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. 2022 Aug;27(8):635-644.
doi: 10.1111/resp.14267. Epub 2022 May 5.

Inhalational exposures in patients with fibrotic interstitial lung disease: Presentation, pulmonary function and survival in the Canadian Registry for Pulmonary Fibrosis

Cathryn T Lee  1 , Mary E Strek  1 , Ayodeji Adegunsoye  1 , Alyson W Wong  2   3 , Deborah Assayag  4 , Gerard Cox  5 , Charlene D Fell  6 , Jolene H Fisher  7 , Andrea S Gershon  7 , Andrew J Halayko  8 , Nathan Hambly  5 , Nasreen Khalil  9 , Martin Kolb  5 , Stacey D Lok  10 , Hélène Manganas  11 , Veronica Marcoux  10 , Julie Morisset  11 , Mohsen Sadatsafavi  12 , Shane Shapera  7 , Teresa To  13 , Pearce Wilcox  2 , Christopher J Ryerson  2   3 , Kerri A Johannson  6
Affiliations

Inhalational exposures in patients with fibrotic interstitial lung disease: Presentation, pulmonary function and survival in the Canadian Registry for Pulmonary Fibrosis

Cathryn T Lee et al. Respirology. 2022 Aug.

Abstract

Background and objective: Inhalational exposures are a known cause of interstitial lung disease (ILD), but little is understood about their prevalence across ILD subtypes and their relationship with pulmonary function and survival.

Methods: Patients with fibrotic ILD were identified from the multicentre Canadian Registry for Pulmonary Fibrosis. Patients completed questionnaires regarding ILD-related occupational and environmental exposures. The relationship between exposures and the outcomes of baseline age, gender, family history, pulmonary function and survival was analysed using linear and logistic regression models, linear mixed-effect regression models and survival analysis using multivariable Cox proportional hazards along with the log-rank test.

Results: There were 3820 patients included in this study, with 2385 (62%) having ILD-related inhalational exposure. Exposed patients were younger, particularly in the idiopathic pulmonary fibrosis subgroup. Inhalational exposure was associated with male gender (adjusted OR 1.46, 95% CI 1.28-1.68, p < 0.001) and family history of pulmonary fibrosis (adjusted OR 1.73, 95% CI 1.40-2.15, p < 0.001). Patients with any inhalational exposure had improved transplant-free survival (hazard ratio 0.81, 95% CI 0.71-0.92, p = 0.001); this effect persisted across diagnostic subtypes. The relationship between exposures and annual change in forced vital capacity varied by ILD subtype.

Conclusion: Patients with fibrotic ILD report high prevalence of inhalational exposures across ILD subtypes. These exposures were associated with younger age at diagnosis, male gender and family history of pulmonary fibrosis. Identification of an inhalational exposure was associated with a survival benefit. These findings suggest that inhaled exposures may impact clinical outcomes in patients with ILD, and future work should characterize the mechanisms underlying these relationships.

Keywords: CARE-PF; Canadian Registry for Pulmonary Fibrosis; fibrotic interstitial lung disease; inhalational exposure; occupational exposure.

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Conflict of interest statement

