Treatment of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis: A position statement from the Thoracic Society of Australia and New Zealand 2023 revision.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease leading to significant morbidity and mortality. In 2017 the Thoracic Society of Australia and New Zealand (TSANZ) and Lung Foundation Australia (LFA) published a position statement on the treatment of IPF. Since that time, subsidized anti-fibrotic therapy in the form of pirfenidone and nintedanib is now available in both Australia and New Zealand. More recently, evidence has been published in support of nintedanib for non-IPF progressive pulmonary fibrosis (PPF). Additionally, there have been numerous publications relating to the non-pharmacologic management of IPF and PPF. This 2023 update to the position statement for treatment of IPF summarizes developments since 2017 and reaffirms the importance of a multi-faceted approach to the management of IPF and progressive pulmonary fibrosis.

Telomere biology disorder presenting acutely with pulmonary fibrosis and hepatopulmonary syndrome in a young adult male.

A 33-year-old man presented with acute dyspnoea and profound hypoxaemia, and had clubbing, greying of hair, orthodeoxia and fine inspiratory crackles. CT chest showed established pulmonary fibrosis in a usual interstitial pneumonia pattern. Additional investigations revealed a small patent foramen ovale, pancytopenia, and oesophageal varices and portal hypertensive gastropathy from liver cirrhosis. Telomere length testing demonstrated short telomeres (<1st percentile), confirming the diagnosis of a telomere biology disorder. An interstitial lung disease gene panel identified a pathogenic variant in TERT (c.1700C>T, p.(Thr567Met)) and a variant of uncertain significance in PARN (c.1159G>A, p.(Gly387Arg)). Combined lung and liver transplantation was deemed not suitable due to frailty and severe hepatopulmonary syndrome, and he died 56 days after presentation. Early recognition of the short telomere syndrome is important, and its multi-organ involvement poses challenges to management. Genetic screening may be important in younger patients with pulmonary fibrosis or in unexplained liver cirrhosis.

Long-term exposure to low concentrations of air pollution and decline in lung function in people with idiopathic pulmonary fibrosis: Evidence from Australia.

BACKGROUND AND OBJECTIVE: Little is known about the association between ambient air pollution and idiopathic pulmonary fibrosis (IPF) in areas with lower levels of exposure. We aimed to investigate the impact of air pollution on lung function and rapid progression of IPF in Australia. METHODS: Participants were recruited from the Australian IPF Registry (n = 570). The impact of air pollution on changes in lung function was assessed using linear mixed models and Cox regression was used to investigate the association with rapid progression. RESULTS: Median (25th-75th percentiles) annual fine particulate matter (<2.5 µm, PM2.5 ) and nitrogen dioxide (NO2 ) were 6.8 (5.7, 7.9) µg/m3 and 6.7 (4.9, 8.2) ppb, respectively. Compared to living more than 100 m from a major road, living within 100 m was associated with a 1.3% predicted/year (95% confidence interval [CI] -2.4 to -0.3) faster annual decline in diffusing capacity of the lungs for carbon monoxide (DLco). Each interquartile range (IQR) of 2.2 µg/m3 increase in PM2.5 was associated with a 0.9% predicted/year (95% CI -1.6 to -0.3) faster annual decline in DLco, while there was no association observed with NO2 . There was also no association between air pollution and rapid progression of IPF. CONCLUSION: Living near a major road and increased PM2.5 were both associated with an increased rate of annual decline in DLco. This study adds to the evidence supporting the negative effects of air pollution on lung function decline in people with IPF living at low-level concentrations of exposure.

Machine learning in radiology: the new frontier in interstitial lung diseases.

