Metabolic Risk Factors and the Development of World Trade Center Lung Disease

Longitudinal epidemiologic studies have shown that long-term exposure to particulate matter (PM) air pollution can be associated with steeper loss of lung function over time (1). Metabolic syndrome (MetSyn), which is characterized by a combination of metabolic risk factors such as dyslipidemia, hypertension, large abdominal girth, and poor glycemic control (2), has also been associated with lower lung volumes, more rapid function decline, and developing asthma (3–5). Less is known, however, about how PM exposure and metabolic risk factors longitudinally synergize in causing respiratory disease. This is an important public health question given the overwhelming prevalence of obesity and MetSyn and the wide population exposure to PM pollution. Although not a model of chronic PM exposure, World Trade Center (WTC) cohort studies do provide a unique opportunity to understand the adverse health impacts of an acute massive PM exposure and how the risk of subsequently developing lung disease can potentially be modified by metabolic factors. This was initially studied in a nested case-control study of workers from the Fire Department of New York, in which abnormal baseline high-density lipoprotein and triglycerides were an independent risk factor of greater susceptibility to lung function impairment after September 11 (6); however, this study was limited by a single point in time metabolic biomarker assessment.

To further understand the temporal relationship of MetSyn, exposure intensity, and lung dysfunction, in this issue of the Journal, Kwon and colleagues (pp. 1035–1047) used data from 5,738 rescue and recovery active workers who were part of the baseline WTC cohort and had spirometry testing within 180 days of September 11. Over 52,000 pulmonary function tests (on average 9.1/subject; SD, 2.6) measured from September 11 until August 2017 were used for this analysis (7). To assess the temporality associations between lung function and MetSyn, spirometry measurements were aligned to all other clinical measurements within 180 days to best measure concurrent associations. Clinical parameters including weight, blood pressure, glucose, and lipid panel were measured at WTC entry and repeated at longitudinal follow-up times. Exposure intensity was obtained from questionnaires and defined by the time of arrival at September 11 and subsequent working months at the WTC site. The investigators proposed a multidimensional analytic approach to adequately capture the complex interplay between MetSyn components, comorbidities, and the study outcomes, which included having at least one FEV₁% predicted <lower limit of normal as primary (WTC–lung injury [LI]) and the FVC% predicted <lower limit of normal, FEV₁/FVC as secondary. At baseline, those with WTC-LI were more likely to have lower FEV₁% predicted and meet criteria for MetSyn. Longitudinally, increasing body mass index categories or having additional MetSyn criteria were associated in a dose–response fashion with the primary outcome. When investigating the temporal associations of MetSyn with WTC-LI, elevated triglycerides had the highest hazard ratio, followed by low high-density lipoprotein and obesity. The intensity of PM exposure was a significant factor, and of greater magnitude than smoking, in all the time to event models.

These results are consistent with prior cohort studies and certainly contribute to strengthening the causality between metabolic dysregulation and subsequent lung impairment. Some of the more exciting and novel results from this study included: 1) the use of a partially linear single index hazards model to develop a MetSyn single index to jointly estimate the relative contribution of its components, which showed that although a lower index moderately decreased the risk of WTC-LI, a positive one exponentially increased it; and 2) dynamic risk profiling to estimate the rate of change of MetSyn on the onset time of disease to determine how MetSyn recovery reduces lung disease, which showed that improvements in hypertension, body mass index, and dyslipidemia were associated with a substantial risk reduction in WTC-LI. These results agree with a cohort study showing that improvements in MetSyn components after bariatric surgery can, independently of the amount of body weight lost, improve pulmonary outcomes (8).

There are several key takeaway points from this study. First, MetSyn components incrementally and exponentially augment the risk for developing lung impairment independently of other confounders and competing risks. Second, each MetSyn component, probably through independent and synergistic mechanisms (9), increases the risk for developing lung disease. Third, improving MetSyn could substantially reduce the risk of losing lung function.

There are important study limitations to consider, which potentially limit the external validity of these findings. This is a large cohort of exposed individuals with and without WTC-LI. It is therefore impossible to tease out the impact of MetSyn on lung function in individuals that were not massively exposed to PM during September 11. Given this important limitation, it is difficult to extrapolate whether MetSyn or its components would longitudinally interact with air pollution PM to induce lung disease; however, this possibility is supported by large cross-sectional studies (10, 11).

Taken together, despite limitations, the results from this large and well-done longitudinal study strongly support a causal relationship for metabolic dysregulations as risk factors for developing lung disease. The time has come to think of MetSyn not only as a cardiovascular risk factor but also as a modifiable pulmonary one as well.