CARE‐PF is supported by Boehringer Ingelheim. The study sponsor had no input on the research question, study design, data analysis, interpretation of results or production of the manuscript. Cathryn T. Lee has received grant funding from the National Institute of Health (T32HL007605). Ayodeji Adegunsoye has received grant funding from the National Institute of Health (K23HL146942), American College of Chest Physicians and the Pulmonary Fibrosis Foundation, and honoraria from Boehringer Ingelheim. Mary E. Strek has received grants from Boehringer Ingelheim and Galapagos, honoraria from the American College of Chest Physicians, served on an advisory board for Fibrogen, served on committees for the American Thoracic Society and received medical writing support from Boehringer Ingelheim. Alyson W. Wong has received honoraria from Boehringer Ingelheim and AstraZeneca. Deborah Assayag has received a research grant from Boehringer Ingelheim Canada and served on advisory boards for Hoffman LaRoche Canada and Boehringer Ingelheim Canada. Charlene D. Fell has received personal fees from Brigham & Women's Hospital, Novartis and Galapagos; honoraria from Boehringer Ingelheim and Roche Canada; and has leadership roles with the Canadian Pulmonary Fibrosis Foundation and the Canadian Thoracic Society. Jolene H. Fisher has received grants from the Canadian Pulmonary Fibrosis Foundation and the University of Toronto, consulting fees from Boehringer Ingelheim and AstraZeneca and is a member of the Canadian Pulmonary Fibrosis Advisory Board. Andrew J. Halayko is a member of the American Thoracic Society Board of Directors, including the Finance Committee. Nathan Hambly has received grants and personal fees from Boehringer Ingelheim, Roche, Janssen and Bayer. Martin Kolb has received grants from Boehringer Ingelheim, Pieris and Roche; consulting fees from Boehringer Ingelheim, Roche, Horizon, Cipla, Abbvie, Belerophon, Algernon and CSL Behring; honoraria from Novartis, Boehringer Ingelheim and Roche; payment for expert testimony from Roche; served on advisory boards for Covance and United Therapeutics; and receives a Chief Editor allowance from the ERJ. Stacey D. Lok has received honoraria from Boehringer Ingelheim. Hélène Manganas has received research grants from Boehringer Ingelheim, Galapagos and BMS, and participates in an advisory board for Boehringer Ingelheim. Veronica Marcoux has received grants from AstraZeneca and Roche, consulting fees from Boehringer Ingelheim Canada and Roche LTD and honoraria from Boehringer Ingelheim. Julie Morisset has received consulting fees from Hoffman‐La Roche and Boehringer Ingelheim, honoraria from Hoffman‐La Roche and Boehringer Ingelheim and participated on advisory boards for Hoffman‐La Roche and Boehringer Ingelheim. Shane Shapera has received honoraria from Hoffman‐LaRoche Canada, Boehringer Ingelheim and AstraZeneca Canada; participated in advisory boards for Hoffman‐La Roche Canada and Boehringer Ingelheim; and participated in clinical trial research for Hoffman‐La Roche Canada, Boehringer Ingelheim, Galapagos, Galecto and Gilead Pharmaceuticals. Pearce Wilcox has received consulting fees from Boehringer Ingelheim, honoraria from Vertex and Glaxo Smith Kline and served on an advisory board for the Cystic Fibrosis Foundation. Christopher J. Ryerson has received grant funding from Boehringer Ingelheim and Hoffmann‐La Roche; consulting fees from Boehringer Ingelheim, Hoffman‐La Roche, AstraZeneca and Veracyte; honoraria from Boehringer Ingelheim and Hoffmann‐La Roche; and travel support from Cipla Ltd and Boehringer Ingelheim. Kerri A. Johannson has received grants from Three Lakes Foundation, Chest Foundation, University of Calgary CSM and University Hospital Foundation; consulting fees from Boehringer Ingelheim, Hoffman‐La Roche Ltd, Pliant Therapeutics, Blade Therapeutics, Theravance and Three Lakes Foundation; honoraria from Boehringer Ingelheim and Hoffman‐La Roche Ltd; and served on an advisory board for PFOX trial. Gerard Cox, Andrea S. Gershon, Nasreen Khalil, Mohsen Sadatsafavi and Teresa To have no conflicts of interest to disclose.

Figures

FIGURE 1
FIGURE 1
Prevalence of inhalational exposure type by interstitial lung disease subtype. CTD, connective tissue disease; HP, hypersensitivity pneumonitis; IPF, idiopathic pulmonary fibrosis
FIGURE 2
FIGURE 2
Relationship between annual change in FVC and exposure status, stratified by interstitial lung disease diagnosis. Positive values represent yearly FVC improvement, while negative values represent yearly FVC decline. Bracket with * indicates p < 0.05 compared to no exposure. CTD, connective tissue disease; FVC, forced vital capacity; HP, hypersensitivity pneumonitis; IPF, idiopathic pulmonary fibrosis
FIGURE 3
FIGURE 3
(A) Kaplan–Meier curve of transplant‐free survival of the entire cohort by inhalational exposure. (B) Relationship between any exposure and hazard of lung transplant or death, by interstitial lung disease subtype. Hazard ratios below 1 indicate that exposure decreases the likelihood of lung transplant or death. CTD, connective tissue disease; HP, hypersensitivity pneumonitis; IPF, idiopathic pulmonary fibrosis
FIGURE 4
FIGURE 4
Relationship between exposure subtypes and hazard of lung transplant or death, by interstitial lung disease subtype. Hazard ratios (HRs) above 1 indicate that exposure increases the likelihood of lung transplant or death, while HRs below 1 indicate that exposure decreases the likelihood of lung transplant or death. (A) Organic exposure (compared to no inhalational exposure), (B) inorganic exposure (compared to no exposure history) and (C) both organic and inorganic exposures (compared to no exposure history). CTD, connective tissue disease; HP, hypersensitivity pneumonitis; IPF, idiopathic pulmonary fibrosis
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