Challenges for the effective management of interstitial lung diseases (ILDs) include difficulties with the early detection of disease, accurate prognostication with baseline data, and accurate and precise response to therapy. The purpose of this Review is to describe the clinical and research gaps in the diagnosis and prognosis of ILD, and how machine learning can be applied to image biomarker research to close these gaps. Machine-learning algorithms can identify ILD in at-risk populations, predict the extent of lung fibrosis, correlate radiological abnormalities with lung function decline, and be used as endpoints in treatment trials, exemplifying how this technology can be used in care for people with ILD. Advances in image processing and analysis provide further opportunities to use machine learning that incorporates deep-learning-based image analysis and radiomics. Collaboration and consistency are required to develop optimal algorithms, and candidate radiological biomarkers should be validated against appropriate predictors of disease outcomes.

Multi-center evaluation of baseline neutrophil-to-lymphocyte (NLR) ratio as an independent predictor of mortality and clinical risk stratifier in idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess the potential of neutrophil-to-lymphocyte ratio (NLR) to predict outcomes in IPF. Methods: We adopted a two-stage discovery (n = 71) and validation (n = 134) design using patients from the UCL partners (UCLp) cohort. We then combined discovery and validation cohorts and included an additional 794 people with IPF, using real-life data from 5 other UK centers, to give a combined cohort of 999 patients. Data were collected from patients presenting over a 13-year period (2006-2019) with mean follow up of 3.7 years (censoring: 2018-2020). Findings: In the discovery analysis, we showed that high values of NLR (>/ = 2.9 vs < 2.9) were associated with increased risk of mortality in IPF (HR 2.04, 95% CI 1.09-3.81, n = 71, p = 0.025). This was confirmed in the validation (HR 1.91, 95% CI 1.15-3.18, n = 134, p = 0.0114) and combined cohorts (HR 1.65, n = 999, 95% CI 1.39-1.95; p < 0·0001). NLR correlated with GAP stage and GAP index (p < 0.0001). Stratifying patients by NLR category (low/high) showed significant differences in survival for GAP stage 2 (p < 0.0001), however not for GAP stage 1 or 3. In a multivariate analysis, a high NLR was an independent predictor of mortality/progression after adjustment for individual GAP components and steroid/anti-fibrotic use (p < 0·03). Furthermore, incorporation of baseline NLR in a modified GAP-stage/index, GAP-index/stage-plus, refined prognostic ability as measured by concordance (C)-index. Interpretation: We have identified NLR as a widely available test that significantly correlates with lung function, can predict outcomes in IPF and refines cohort staging with GAP. NLR may allow timely prioritisation of at-risk patients, even in the absence of lung function. Funding: Breathing Matters, GSK, CF Trust, BLF-Asthma, MRC, NIHR Alpha-1 Foundation.

Quantitative computed tomography predicts outcomes in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Prediction of disease course in patients with progressive pulmonary fibrosis remains challenging. The purpose of this study was to assess the prognostic value of lung fibrosis extent quantified at computed tomography (CT) using data-driven texture analysis (DTA) in a large cohort of well-characterized patients with idiopathic pulmonary fibrosis (IPF) enrolled in a national registry. METHODS: This retrospective analysis included participants in the Australian IPF Registry with available CT between 2007 and 2016. CT scans were analysed using the DTA method to quantify the extent of lung fibrosis. Demographics, longitudinal pulmonary function and quantitative CT metrics were compared using descriptive statistics. Linear mixed models, and Cox analyses adjusted for age, gender, BMI, smoking history and treatment with anti-fibrotics were performed to assess the relationships between baseline DTA, pulmonary function metrics and outcomes. RESULTS: CT scans of 393 participants were analysed, 221 of which had available pulmonary function testing obtained within 90 days of CT. Linear mixed-effect modelling showed that baseline DTA score was significantly associated with annual rate of decline in forced vital capacity and diffusing capacity of carbon monoxide. In multivariable Cox proportional hazard models, greater extent of lung fibrosis was associated with poorer transplant-free survival (hazard ratio [HR] 1.20, p < 0.0001) and progression-free survival (HR 1.14, p < 0.0001). CONCLUSION: In a multi-centre observational registry of patients with IPF, the extent of fibrotic abnormality on baseline CT quantified using DTA is associated with outcomes independent of pulmonary function.

