Air pollution has various effects in fibrotic ILD
Air pollution has various effects on patients with fibrotic interstitial lung disease, according to preliminary research presented at the PFF Summit.
“There is evidence to indicate that airborne pollutants are associated with preclinical ILD — in other words, interstitial lung abnormalities and possibly the incidence of idiopathic pulmonary fibrosis. Other studies performed in patients with IPF have demonstrated that the variety of different pollutants are associated with adverse clinical outcomes, including acute exacerbations, lung function, decline and mortality,” Gillian C. Goobie, MD, FRCPC, PhD candidate in the department of human genetics at the Graduate School of Public Health at the University of Pittsburgh; PGY7 research fellow in the Clinician Investigator Program at the University of British Columbia, Vancouver, Canada; and 2020-2022 Pulmonary Fibrosis Foundation Scholar, said during the presentation. “But many of these studies are limited by some common factors, so there’s minimal consideration of non-IPF fibrotic ILD patients.”
Impacts of air pollution exposure
Goobie presented data on the impact of satellite-derived fine particulate matter (PM2.5) exposure on mortality, baseline lung function and lung function decline in 1,424 patients with fibrotic ILD (median age, 65.7 years; 44% women)
Using a dataset of aerosol optical depth measurements from Dalhousie University, researchers estimated air pollution exposures of PM2.5 and combined these estimates with chemical transport models and ground-based pollutant measurements to create an accurate and precise estimate of North American PM2.5 levels in any region.
Median PM2.5 exposure 5 years before fibrotic ILD diagnosis in this patient population was 11.4 µg/m3. From time to fibrotic ILD diagnosis to the time of censoring, which was defined as death, lung transplant or follow-up cessation, median PM2.5 exposure was 9.7 µg/m3. In addition, median PM2.5 exposure was 9.4 µg/m3 in the 5 years prior to censoring.
“Patients who were diagnosed earlier tended to have higher exposures to PM2.5 during their disease as compared to patients that were diagnosed later, and this is likely reflective of improving air quality over time, especially in the western Pennsylvania region where the Simmons Center for Interstitial Lung Disease at UMPC resides, and this may be due to the decrease in coal and industry-related pollution,” Goobie said.
Goobie and colleagues aim to perform the same analyses on 2,000 more patients from the Pulmonary Fibrosis Foundation patient registry and 4,000 more patients from the Canadian Registry for Pulmonary Fibrosis. Thus, this will be the largest evaluation of the impact of air pollution in patients with fibrotic ILDs and the only evaluation to assess fibrotic ILDs as a group, rather than specific diagnostic subgroups, according to Goobie.
Mortality analysis
Goobie presented results of a mortality analysis that separated patients into quartiles based on exposure to PM2.5: with quartile one (PM2.5 < 8.24 µg/m3), quartile two (PM2.5 8.25-9.71 µg/m3), quartile three (PM2.5 9.72-11.34 µg/m3) and quartile four (PM2.5 > 11.35 µg/m3).
From the time of fibrotic ILD diagnosis to censoring, higher PM2.5 exposures and higher mortality HRs were recorded among patients in quartile three (HR = 1.46; 95% CI, 1.13-1.9) and four (HR = 1.81; 95% CI, 1.39-2.35) compared with patients in quartile two (HR = 1.24; 95% CI, 0.96-1.62). For continuous PM2.5, for each 1 µg/m3 PM2.5 increase, mortality risk increased by 11% (HR = 1.11; 95% CI, 1.07-1.15), Goobie said.
Higher PM2.5 exposure in the 5 years prior to censoring was associated with increased mortality, with higher HRs among patients in quartile two (HR = 1.99; 95% CI, 1.42-2.78), three (HR = 3.41; 95% CI, 2.47-4.72) and four (HR = 6.14; 95% CI, 4.36-8.64) compared with the lowest quartile. For continuous PM2.5, for each 1 µg/m3 PM2.5 increase, mortality risk increased by 24% (HR = 1.24; 95% CI, 1.19-1.28), Goobie said.
Higher PM2.5 exposure in the 5 years prior to fibrotic ILD diagnosis was not consistently associated with increased mortality, according to Goobie. Patients in quartile two (HR = 1.41; 95% CI, 1.09-1.84) and three (HR = 1.32; 95% CI, 1.02-1.7) had significantly higher mortality compared with the lowest quartile. However, among patients in quartile four there was no significant difference in mortality risk (HR = 1.19; 95% CI, 0.91-1.57). For continuous PM2.5, there was no significance for each 1 µg/m3 PM2.5 increase (HR = 1.02; 95% CI, 0.98-1.06), according to the results.
All mortality analyses were adjusted for sex, age at diagnosis, smoking history, race, neighborhood disadvantage and baseline FVC and diffusing capacity for carbon monoxide (DLCO).
Lung function analysis
Goobie also presented results of a lung function analysis adjusted for age at diagnosis, sex, smoking history, race and neighborhood disadvantage. Patients living in the highest quartile of PM2.5 exposure in the 5 years prior to fibrotic ILD diagnosis had a lower FVC at baseline. For each 1 µg/m3 PM2.5 increase in the 5 years prior to diagnosis, baseline FVC decreased by 1%. There was no significant association between quartiles or continuous PM2.5 in this model with baseline DLCO, according to Goobie.
In the model exploring the association during disease experience, patients in quartile four had an additional 1.54 U decrease in percent predicted FVC per year compared with quartile one (beta = –1.54; 95% CI, –2.69 to –0.38). For each 1 µg/m3 PM2.5 increase during the course of disease, patients experienced an additional 0.25 U FVC decline per year, according to the results.
In PM2.5 exposure in 5 years prior to censoring interaction with time, patients in quartile two and four experienced significant interactions with time compared with quartile one.
In the same analysis for DLCO, the researchers reported a significant interaction with time for patients in quartile four compared with quartile one. However, continuous PM2.5 exposure in this model did not meet statistical significance. When evaluating DLCO in the 5 years prior to censoring, there was significance for patients in quartiles three and four compared with quartile one. For each 1 µg/m3 PM2.5 increase, there was an additional 0.31 U DLCO decrease per year.
Future research
Goobie highlighted other research during the presentation.
“We know that there are both peripheral blood and lung tissue changes in DNA methylation that are seen in patients with IPF, which is the most common form of ILD, in comparison to controls,” Goobie said, referencing a study that “demonstrated that there were around 147 differentially methylated regions in patients with IPF compared to controls, and a number of these differentially methylated regions were associated with genetic loci of relevance to ILD pathophysiology.”
Other research showed that exposure to nitrogen dioxide pollutants was associated with altered DNA methylation patterns and these alterations may mediate some associations between air pollution exposure and lung function decline.
According to Goobie, the next steps for research are as follows:
- Confirm these results with the Pulmonary Fibrosis Foundation patient registry cohort and the Canadian cohort.
- Perform multiple analyses to consider impacts of other pollutants on one another.
- Acquire pulmonary fibrosis samples to perform the LINE-1 DNA methylation analysis.
- Perform studies investigating air pollution’s impact on other epigenetic mechanisms, including histone modifications and non-coding RNAs.
- Continue advocating for better air pollution policies to protect patients with ILD.