Nonsmokers with normal pre-9/11 lung function, dyslipidemia, elevated heart rate, and leptin greater than or equal to 10,300 pg/ml within 6 months of 9/11 had significantly increased risk of developing abnormal lung function over the subsequent 6 years. In contrast, patients with elevated amylin were significantly protected from post-9/11 decline in lung function. Dyslipidemia, elevated heart rate, and leptin were independent risk factors, whereas amylin is a protective factor for subsequent decline in lung function and significantly altered the odds of being a case in a confounder-adjusted multibiomarker model. Elevated glucose and reduced pancreatic polypeptide predicted impaired lung function in single biomarker model, but their effect became nonsignificant in the final model. In this limited cohort of 237 patients, we did not observe a significant impact of arrival time on lung function previously observed (1
). The logistic regression model also showed that BMI at SPE was not significantly associated with case status (data not shown). The biomarker models were adjusted for age, BMI at SPE, race, and WTC arrival time, suggesting these potential confounders did not account for the impact of the biomarkers on the observed post-9/11 lung impairment. These novel findings suggest biomarkers of MetSyn may promote lung function impairment.
Cases and control subjects were defined by FEV1 at SPE. Control subjects maintained normal lung function, whereas cases developed abnormal FEV1 by SPE. Using FEV1 as single measure of lung function could lead to misclassification because FEV1 is reduced in restriction and obstruction. In prior investigation, however, it was observed that obstruction caused most abnormal FEV1. Cases in the pilot study have low FEV1/FVC ratio (median, 72; interquartile range, 65–77), confirming that FEV1 less than LLN is a surrogate for obstruction in this population. We therefore believe that FEV1 less than LLN is the single best outcome measure to define lung injury in the FDNY cohort at each point of interest. Although misclassification may occur when using FEV1 less than LLN as a single measure of abnormal lung function, it does not prevent detecting strong associations between biomarkers and lung injury. Cases and control subjects were similar in two important characteristics. First, cases and control subjects arrived at WTC before September 13th, were intensely exposed to dust and smoke, and experienced the same drop in FEV1 within 6 months post-9/11. This suggests a similar response to acute irritant exposure. Second, in the 3 years pre-9/11, there was no significant difference in FEV1 decline, demonstrating that cases do not have accelerated decline of lung function normally. Cases and control subjects differed in two significant ways. Cases had significantly lower, but normal FEV1 in their pre-9/11 PFT with median FEV1 of 88% predicted compared with 108% in control subjects. One explanation of this difference is that their susceptibility to intense irritant exposure produced clinically significant divergence in the groups over time. Another explanation is that subjects with lower baseline pre-9/11 FEV1 were closer to LLN, and therefore needed a smaller relative decline to drop below LLN post-9/11. The second difference is that cases had a median rate of decline of 89 ml/yr, whereas control subjects increased 42 ml/yr between MME and SPE. This demonstrates a disease process in cases that produced progressive loss of lung function for years after the insult. In contrast, control subjects had a small but measurable increase in lung function after the initial insult, indicating some restorative capacity in this group.
This case-control study was nested within a larger, intensively evaluated, longitudinally followed cohort. The differences of biomarkers between cases and control subjects appear before clinical disease presentation, making reverse causation less likely. The appearance of these risk factors before subjects presenting for SPE may indicate that biomarkers of MetSyn are involved in the development of lung function impairment. The study cohort was narrowly defined to eliminate potential confounders, such as prior lung disease, sex, and tobacco use. Cases that developed abnormal lung function and control subjects that preserved lung function after 9/11 came from the same restricted study cohort. Both groups had similar representation of individuals with high BMI and early arrival time. The logistic models effectively adjusted for these confounders. Thus, we were able to observe three significant and independent risk factors that interacted with WTC exposure to increase the risk of developing lung disease in this study. We also found one protective factor, which improved the ability of the model to predict abnormal lung function.
