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. 2024 Apr 4;63(4):2300127.
doi: 10.1183/13993003.00127-2023. Print 2024 Apr.

Mortality surrogates in combined pulmonary fibrosis and emphysema

An Zhao  1   2 , Eyjolfur Gudmundsson  1   2 , Nesrin Mogulkoc  3 , Coline van Moorsel  4 , Tamera J Corte  5 , Pardeep Vasudev  1   2 , Chiara Romei  6 , Robert Chapman  7 , Tim J M Wallis  8 , Emma Denneny  7 , Tinne Goos  9   10 , Recep Savas  11 , Asia Ahmed  12 , Christopher J Brereton  8 , Hendrik W van Es  4 , Helen Jo  5 , Annalisa De Liperi  6 , Mark Duncan  12 , Katarina Pontoppidan  8 , Laurens J De Sadeleer  10   13 , Frouke van Beek  4 , Joseph Barnett  14 , Gary Cross  15 , Alex Procter  12 , Marcel Veltkamp  4   16 , Peter Hopkins  17 , Yuben Moodley  18   19 , Alessandro Taliani  6 , Magali Taylor  12 , Stijn Verleden  20 , Laura Tavanti  21 , Marie Vermant  9   10 , Arjun Nair  12 , Iain Stewart  22 , Sam M Janes  23 , Alexandra L Young  2   24 , David Barber  25 , Daniel C Alexander  2 , Joanna C Porter  7 , Athol U Wells  26   27 , Mark G Jones  8 , Wim A Wuyts  9   10 , Joseph Jacob  28   2   23
Affiliations

Mortality surrogates in combined pulmonary fibrosis and emphysema

An Zhao et al. Eur Respir J. .

Abstract

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.

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Conflict of interest statement

Conflict of interest: J. Jacob reports fees from Boehringer Ingelheim, Roche, NHSX, Takeda and GlaxoSmithKline, unrelated to the submitted work, and was supported by Wellcome Trust Clinical Research Career Development Fellowship 209553/Z/17/Z and the NIHR Biomedical Research Centre at University College London. N. Mogulkoc reports grant TUBITAK (EJP Rare Disease project “COCOS-IPF”), fees from Boehringer Ingelheim, Roche, and Nobel Turkey unrelated to the submitted work, and received support for travel to meetings from Roche and Actelion. T.J. Corte reports unrestricted educational grants from Boehringer Ingelheim, Roche, Biogen and Galapagos, fees from Roche, BMS, Boehringer Ingelheim, Vicore and DevPro, assistance for travel to meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board for Roche, BMS, Boehringer Ingelheim, Vicore, Ad Alta, Bridge Biotherapeutics and DevPro. P. Vasudev reports financial interests from Blackford Analysis. T. Goos is supported by Research Foundation Flanders (1S73921N). L.J. De Sadeleer is supported by Marie Sklodowska-Curie actions postdoctoral fellowship within the European Union's Horizon Europe research and innovation programme. H. Jo reports fees from Boehringer Ingelheim and Roche, and received assistance for travel to meetings from Boehringer Ingelheim and Roche. S. Verleden reports consultancy fees from Boehringer Ingelheim and Sanofi. M. Vermant is supported by an FWO (Research Flanders Foundation) fellowship. S.M. Janes reports fees from AstraZeneca, Bard1 Bioscience, Achilles Therapeutics and Jansen unrelated to the submitted work, received assistance for travel to meetings from AstraZeneca and Takeda, and is the investigator lead on grants from GRAIL Inc., GlaxoSmithKline plc and Owlstone. A.U. Wells reports personal fees and non-financial support from Boehringer Ingelheim, Bayer and Roche Pharmaceuticals, and personal fees from Blade, outside of the submitted work. The remaining authors report no relevant conflicts of interest.

Figures

Figure 1
Figure 1. Computed tomography images of three subjects with 10% emphysema scored visually.
A 59-year-old male 5-pack-year ex-smoker with axial (a) and coronal (b) imaging shows extensive upper lobe paraseptal emphysema (black arrows) and also centrilobular emphysema (white arrows) in a predominantly upper lobe distribution. Fibrosis with traction bronchiectasis, ground glass opacification and reticulation is seen in a lower zone predominant distribution. Figure c+d show respectively axial and coronal images of mixed paraseptal (black arrows) and centrilobular emphysema (white arrows) in a 60-year-old male 17-pack-year ex-smoker. Axial images in a 72-year-old male 20-pack-year ex-smoker demonstrate a predominantly paraseptal distribution of emphysema (black arrows) in the upper (e) and lower (f) lobes with minimal centrilobular emphysema (white arrow).
Figure 2
Figure 2
Identification of CPFE subtypes and subtype disease progression modelled by SuStaIn in the derivation cohort (a) and replication cohort (b). The rows show progression patterns of fibrosis extent (in red) and emphysema extent (in blue) in 6 lung zones (upper, middle and lower) in the two CPFE subtypes identified by SuStaIn: Fibrosis-Dominant CPFE and Matched-CPFE. Seven disease stages are highlighted, expressed as z-score intervals. In the Fibrosis-Dominant CPFE subtype comprising 60% of the derivation cohort and 60% of the replication cohort (top two rows in (a) and (b)), fibrosis is more severe at an early stage followed by a later emergence of emphysema. In the Matched-CPFE subtype comprising 40% of the derivation cohort and 39% of the replication cohort (bottom two rows in (a) and (b)), fibrosis and emphysema get worse together, with later stages showing relatively more extensive emphysema and less fibrosis compared to the Fibrosis-Dominant CPFE subtype. The upper lobe predominance of emphysema seen at early disease stages no longer exists in the later stages of the Matched-CPFE subtype. CPFE: combined pulmonary fibrosis and emphysema. This figure was produced with the assistance of Servier Medical Art (https://smart.servier.com).
Figure 3
Figure 3
Kaplan-Meier curves of non-CPFE IPF patients (red), CPFE patients with emphysema <10% (green) and CPFE patients with emphysema ≥10% (blue) in the derivation cohort (a), the replication cohort (b), combined derivation and replication cohort patients qualifying for therapeutic trials (c). Log-rank tests show a significant difference in mortality between the three subtypes in all three analyses.
See this image and copyright information in PMC

Comment in

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