Deep Learning-based Outcome Prediction in Progressive Fibrotic Lung Disease Using High-Resolution Computed Tomography.

Rationale: Reliable outcome prediction in patients with fibrotic lung disease using baseline high-resolution computed tomography (HRCT) data remains challenging. Objectives: To evaluate the prognostic accuracy of a deep learning algorithm (SOFIA [Systematic Objective Fibrotic Imaging Analysis Algorithm]), trained and validated in the identification of usual interstitial pneumonia (UIP)-like features on HRCT (UIP probability), in a large cohort of well-characterized patients with progressive fibrotic lung disease drawn from a national registry. Methods: SOFIA and radiologist UIP probabilities were converted to Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED)-based UIP probability categories (UIP not included in the differential, 0-4%; low probability of UIP, 5-29%; intermediate probability of UIP, 30-69%; high probability of UIP, 70-94%; and pathognomonic for UIP, 95-100%), and their prognostic utility was assessed using Cox proportional hazards modeling. Measurements and Main Results: In multivariable analysis adjusting for age, sex, guideline-based radiologic diagnosis, anddisease severity (using total interstitial lung disease [ILD] extent on HRCT, percent predicted FVC, DlCO, or the composite physiologic index), only SOFIA UIP probability PIOPED categories predicted survival. SOFIA-PIOPED UIP probability categories remained prognostically significant in patients considered indeterminate (n = 83) by expert radiologist consensus (hazard ratio, 1.73; P < 0.0001; 95% confidence interval, 1.40-2.14). In patients undergoing surgical lung biopsy (n = 86), after adjusting for guideline-based histologic pattern and total ILD extent on HRCT, only SOFIA-PIOPED probabilities were predictive of mortality (hazard ratio, 1.75; P < 0.0001; 95% confidence interval, 1.37-2.25). Conclusions: Deep learning-based UIP probability on HRCT provides enhanced outcome prediction in patients with progressive fibrotic lung disease when compared with expert radiologist evaluation or guideline-based histologic pattern. In principle, this tool may be useful in multidisciplinary characterization of fibrotic lung disease. The utility of this technology as a decision support system when ILD expertise is unavailable requires further investigation.

TELO-SCOPE study: a randomised, double-blind, placebo-controlled, phase 2 trial of danazol for short telomere related pulmonary fibrosis.

INTRODUCTION: Recent discoveries have identified shortened telomeres and related mutations in people with pulmonary fibrosis (PF). There is evidence to suggest that androgens, including danazol, may be effective in lengthening telomeres in peripheral blood cells. This study aims to assess the safety and efficacy of danazol in adults and children with PF associated with telomere shortening. METHODS AND ANALYSIS: A multi-centre, double-blind, placebo-controlled, randomised trial of danazol will be conducted in subjects aged >5 years with PF associated with age-adjusted telomere length ≤10th centile measured by flow fluorescence in situ hybridisation; or in children, a diagnosis of dyskeratosis congenita. Adult participants will receive danazol 800 mg daily in two divided doses or identical placebo capsules orally for 12 months, in addition to standard of care (including pirfenidone or nintedanib). Paediatric participants will receive danazol 2 mg/kg/day orally in two divided doses or identical placebo for 6 months. If no side effects are encountered, the dose will be escalated to 4 mg/kg/day (maximum 800 mg daily) orally in two divided doses for a further 6 months. The primary outcome is change in absolute telomere length in base pairs, measured using the telomere shortest length assay (TeSLA), at 12 months in the intention to treat population. ETHICS AND DISSEMINATION: Ethics approval has been granted in Australia by the Metro South Human Research Ethics Committee (HREC/2020/QMS/66385). The study will be conducted and reported according to Standard Protocol Items: Recommendations for Interventional Trials guidelines. Results will be published in peer-reviewed journals and presented at international and national conferences. TRIAL REGISTRATION NUMBERS: NCT04638517; Australian New Zealand Clinical Trials Registry (ACTRN12620001363976p).

