Mortality surrogates in combined pulmonary fibrosis and emphysema.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts. METHODS: Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide (D LCO) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups. RESULTS: In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline D LCO compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year D LCO decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations. CONCLUSION: When assessing disease progression in IPF, D LCO decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients.

Delineating associations of progressive pleuroparenchymal fibroelastosis in patients with pulmonary fibrosis.

Background: Computer quantification of baseline computed tomography (CT) radiological pleuroparenchymal fibroelastosis (PPFE) associates with mortality in idiopathic pulmonary fibrosis (IPF). We examined mortality associations of longitudinal change in computer-quantified PPFE-like lesions in IPF and fibrotic hypersensitivity pneumonitis (FHP). Methods: Two CT scans 6-36 months apart were retrospectively examined in one IPF (n=414) and one FHP population (n=98). Annualised change in computerised upper-zone pleural surface area comprising radiological PPFE-like lesions (Δ-PPFE) was calculated. Δ-PPFE >1.25% defined progressive PPFE above scan noise. Mixed-effects models evaluated Δ-PPFE against change in visual CT interstitial lung disease (ILD) extent and annualised forced vital capacity (FVC) decline. Multivariable models were adjusted for age, sex, smoking history, baseline emphysema presence, antifibrotic use and diffusion capacity of the lung for carbon monoxide. Mortality analyses further adjusted for baseline presence of clinically important PPFE-like lesions and ILD change. Results: Δ-PPFE associated weakly with ILD and FVC change. 22-26% of IPF and FHP cohorts demonstrated progressive PPFE-like lesions which independently associated with mortality in the IPF cohort (hazard ratio 1.25, 95% CI 1.16-1.34, p<0.0001) and the FHP cohort (hazard ratio 1.16, 95% CI 1.00-1.35, p=0.045). Interpretation: Progression of PPFE-like lesions independently associates with mortality in IPF and FHP but does not associate strongly with measures of fibrosis progression.

Pleuroparenchymal fibroelastosis in idiopathic pulmonary fibrosis: Survival analysis using visual and computer-based computed tomography assessment.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and pleuroparenchymal fibroelastosis (PPFE) are known to have poor outcomes but detailed examinations of prognostic significance of an association between these morphologic processes are lacking. METHODS: Retrospective observational study of independent derivation and validation cohorts of IPF populations. Upper-lobe PPFE extent was scored visually (vPPFE) as categories of absent, moderate, marked. Computerised upper-zone PPFE extent (cPPFE) was examined continuously and using a threshold of 2·5% pleural surface area. vPPFE and cPPFE were evaluated against 1-year FVC decline (estimated using mixed-effects models) and mortality. Multivariable models were adjusted for age, gender, smoking history, antifibrotic treatment and diffusion capacity for carbon monoxide. FINDINGS: PPFE prevalence was 49% (derivation cohort, n = 142) and 72% (validation cohort, n = 145). vPPFE marginally contributed 3-14% to variance in interstitial lung disease (ILD) severity across both cohorts.In multivariable models, marked vPPFE was independently associated with 1-year FVC decline (derivation: regression coefficient 18·3, 95 CI 8·47-28·2%; validation: 7·51, 1·85-13·2%) and mortality (derivation: hazard ratio [HR] 7·70, 95% CI 3·50-16·9; validation: HR 3·01, 1·33-6·81). Similarly, continuous and dichotomised cPPFE were associated with 1-year FVC decline and mortality (cPPFE ≥ 2·5% derivation: HR 5·26, 3·00-9·22; validation: HR 2·06, 1·28-3·31). Individuals with cPPFE ≥ 2·5% or marked vPPFE had the lowest median survival, the cPPFE threshold demonstrated greater discrimination of poor outcomes at two and three years than marked vPPFE. INTERPRETATION: PPFE quantification supports distinction of IPF patients with a worse outcome independent of established ILD severity measures. This has the potential to improve prognostic management and elucidate separate pathways of disease progression. FUNDING: This research was funded in whole or in part by the Wellcome Trust [209,553/Z/17/Z] and the NIHR UCLH Biomedical Research Centre, UK.

Mortality in combined pulmonary fibrosis and emphysema patients is determined by the sum of pulmonary fibrosis and emphysema.

In patients with combined pulmonary fibrosis and emphysema, emphysema and fibrosis do not have a synergistic effect that results in worsened survival when compared to IPF patients without emphysema https://bit.ly/35EJMo6.

New Perspectives on Difficult Asthma; Sex and Age of Asthma-Onset Based Phenotypes.

BACKGROUND: Asthma is a diverse condition that differs with age and sex. However, it remains unclear how sex, age of asthma onset, and/or their interaction influence clinical expression of more problematic adult "difficult" asthma. OBJECTIVES: To better understand the clinical features of difficult asthma within a real-world clinical setting using novel phenotypic classification, stratifying subjects by sex and age of asthma onset. METHODS: Participants in a longitudinal difficult asthma clinical cohort study (Wessex AsThma CoHort of difficult asthma; WATCH), United Kingdom (n = 501), were stratified into 4 difficult asthma phenotypes based on sex and age of asthma onset (early <18 years or adult ≥18 years) and characterized in relation to clinical and pathophysiological features. RESULTS: The cohort had more female participants (65%) but had similar proportions of participants with early- or adult-onset disease. Early-onset female disease was commonest (35%), highly atopic, with good spirometry and strong associations with some physical comorbidities but highest psychophysiologic comorbidities. Adult-onset females also had considerable psychophysiologic comorbidities and highest obesity, and were least atopic. Amongst male subjects, proportionately more had adult-onset disease. Early-onset male disease was rarest (14%) but associated with worst lung function, high smoking, atopy, and fungal sensitization. Despite shortest disease duration, adult-onset males had highest use of maintenance oral corticosteroid, poor lung function, and highest fractional exhaled nitrogen oxide in spite of highest smoking prevalence. CONCLUSIONS: This study shows that sex, age of asthma onset, and their interactions influence different clinical manifestations of difficult asthma and identifies a greater risk for lung function loss and oral corticosteroid dependence associated with smoking in adult-onset male subjects.