Exposure to PM <sub>2·5</sub> Is a Risk Factor for Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Abstract

Background: Ozone and nitrogen dioxide exposure over the preceding 0-42 days is a risk factor for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). However, the comprehensive roles of exposure to airborne particulate matter in AE-IPF remain unclear. Methods: Japanese patients with IPF were identified using the nationwide registry. Relationship between AE-IPF incidence and the eight air pollutant levels, including particulate matter <2·5 µm (PM2·5) and suspended particle matter (SPM), was assessed using Cox proportional hazards models after adjusting for several covariates. Two bulks of time (weekly and monthly time windows) sensitivity analyses were conducted to determine the highest risk exposure time window prior to the diagnosis of AE-IPF. Findings: Overall, 152 patients with surgical lung biopsy-diagnosed IPF were analyzed. Increased AE-IPF incidence was positively associated with an increased PM2·5 level (adjusted hazard ratio: 2·74; 95% confidence interval: 1·46-5·14) by 10 µg/m³ over the preceding 0-42 days. Weekly sensitivity analysis over the 12-week period demonstrated that the highest exposure risk to PM2·5 for AE-IPF was at 6th week prior to diagnosis. Monthly sensitivity analysis over the 6-month period demonstrated that the exposure periods for PM2·5 significantly associated with the risk for AE-IPF were recorded only during the period between 1 and 3 months prior to diagnosis. Interpretation: Our results show that PM2·5 is a risk factor for AE-IPF, and exposure time window related to AE-IPF may lie during the first 3 months, particularly at 6th week prior to diagnosis. Funding Statement: The authors declared: No specific funding. The underlying research reported by Fujisawa and colleagues was funded by the Practical Research Project for Rare Intractable Disease from the Japan Agency for Medical Research Group under the aegis of the Ministry of Health, Ministry of Health, Labor and Welfare, Japan. Declaration of Interests: MT reports grants from GlaxoSmithKline outside the submitted work, and received speakers fees from Boehringer Ingelheim and MSD outside the submitted work. Kyamasaki received speakers fees from Novartis outside the submitted work. TKido received speakers fees from Asahi Kasei, AstraZeneca, Boehringer Ingelheim, and TEIJIN outside the submitted work. NS received consultancy or speakers fees from Boehringer Ingelheim, CHUGAI, and Daiichi Sankyo outside the submitted work. TKawanami received speakers fees from KYORIN outside the submitted work. KK received speakers fees from Boehringer Ingelheim outside the submitted work. RE reports grants from the Japan Society for the Promotion of Science outside the submitted work, and received speakers fees from AstraZeneca, Boehringer Ingelheim，Daiichi Sankyo, EISAI, KYORIN and SHIONOGI outside the submitted work. YS reports grants from the Japan Society for the Promotion of Science, and the Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care outside the submitted work, and received industry-academic funding from MSD and Novartis outside the submitted work. HM received industry-academic funding from Asahi Kasei, Astellas, Boehringer Ingelheim, CHUGAI, Daiichi Sankyo, EISAI, Eli Lilly, Fujifilm, GlaxoSmithKline, KYORIN, Meiji Seika, MSD, Novartis, ONO, Oxford Immunotec, Pfizer, SHIONOGI, Sumitomo Dainippon, TAIHO, TAISHO, TAKEDA, TEIJIN, TORAY, TORII, Toyama Chemical, and Yakult outside the submitted work, and consultancy or speakers fees from Abbott, Asahi Kasei, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers, CHUGAI, Daiichi Sankyo, Denka Seiken, Eli Lilly, Fujifilm, GlaxoSmithKline, KYORIN, Meiji Seika, MSD, Mylan, Nihon Pharmaceutical, Nikkei Radio, Novartis, ONO, Pfizer, SHIONOGI, Sumitomo Dainippon, TAIHO, TAISHO, TEIJIN, TORAY, and Toyama Chemical outside the submitted work. TS received industry-academic funding from Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers, CHUGAI, Eli Lilly, Daiichi Sankyo, KYORIN, MITSUBISHI, MSD, Novartis, ONO, Pfizer, Sanofi, SHIONOGI, TAIHO, TAISHO, Taisho Toyama, TAKEDA, TANABE, and TEIJIN outside the submitted work, and consultancy or speakers fees from Astellas, AstraZeneca, Boehringer Ingelheim, CHUGAI, Eli Lilly, KYORIN, Daiichi Sankyo, SHIONOGI, MSD, Novartis, ONO, Pfizer, TAISHO, Taisho Toyama, and Tanabe Mitsubishi outside the submitted work. KYatera received industry-academic funding from Boehringer Ingelheim, GlaxoSmithKline, KYORIN, MSD, Novartis, ONO, Pfizer, TAIHO, TAISHO, and TEIJIN outside the submitted work, and consultancy or speakers fees from Asahi Kasei, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers, CHUGAI, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, KYORIN, MSD, Novartis, ONO, Pfizer, SHIONOGI, TAIHO, TAISHO, TEIJIN, and Toa Eiyo outside the submitted work. All other authors declare no competing interests. Ethics Approval Statement: The present study was approved by the institutional review boards of the University of Occupational and Environmental Health, Kitakyushu, Japan (18-013) and the Hamamatsu University School of Medicine, Hamamatsu, Japan (19-003).