Interstitial pneumonia with autoimmune features: challenges and controversies.

The presence of clinical, serological and/or radiological features suggestive, but not confirmatory, of a defined connective tissue disease in patients with interstitial lung disease is a relatively frequent occurrence. In 2015, the European Respiratory Society and the American Thoracic Society proposed classification criteria for the interstitial pneumonia with autoimmune features (IPAF) research entity to capture such patients in a standardised manner, with the intention of nurturing clinical research. This initiative resulted in the publication of several series of IPAF patients, with significant variation between cohorts in clinical characteristics, outcome and the application of IPAF criteria in patient selection. From this increasing body of published work, it has become apparent that revision of IPAF criteria is now required in order to justify the eventual designation of IPAF as a standalone diagnostic term, as opposed to a provisional entity put forward as a basis for clinical research. This review covers the current state of IPAF, conclusions that can and cannot be drawn from the IPAF evidence base, and ongoing uncertainties that require further expert group consideration.

Disease pathology in fibrotic interstitial lung disease: is it all about usual interstitial pneumonia?

The interstitial pneumonias comprise a diverse group of diseases that are typically defined by their cause (either idiopathic or non-idiopathic) and their distinct histopathological features, for which radiology, in the form of high-resolution CT, is often used as a surrogate. One trend, fuelled by the failure of conventional therapies in a subset of patients and the broad-spectrum use of antifibrotic therapies, has been the focus on the progressive fibrosing phenotype of interstitial lung disease. The histological pattern, known as usual interstitial pneumonia, is the archetype of progressive fibrosis. However, it is clear that progressive fibrosis is not exclusive to this histological entity. Techniques including immunohistochemistry and single-cell RNA sequencing are providing pathogenetic insights and, if integrated with traditional histopathology, are likely to have an effect on the pathological classification of interstitial lung disease. This review, which focuses on the histopathology of interstitial lung disease and its relationship with progressive fibrosis, asks the question: is it all about usual interstitial pneumonia?

Airway Telomere Length in Lung Transplant Recipients.

Introduction: Chronic lung allograft dysfunction (CLAD) represents the major impediment to long term survival following lung transplantation. Donor and recipient telomere length have been shown to associate with lung transplant outcomes, including CLAD. In this study we aimed to measure the telomere lengths of bronchial and bronchiolar airway cells in lung allografts early after transplantation and to investigate associations with CLAD and all-cause mortality. Methods: This prospective, longitudinal study was performed at The Prince Charles Hospital, Australia. Airway cells were collected via bronchial and bronchiolar airway brushings at post-transplant bronchoscopies. The relative telomere length in airway cells was determined by quantitative PCR based on the T/S ratio. All patients were censored for CLAD and all-cause mortality in August 2020. Results: In total 231 bronchoscopies incorporating transbronchial brush and bronchial brush were performed in 120 patients. At the time of censoring, 43% and 35% of patients, respectively, had developed CLAD and had died. Airway bronchiolar and bronchial telomere lengths were strongly correlated (r=0.78, p<0.001), confirming conservation of telomere length with airway branch generation. Both the bronchiolar (r = -0.34, p<0.001) and bronchial (r = -0.31, p<0.001) telomere length decreased with age. Shorter airway telomere length was associated with older donor age and higher donor pack-year smoking history. Neither the bronchiolar nor the bronchial airway telomere length were associated with the development of CLAD (HR 0.39 (0.06-2.3), p=0.30; HR 0.66 (0.2-1.7), p=0.39, respectively) or all-cause mortality (HR 0.92 (0.2-4.5), p=0.92; HR 0.47 (0.1-1.9), p=0.28, respectively). Conclusions: In this cohort, airway telomere length was associated with donor age and smoking history but was not associated with the future development of CLAD or all-cause mortality.