Oldham discusses the study by Sanders and colleagues on interstitial lung abnormalities (ILA) and aging biomarkers. The researchers sought to address the link between ILAs detected by chest computed ...tomography in participants from the Framingham Heart Study and plasma biomarkers of accelerated aging. To validate their GDF15 findings, Sanders and colleagues tested the association between this biomarker and ILAs in an independent cohort drawn from COPD gene study (NCT00608764). GDF15 was again associated with ILA presence, with each unit increase in log transformed value increasing the odds of ILA presence by greater than eightfold.
Immunosuppression was associated with adverse events for patients with idiopathic pulmonary fibrosis (IPF) in the PANTHER-IPF (Evaluating the Effectiveness of Prednisone, Azathioprine and
...-Acetylcysteine in Patients with IPF) clinical trial. The reason why some patients with IPF experience harm is unknown.
To determine whether age-adjusted leukocyte telomere length (LTL) was associated with the harmful effect of immunosuppression in patients with IPF.
LTL was measured from available DNA samples from PANTHER-IPF (interim analysis,
= 79; final analysis,
= 118). Replication cohorts included ACE-IPF (Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis) (
= 101) and an independent observational cohort (University of Texas Southwestern Medical Center-IPF,
= 170). LTL-stratified and medication-stratified survival analyses were performed using multivariable Cox regression models for composite endpoint-free survival.
Of the subjects enrolled in the PANTHER-IPF and ACE-IPF, 62% (49/79) and 56% (28/50) had an LTL less than the 10th percentile of normal, respectively. In PANTHER-IPF, exposure to prednisone/azathioprine/
-acetylcysteine was associated with a higher composite endpoint of death, lung transplantation, hospitalization, or FVC decline for those with an LTL less than the 10th percentile (hazard ratio, 2.84; 95% confidence interval, 1.02-7.87;
= 0.045). This finding was replicated in the placebo arm of ACE-IPF for those exposed to immunosuppression (hazard ratio, 7.18; 95% confidence interval, 1.52-33.84;
= 0.013). A propensity-matched University of Texas Southwestern Medical Center IPF cohort showed a similar association between immunosuppression and composite endpoints (death, lung transplantation, or FVC decline) for those with an LTL less than the 10th percentile (hazard ratio, 3.79; 95% confidence interval, 1.73-8.30;
= 0.00085). An interaction was found between immunosuppression and LTL for the combined PANTHER-IPF and ACE-IPF clinical trials (
= 0.048), and the University of Texas Southwestern Medical Center IPF cohort (
= 0.00049).
LTL is a biomarker that may identify patients with IPF at risk for poor outcomes when exposed to immunosuppression.
Spagnolo and Oldham discuss the study by Molyneaux and coworkers on CYFRA 21-1 as an idiopathic pulmonary fibrosis (IPF) biomarker. IPF is an inexorably progressive interstitial lung disease of ...unknown origin with limited therapeutic options. Although the mechanisms underpinning IPF pathogenesis have yet to be fully elucidated, susceptibility is likely driven by complex interactions between genetic, environmental, and demographic risk factors. Among susceptible individuals, repetitive alveolar injury appears to cause aberrant activation of alveolar epithelial cells, which secrete profibrotic mediators that induce the expansion of hyperactive and apoptosis-resistant mesenchymal cells. These cells produce an excess of extracellular matrix, which leads to irreversible distortion of the lung parenchyma and progressive organ failure. Despite these mechanistic insights, limited understanding of disease etiology continues to hinder prevention and development of novel pharmacotherapies.
Gastroesophageal reflux disease (GERD) is a common comorbidity in patients with interstitial lung disease (ILD). We built and validated a model using the national inpatient sample (NIS) database to ...assess the contributory role of GERD in ILD-related hospitalizations mortality.
In this retrospective analysis, we extracted ILD-related hospitalizations data between 2007 and 2019 from the NIS database. Univariable logistic regression was used for predictor selection. Data were split into the training and validation cohorts (0.6 and 0.4, respectively). We used decision tree analysis (classification and regression tree, CART) to create a predictive model to explore the role of GERD in ILD-related hospitalizations mortality. Different metrics were used to evaluate our model. A bootstrap-based technique was implemented to balance our training data outcome to improve our model metrics in the validation cohort. We conducted a variance-based sensitivity analysis to evaluate GERD's importance in our model.
The model had a sensitivity of 73.43%, specificity of 66.15%, precision of 0.27, negative predictive value (NPV) of 93.62%, accuracy of 67.2%, Matthews Correlation Coefficient (MCC) of 0.3, F1 score of 0.4, and area under the curve (AUC) for the receiver operating characteristic (ROC) curve of 0.76. GERD did not predict survival in our cohort. GERD contribution to the model was ranked the eleventh among twenty-nine variables included in this analysis (importance of 0.003, normalized importance of 5%). GERD was the best predictor in ILD-related hospitalizations who didn't receive mechanical ventilation.
