Background Idiopathic pulmonary fibrosis (IPF) with co-existent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may be associated with reduced FVC decline compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts.

Methods Visual emphysema extent (CPFE:non-CPFE: derivation cohort=317:183; replication cohort=358:152), scored on computed tomography imaging subgrouped CPFE patients using either a) 10%, or b) 15% visual emphysema threshold, or c) an unsupervised machine learning model considering emphysema and ILD extents. Baseline characteristics, 1-year forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLco) decline (linear mixed effects models), and their associations with mortality (multivariable Cox regression models) were compared across CPFE and non-CPFE subgroups.

Results In both IPF cohorts, CPFE patients with >10% emphysema had a greater smoking history and lower baseline DLco compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with >10% emphysema, 1-year DLco decline was a better indicator of mortality than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials.

Results were replicated in the >15% emphysema population 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 comparable mortality associations.

Conclusion When assessing disease progression in IPF, DLco decline should be considered in patients with >10% emphysema and a >5% 1-year FVC decline threshold considered in non-CPFE IPF patients.

JJ reports fees from Boehringer Ingelheim, Roche, NHSX, Takeda and GlaxoSmithKline unrelated to the submitted work. JJ was supported by Wellcome Trust Clinical Research Career Development Fellowship 209553/Z/17/Z and the NIHR Biomedical Research Centre at University College London. NM reports grant TUBITAK (EJP Rare Disease project "COCOS-IPF"), fees from Boehringer, Ingelheim, Roche, and Nobel Turkey unrelated to the submitted work. NM received support for travel to ATS 2020 and ATS 2021 from Roche, and to ERS 2020 from Actelion. TG is supported by Research Foundation-Flanders (FWO)-1S73921N. LJDS is supported by Marie Sklodowska-Curie actions post-doctoral fellowship within the European Union's Horizon Europe research and innovation programme. HJ reports fees from Boehringer ingelheim and Roche. HJ received assistance for travel to meetings from Boehringer Ingelheim and Roche. SV reports consultancy fees from Boehringer-Ingelheim and Sanofi. MV is supported by FWO (Research Flanders Foundation) Fellowship. SMJ reports fees from Astra-Zeneca, Bard1 Bioscience, Achilles Therapeutics, and Jansen unrelated to the submitted work. SMJ received assistance for travel to meetings from Astra Zeneca to American Thoracic Conference 2018 and from Takeda to World Conference Lung Cancer 2019 and is the Investigator Lead on grants from GRAIL Inc, GlaxoSmithKline plc and Owlstone. AUW reports personal fees and non-financial support from Boehringer Ingelheim, Bayer and Roche Pharmaceuticals; and personal fees from Blade, outside of the submitted work. AZ, EG, CvM, RC, TJMW, ED, RS, AA, CJB, HWvE, MD, KP, FvB, GC, AP, MV, YM, MT, AN, IS, ALY, DB, DCA, JCP, MGJ, RS, WAW report no relevant conflicts of interest.

This research was funded in whole or in part by the Wellcome Trust [209553/Z/17/Z]. This project, JJ, EG, ED, SMJ and JCP were also supported by the NIHR UCLH Biomedical Research Centre, UK. MGJ, TJMW and CJB acknowledge the support of the NIHR Southampton Biomedical Research Centre. AZ was supported by CSC-UCL Joint Research Scholarship. The Australian IPF Registry is an initiative of Lung Foundation Australia and is supported by Foundation partners Boehringer Ingelheim, Roche Products Pty. Limited.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Research ethics committees of: St Antonius Hospitals, Leuven University Hospital, Southampton University Hospitals, Pisa University Hospitals, University College London Hospitals, Izmir University Hospital and the Sydney Local Health District Board gave ethical approval for this work. Further approval for this retrospective study of clinically indicated pulmonary function and CT data were obtained from Leeds East Research Ethics Committee: 20/YH/0120.

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