 49 (74.2%) cases, including endobronchial mass (21, 31.8%) and external compression (7, 10.6%). Malignancy was identified in 20 (30.3%) cases. In 62 patients (93.9%), the bronchoscopy resulted in partial or complete reopening of the RML bronchus. The therapeutic bronchoscopic procedures were balloon dilatation (19), laser ablation (17), mechanical debridement (12), endobronchial stent insertion (11), and cryoablation (6). Conclusions Malignancy was identified as the etiology of RML syndrome in approximately 25% of cases, suggesting bronchoscopy should be performed in every case of RML atelectasis. To our knowledge, this is the first reported series of endobronchial stenting of the RML bronchus in the context of RML syndrome

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix–fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH4OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of ‘HIF1α signaling pathway’ (KEGG, p < 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib

Risk factors for functional decline among survivors of Gram-negative bloodstream infection: A prospective cohort study

To identify risk factors for functional decline after hospitalization for Gram-negative bacteremia

Seven versus fourteen Days of Antibiotic Therapy for uncomplicated Gram-negative Bacteremia: a Non-inferiority Randomized Controlled Trial

Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited

External Validity of a Randomized Controlled Trial on Duration of Antibiotics for the Treatment of Gram-Negative Bacteremia

Introduction: Reports regarding the external validity of randomized controlled trials (RCTs) are scarce. We aimed to assess the population external validity of an investigator-initiated RCT on the duration of antibiotics for the treatment of Gram-negative bacteremia by comparing patients included in the RCT to patients that were not included in the trial. Methods: Hospitalized patients with Gram-negative bacteremia were recruited into an RCT and randomized to receive 7 or 14 days of covering antibiotic therapy in Israel and Italy from 2013 to 2017. In a concomitant observational study, RCT participants were compared with patients who fulfilled the inclusion criteria but were not included in the trial due to participation in other trials, discharge before approached by researchers, refusal to participate, or unwillingness of the treating physician to allow participants' recruitment. Results: Six hundred and four RCT patients were compared with 613 nonincluded patients. Almost 50% of nonincluded patients (288/613) were dependent on others for activities of daily living at baseline compared to 37.7% of RCT participants (228/604). Dementia was nearly 2-fold more frequent in nonincluded patients than those included (5.9% [36/613] versus 3.6% [22/604], p = 0.07). Patients who were not included in the RCT were more likely to acquire their infection in the hospital (53.3% [327/613] versus 29.1% [176/604], p < 0.001). The primary composite outcome of mortality, clinical failure, readmissions, or extended hospitalization at 90 days occurred in 353 of 613 nonincluded patients (57.6%) compared to 299 of 604 RCT participants (49.6%), p = 0.005. However, on multivariate analysis noninclusion in the RCT was not an independent risk factor for clinical failure and mortality. Conclusions: RCTs, even with broad eligibility criteria, do not represent the whole spectrum of patients and leave out a population with more severe illness for whom the evidence is lacking