In the subjects, there is a trend for an association between classically defined MetSyn and eventual FEV1
loss. Large cross-sectional studies demonstrate MetSyn and reduced lung function are associated with the obesity component (as defined by BMI) of MetSyn. Obesity is the strongest predictor of abnormal pulmonary function (18
). The findings are consistent with other WTC-exposed cohorts in that symptomatic cases had higher BMI than asymptomatic control subjects (34
). Individual MetSyn components were stronger predictors of lung disease than the aggregate case definition. This is not surprising because MetSyn diagnostic criteria have been optimized to predict eventual cardiovascular disease and stroke (12
). The biomarkers of MetSyn (i.e., amylin and leptin) play a key role in metabolism (35
The standard clinical definition of MetSyn includes measures of glucose, HDL, and triglycerides. In this study, cases of lung function impairment had increased prevalence of higher glucose and dyslipidemia compared with control subjects. The longitudinal observations show that glucose intolerance and lipid abnormalities predict abnormal lung function and are consistent with results from large cross-sectional studies demonstrating an association between elevated glucose and abnormal pulmonary function (35
). Mechanisms underlying this association are unclear, but animal models demonstrate that hyperlipidemia is associated with inflammatory lung injury (36
). The significant effect of glucose was lost in the final model, suggesting the impact of glucose on lung function is either indirect or weaker than dyslipidemia.
The elevated heart rate observed in cases suggests altered autonomic balance in patients who progressed to abnormal lung function (41
). Elevated heart rate has been linked to lower levels of pancreatic polypeptide and subsequent elevation in serum glucose (44
). These associations are consistent with our observations. The trend toward elevated systolic blood pressure in cases is also consistent with either higher sympathetic tone in cases or higher parasympathetic tone in control subjects.
Elevated leptin is another MetSyn biomarker that is significantly associated with reduced lung function in large cross-sectional studies (45
). We show that elevated leptin increases the odds of abnormal FEV1
by more than twofold after adjustment for BMI. A role for this adipocyte-derived cytokine in impaired lung function is plausible because leptin has receptors in the lung and is increased in inflammation (41
). The triglycerides and HDL mechanism underlying the association of leptin with lung function is poorly understood.
This report is the first to use human data that describe an association between amylin and lung function. In animal models, there are amylin receptors in the lung (42
). Amylin administration produces reduced pulmonary vascular resistance; increased tracheal mucus; and improved sensitivity to butylcholine, an acetylcholine analog (43
). There are also data in humans that amylin reduces leptin resistance (35
). The reduced risk of developing abnormal lung function in patients with elevated amylin may be mediated by its impact on parasympathetic tone or leptin sensitivity.
This study has several limitations. It uses a single cohort of FDNY rescue workers. In addition, early serum samples from other WTC-exposed cohorts are unavailable, making these findings unique to this cohort. The 13 metabolic analytes combined with five MetSyn clinical parameters had a sensitivity of 41%, suggesting that other pathways to lung disease remain unidentified in this analysis. Serum inflammatory biomarkers are also elevated in COPD exacerbations (49
). We have recently reported that low α1
-antitrypsin, elevated granulocyte-macrophage colony-stimulating factor, and macrophage-derived chemokine are additional risk factors for the development of WTC-related lung injury (52
). The contribution of the serum glucose became nonsignificant in the final model. It is possible that elevated glucose would be significantly associated with impairment of lung function in a study with more participants. IL-6, a known biomarker of MetSyn, was not significantly different between cases and control subjects. However, levels were below the limits of detection, limiting the ability to interpret this finding. The MetSyn parameters measured are not biomarkers of exposure because all individuals with serum stored during the monitoring arrived at the WTC site within 3 days of its collapse. Because there is no unexposed control group, one cannot determine if WTC exposure is necessary for the observed effect, but it is essential to define the study cohort. For these reasons, replication of these findings in other longitudinally followed populations with and without PM exposure is important.
The results of this study emphasize the importance of rapidly mobilizing resources to conduct medical monitoring and sample banking after a disaster. By identifying individuals at greater risk, early intervention may reduce lung function impairment. Dyslipidemia and elevated leptin and heart rate were observed to be risk factors for development of abnormal lung function. Elevations of serum amylin were found to be protective. MetSyn biomarkers in individuals susceptible to irritant-induced impaired lung function identify pathways that could be responsible for this susceptibility. This insight on protein expression may guide future genetic polymorphism studies in leptin, pancreatic polypeptide, or other regulatory elements. Candidate susceptibility polymorphisms from this cohort could then be assayed in other WTC cohorts to assess their generalizability as risk factors for impaired lung function.