GERD is associated with mild ILD-related hospitalization. Our model-performance measures suggest overall an acceptable discrimination. Our model showed that GERD does not have a prognostic value in ILD-related hospitalization, indicating that GERD per se might not have any impact on mortality in hospitalized ILD patients.
There is an urgent need for simple, cost-effective prognostic biomarkers for idiopathic pulmonary fibrosis (IPF); biomarkers that show potential include monocyte count.
We used pooled data from ...pirfenidone and interferon gamma-1b trials to explore the association between monocyte count and prognosis in patients with IPF.
This retrospective pooled analysis included patients (active and placebo arms) from four Phase III, randomized, placebo-controlled trials: ASCEND (NCT01366209), CAPACITY (NCT00287729 and NCT00287716), and INSPIRE (NCT00075998). Outcomes included IPF progression (≥10% absolute decline in percent predicted forced vital capacity, ≥50 m decline in 6-minute walk distance, or death), all-cause hospitalization, and all-cause mortality over 1 year. The relationship between monocyte count (defined as time-dependent) and outcomes was assessed using bivariate and multivariable models.
This analysis included 2067 patients stratified by monocyte count (at baseline: <0.60 GI/L n=1609, 0.60-<0.95 GI/L n=408, and ≥0.95 GI/L n=50). In adjusted analyses, a higher proportion of patients with monocyte counts of 0.60-<0.95 GI/L or ≥0.95 GI/L versus <0.60 GI/L experienced IPF progression (p=0.016 and p=0.002, respectively), all-cause hospitalization (p=0.030 and p=0.003, respectively), and all cause mortality (p=0.005 and p<0.001, respectively) over 1 year. Change in monocyte count from baseline was not associated with any of the outcomes over 1 year and did not appear to be affected by study treatment.
In patients with IPF, elevated monocyte count was associated with increased risks of IPF progression, hospitalization, and mortality. Monocyte count may provide a simple and inexpensive prognostic biomarker in IPF. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Acute exacerbation of interstitial lung disease (ILD) is associated with a poor prognosis and high mortality. Numerous studies have documented acute exacerbation in idiopathic pulmonary fibrosis ...(IPF), but less is known about these events in other ILDs that may present a progressive-fibrosing phenotype. We propose defining acute exacerbation as an acute, clinically significant respiratory deterioration, typically less than 1 month in duration, together with computerised tomography imaging showing new bilateral glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILDs. Drawing on observations in IPF, it is suspected that epithelial injury or proliferation and autoimmunity are risk factors for acute exacerbation in ILDs that may present a progressive-fibrosing phenotype, but further studies are required. Current acute exacerbation management strategies are based on recommendations in IPF, but no randomised controlled trials of acute exacerbation management have been performed. Although there are no formal strategies to prevent the development of acute exacerbation, possible approaches include antifibrotic drugs (such as nintedanib and pirfenidone), and minimising exposure to infection, airborne irritants and pollutants. This review discusses the current knowledge of acute exacerbation of ILDs that may present a progressive-fibrosing phenotype and acknowledges limitations of the data available.
Proposed criteria for progressive fibrosing interstitial lung disease (PF-ILD) have been linked to increased mortality risk, but lung function trajectory after satisfying individual criteria remains ...unknown. Because survival is rarely employed as the primary end-point in therapeutic trials, identifying PF-ILD criteria that best predict subsequent change in forced vital capacity (FVC) could improve clinical trial design.
A retrospective, multicentre longitudinal cohort analysis was performed in consecutive patients with fibrotic connective tissue disease-associated ILD (CTD-ILD), chronic hypersensitivity pneumonitis and idiopathic interstitial pneumonia at three US centres (test cohort) and one UK centre (validation cohort). 1-year change in FVC after satisfying proposed PF-ILD criteria was estimated using joint modelling. Subgroup analyses were performed to determine whether results varied across key subgroups.
1227 patients were included, with CTD-ILD predominating. Six out of nine PF-ILD criteria were associated with differential 1-year change in FVC, with radiological progression of fibrosis, alone and in combination with other features, associated with the largest subsequent decline in FVC. Findings varied significantly by ILD subtype, with CTD-ILD demonstrating little change in FVC after satisfying most PF-ILD criteria, while other ILDs showed significantly larger changes. Findings did not vary after stratification by radiological pattern or exposure to immunosuppressant therapy. Near-term change in FVC after satisfying proposed PF-ILD criteria was heterogeneous depending on the criterion assessed and was strongly influenced by ILD subtype.
These findings may inform future clinical trial design and suggest ILD subtype should be taken into consideration when applying PF-ILD criteria.
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