Biomarkers of World Trade Center Particulate Matter Exposure: Physiology of Distal Airway and Blood Biomarkers that Predict FEV₁ Decline

Abstract

Biomarkers can be important predictors of disease severity and progression. The intense exposure to particulates and other toxins from the destruction of the World Trade Center (WTC) overwhelmed the lung's normal protective barriers. The Fire Department of New York (FDNY) cohort not only had baseline pre-exposure lung function measures but also had serum samples banked soon after their WTC exposure. This well-phenotyped group of highly exposed first responders is an ideal cohort for biomarker discovery and eventual validation. Disease progression was heterogeneous in this group in that some individuals subsequently developed abnormal lung function while others recovered. Airflow obstruction predominated in WTC-exposed patients who were symptomatic. Multiple independent disease pathways may cause this abnormal FEV1 after irritant exposure. WTC exposure activates one or more of these pathways causing abnormal FEV1 in an individual. Our hypothesis was that serum biomarkers expressed within 6 months after WTC exposure reflect active disease pathways and predict subsequent development or protection from abnormal FEV1 below the lower limit of normal known as WTC-Lung Injury (WTC-LI). We utilized a nested case-cohort control design of previously healthy never smokers who sought subspecialty pulmonary evaluation to explore predictive biomarkers of WTC-LI. We have identified biomarkers of inflammation, metabolic derangement, protease/antiprotease balance, and vascular injury expressed in serum within 6 months of WTC exposure that were predictive of their FEV1 up to 7 years after their WTC exposure. Predicting future risk of airway injury after particulate exposures can focus monitoring and early treatment on a subset of patients in greatest need of these services.

Figure 1. WTC-FDNY Biomarker Timeline and development of Nested Case- Cohort Control Study Design

Summary of phenotyping that was done on the cohort and case susceptible and resistant to WTC-LI are shown in the inclusion criteria to develop the baseline cohort. Overlapping of cohort control with cases susceptible and resistant to WTC-LI is highlighted in the dashed red circle.

Figure 2. Overview of Biomarkers predicting WTC-LI as defined by FEV₁ < LLN

A. Utilizing a Susceptible case-cohort control design B. Utilizing a resistant case-cohort control design. *Represents relative risk ^†Not previously published