The destruction of the World Trade Center (WTC) on September 11, 2001 (9/11) released an estimated 10 million tons of material, exposing rescue workers to an immense cloud of caustic dust and large-sized particulate matter. These workers experienced high rates of upper- and lower-airway injury, evidenced by an excessive loss of lung function. Since 2001, researchers at NYU Langone Health have been working with the Fire Department of New York (FDNY) Bureau of Health Services to shed light on the mechanisms driving persistent lung injury.

Immediately following the disaster, the FDNY began implementing protocols for retrieving, processing, and banking serum from the WTC-exposed rescue workers (firefighters, paramedics, and emergency medical technicians), creating what has become a well-characterized cohort of nearly 12,500 rescue workers.

“What is unique about the firefighter population is that we have pre-exposure lung function tests for many of the subjects, and so we know they were normal before they fell off the cliff,” says Michael D. Weiden, MD, professor of medicine, whose clinical research is focusing on how inflammation influences lung function in the exposed rescue workers.

In related and often overlapping research, Anna Nolan, MD, associate professor of medicine and pulmonary, critical care, and sleep medicine, is focusing on the metabolome’s influence on lung function in this cohort. Both are studying candidate biomarkers that predict lung injury, which could lead to early screening tools, better informed treatment, and future therapeutic targets. In addition, Dr. Nolan is identifying predictors of other conditions prevalent in this cohort, including gastroesophageal reflux disease (GERD) and Barrett’s esophagus.

Inflammatory Biomarkers Predict Risk

In a recent longitudinal analysis of 15 years of data collected from more than 9,000 previously healthy firefighters from this cohort, Dr. Weiden and colleagues found that, in 12.7 percent of subjects, brief exposure to WTC toxins set off an inflammatory process that caused accelerated decline of lung function that began in the first year and has been unrelenting since. “There is no evidence that this decline is stopping in these patients. It hasn’t plateaued. It’s just continuing downward,” says Dr. Weiden.

The team also observed that firefighters who had elevated levels of two leukocytes (eosinophils and neutrophils) in their first CBC tests immediately following 9/11 had an associated increased risk for accelerated lung function decline and chronic obstructive pulmonary disease (COPD), suggesting that these two biomarkers of inflammation could be used to predict, prior to the development of disease, which exposed rescue workers are most at risk.

These findings likely translate beyond this cohort to the larger WTC-exposed community, as well as other occupationally and environmentally exposed groups. (In fact, Joan Reibman, MD, professor of medicine and pulmonary, critical care, and sleep medicine, in an earlier study of community members exposed to the WTC toxins, found an association between current levels of eosinophils and risk of airway injury.)

Many studies have focused on occupational biomarker identification. The link between eosinophils and COPD, for example, has been established. “But most research starts the movie when people are already damaged. In our cohort, we get a snapshot early on and it suggests that there is a subset of the population at risk for progressing to COPD even though they currently have normal lung function, and that’s what sets this apart from most of the literature,” explains Dr. Weiden.

Metabolic Biomarkers Detect Lung Damage

This unique population is also providing a rare window into the connection between the metabolome and lung function. In a recent study led by Dr. Nolan, investigators analyzed serum samples obtained from firefighters within six months of exposure, conducting comprehensive metabolic profiles on small subsets of firefighters with and without lung injury. Using random forests analysis, the team’s preferred machine-learning technique, they identified a refined metabolic profile based on levels of 580 metabolites. Five clusters of metabolites emerged from this profile as biologically plausible pathways associated with loss of lung function, including some previously known mediators of lung disease like sphingolipids and some new associations like fatty acids and branched-chain amino acids.

The study offers the first evidence that metabolic blood tests conducted within months of the WTC disaster could help detect obstructive airway disease in those exposed, along with other disaster victims exposed to fire, smoke, and toxic chemicals. Dr. Nolan’s findings also raise the possibility that correcting metabolic imbalances through dietary changes or food supplements could ward off or even reverse loss of lung function, a strategy which is the focus of the currently enrolling Food Intake Restriction for Health Outcome Support and Education (FIREHOUSE) trial.

Predictors of GERD and Barrett’s Esophagus

By 2005, approximately 44 percent of WTC rescue and recovery workers in this cohort had developed symptoms of GERD, which is a risk factor for Barrett’s esophagus. In a recently published paper, Dr. Nolan and her team demonstrated that serum biomarkers taken within six months of WTC exposure were predictive of both GERD and Barrett’s esophagus. Specifically, the researchers found that that C-peptide predicts GERD, IP-10 and fractalkine predict Barrett’s esophagus, and TNF-α predicts both GERD and Barrett’s esophagus. Identification of these key biomarkers and biologically relevant pathways may pave the way for future investigations into pharmacological targets.