Exposure to smoking and organic materials such as mold and dust were among several sources significantly associated with a risk of developing interstitial lung disease (ILD), according to results from a large systematic review and meta-analysis.1
“While there have been small studies in the past investigating the role of inhalational exposures on specific interstitial lung diseases, this is the largest and most comprehensive systematic review and meta-analysis of its kind investigating the role of myriad inhalational exposures on ILD as a whole,” said lead author Cathryn T. Lee, MD, MS, a pulmonary and critical care physician at the University of Chicago.
For the study published in Thorax, researchers used data from the MEDLINE and EMBASE databases from 1990 to 2022 to identify inhalation exposures associated with a diagnosis of ILD. After excluding studies related to sarcoidosis and ILDs with well-established causality, such as hypersensitivity pneumonitis and pneumoconiosis, 96 studies—comprising more than 40,819,116 individuals—were included in the systematic review. Of those patients, 295,167 had a diagnosis of ILD and 40,523,949 were controls. The meta-analysis included 54 studies with 40,490,793 individuals. Of these, 273,899 had an ILD diagnosis and 40,216,894 were controls.
Dr. Lee and colleagues pooled the data where possible and used a random effects model to conduct a multilevel meta-analysis. Exposures associated with significantly increased ILD risk were smoking (OR 1.69, 95% CI 1.47 to 1.94), organic exposures (OR 1.56, 95% CI 1.12 to 2.16), metals (OR 1.52, 95% CI 1.07 to 2.16), dust (OR 1.45, 95% CI 1.20 to 1.76), and asbestos (OR 1.53, 95% CI 1.08 to 2.15). Exposures to silica and fumes showed positive associations with ILD, with trends toward statistical significance, though these estimates are less precise due to rarer exposures.
“We were surprised to find that air pollutants did not have a significant association with ILD incidence, especially given their known effect on ILD progression,” Dr. Lee said. “We think this may be related to the heterogenous composition of air pollution itself but did not have significant power in order to test for individual pollutant effects. Future research should clarify the relationship between air pollution and incident ILD.”
Insights not revealed by this study, including the mechanistic pathways linking exposures to fibrosis and inflammation as well as gene-environment interactions and individual susceptibility, could be additonal areas for future research.
Dr. Lee acknowledged several limitations of the study, including the imperfect classification of individual exposure types into groups and the high risk of bias, as all included studies were observational. Additionally, the definition of ILD was highly variable and not standardized, as diagnoses could have been based on clinical observation, imaging, or administrative codes.
Bradford C. Bemiss, MD, MSc, a pulmonologist at Northwestern Medicine, Chicago, who was not affiliated with the study, said the findings underscore the importance of asking patients with ILD about potential workplace inhalation exposures.
“Even in cases of IPF, idiopathic disease, there is often a possible trigger for exposure if questioned in the right way at disease presentation,” he said. “We often describe the process of IPF and ILD development as a disordered wound healing process. This highlights that there really is injury occurring in patients even when it is not thought to be the primary etiology of their disease.”
He added that he would like to see more questions answered in future research, such as whether mask use reduces ILD risk, how vaping compares to smoking, and if air pollution contributes to an urban-rural divide in ILD cases. Other important factors that would impact future research include studying underrepresented ILD subtypes and gathering data from low- and middle-income countries where exposures and regulations differ.
References
1. Lee C, Gandhi S, Elmrayed S, et al. Inhalational exposures associated with risk of interstitial lung disease: a systematic review and meta-analysis. Thorax. Published online June 15, 2025. doi:10.1136/thorax-2024-222306
