Do Ultrafine Particles Carry Any Weight When It Comes to Progression of Pulmonary Fibrosis? (2024)

Particulate air pollution, measured as the mass of particulate matter with an aerodynamic diameter ⩽2.5 μm (PM_2.5), is a known cause of excess morbidity and mortality, especially in those with underlying respiratory or cardiovascular disease. In this issue of the Journal, Goobie and colleagues (pp. 1082–1090) examined the relationship between exposure to a subset of PM_2.5, ultrafine particles (UFPs; <0.1 μm), and mortality in people with fibrotic interstitial lung disease (fILD) (1). The authors studied two cohorts of patients with fILD, one from the University of Pittsburgh Simmons Center and one from the Pulmonary Fibrosis Foundation Patient Registry (PFF). This study took advantage of a new, well-validated model for estimating UFP across 6 million census blocks in the continental United States (2). Residential addresses were available for the Simmons Center cohort, allowing estimation of UFP concentrations at the census block level. Only ZIP codes were available for the PFF cohort, resulting in less precise exposure estimates. For the Simmons Center cohort, in the fully adjusted model, an increase of 1,000 particles/cm³ was associated with increased mortality or transplant, with a hazard ratio of 1.08 (95% confidence interval, 1.01–1.15). The association was not significant for the PFF cohort, possibly because of the less precise exposure assessments and lower exposure levels for this cohort. FVC was reduced at baseline and decreased more rapidly in association with increases in UFP in both cohorts.

fILD represents a collection of disease processes affecting the lung interstitium, with generally irreversible scarring and lung structure remodeling (3). Idiopathic pulmonary fibrosis is the most common fILD and has the worst prognosis. There is no cure other than lung transplantation. Consensus clinical guidelines have been published (4, 5), but we know little about the factors influencing progression or exacerbations of idiopathic pulmonary fibrosis.

The pathway to fibrosis is thought to involve repeated injury to the alveolar epithelium (6). Inadequate and aberrant repair leads to the activation of profibrotic molecular pathways, with fibroblast migration, activation, and transition to myofibroblasts, and secretion of extracellular matrix. The initiation of fILD occurs at the alveolar epithelium, an important consideration regarding UFP exposure.

Why might UFP be important in fILD progression? UFPs are part of PM_2.5 but behave very differently than larger particles. They weigh next to nothing, contributing very little to PM_2.5 mass concentration, yet dominate in terms of particle number counts (PNCs). Thus, changes in the concentration of UFPs are not reflected in the mass-based measurements of PM_2.5. Compared with larger particles, UFP fractional deposition in the lung is increased (7), increases further with exercise, is increased in people with asthma (8), and is increased in the alveolar space. UFPs have a very high surface area relative to larger particles, with the potential to carry redox-active surface molecules to the alveolar epithelium. Deposited UFPs can move out of the alveolar compartment in part by diffusing through the lipid cell membrane of alveolar epithelial cells, a process that does not involve endocytosis (9, 10). These characteristics make UFPs ideal candidates to initiate injury and repair signaling in the alveolar epithelium and interstitium.

Goobie and colleagues now address this hypothesis with this first report of associations between UFP exposure and fILD mortality. Strengths include the use of a nationwide model for estimates of PNC at the census tract level, two relatively large cohorts of patients with fILD, multipollutant adjustments including PM_2.5 and NO₂, and a number of useful sensitivity and subgroup analyses. The finding of increased mortality and/or transplantation in association with increased PNC in the Simmons Center cohort is supported by worse baseline FVC and more rapid FVC decline in both cohorts, which suggests that UFP exposure accelerates the progression of fILD. The authors argue convincingly that the failure to find significant mortality effects in the PFF cohort is likely related to the less precise geographic exposure assessment in that cohort because only ZIP code locations were available. These findings underline the importance of geographically fine-scale exposure assessments in studying UFP health effects. But a big question remains: how substantial are the health risks of UFP exposure in relation to other pollutants?

Interestingly, Goobie and colleagues, in addition to the report in this issue of the Journal, recently examined the relationship between PM_2.5 exposure and mortality and/or transplantation in patients with fILD (11). In an analysis of pooled individual data from three different fILD cohorts, the hazard ratio for mortality or lung transplantation was 1.09 (95% confidence interval, 1.05–1.14) for each 1-μg/m³ increase in PM_2.5. Figure 1 compares the exposure–response relationships in these two studies, showing rather interesting similarities in the shapes of the curves. Note that, even though the slope of the curve for PM_2.5 appears steeper, its horizontal axis is compressed relative to that of UFP. Although this new report provides evidence of adverse effects of UFP exposure in patients with fILD, those effects do not seem to be worse or different from the effects of PM_2.5.

Looking beyond this study to the overall health risks of UFP exposure, the evidence does not support a conclusion that UFPs are substantially more hazardous, or have different health effects, than PM_2.5. Perspectives and reviews of UFP health effects have reached similar conclusions (12, 13). The U.S. Environmental Protection Agency recently announced a revision of the health-based annual PM_2.5 standard from the current 12.0 μg/m³ to 9.0 μg/m³ (14), but has so far concluded that a separate air quality standard for UFPs is not supported by the evidence. However, our inability to adequately assess UFP exposure has constrained research efforts and has likely biased findings toward the null, so our understanding of the true impact of UFPs remains limited.

This new study (1) does not resolve this conundrum of UFP health risks, but it does provide important new evidence supporting the effects of UFP exposure on fILD progression and mortality. And it suggests that better exposure assessments are needed to truly understand the health risks of UFPs.

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