Predictors of asthma/COPD overlap in FDNY firefighters with World Trade Center dust exposure: a longitudinal study.

Abstract

Background:

Previously healthy firefighters with World Trade Center (WTC) dust exposure developed airway disease. Risk factors for irritant-associated asthma/COPD overlap are poorly defined.

Methods:

The study included 2,137 WTC-exposed firefighters who received a clinically-indicated bronchodilator pulmonary function test (BD-PFT) between 9/11/2001–9/10/2017. A post-BD FEV₁ increase of >12% and 200 ml from baseline defined asthma, and post-BD FEV₁/FVC ratio<0.7 identified COPD cases. Participants who met both criteria had asthma/COPD overlap. Eosinophil levels were measured on screening blood tests performed shortly after 9/11/2001 and prior to BD-PFT; a subgroup of participants also had serum IgE and 21 cytokines measured (N=215). Marginal Cox regression models for multiple events assessed the associations of eosinophil levels or serum biomarkers with subsequent diagnosis, with age, race, smoking, WTC-exposure, first post-9/11 FEV₁/FVC ratio, and BMI included as covariates.

Results:

BD-PFT diagnosed asthma/COPD overlap in 99 individuals (4.6%), isolated-asthma in 202 (9.5%), and isolated-COPD in 215 (10.1%). Eosinophil concentration≥300 cells/μl was associated with increased risk of asthma/COPD overlap (HR: 1.85, 95% CI: 1.16–2.95), but not with isolated-asthma or isolated-COPD. Serum IL-4 also predicted asthma/COPD overlap (HR: 1.51 per doubling of cytokine concentration, 95% CI: 1.17–1.95). Greater IL-21 concentration was associated with both isolated-asthma and isolated-COPD (HR: 1.73, 95% CI: 1.27–2.35 and HR: 2.06, 95% CI: 1.31–3.23, respectively).

Conclusions:

In WTC-exposed firefighters, elevated blood eosinophils and IL-4 levels are associated with subsequent asthma/COPD overlap. Disease-specific Th-2 biomarkers present years before diagnosis suggest patient-intrinsic predisposition to irritant-associated asthma/COPD overlap.

Introduction

The collapse of the World Trade Center (WTC) on September 11, 2001 (9/11) exposed the Fire Department of the City of New York (FDNY) rescue and recovery workers to caustic dust and products of combustion.¹ Subsequently, WTC-exposed rescue and recovery workers had high rates of airway injury, including excessive loss of lung function,² obstructive ventilatory defect³ and airway hyper-reactivity.⁴ Firefighters with elevated post-exposure blood eosinophil concentrations were at increased risk of developing chronic obstructive pulmonary disease (COPD).⁵

Asthma/COPD overlap is a recently defined endotype of COPD,^6–8 with patients experiencing a poorer quality of life and higher mortality compared with patients who have either isolated-COPD or isolated-asthma.^9–11 Risk factors for asthma/COPD overlap are poorly defined, but among those with smoking-related COPD, elevated eosinophils in sputum and blood are biomarkers for this condition.^12,13 There is a need for longitudinal studies to define risk factors for asthma/COPD overlap.¹⁴

The aim of this study was to determine early predictors of asthma/COPD overlap among WTC-exposed firefighters with at least one post-9/11 clinically-indicated pulmonary function test (PFT) with bronchodilator (BD) measurement (N=2,137). The main predictors of interest were blood biomarkers collected during participants’ post9/11 FDNY medical monitoring examination. We also examined these measurements in association with isolated isolated-asthma and with isolated-COPD as a way to understand the unique predictors of asthma/COPD overlap.

Methods

Study Population

The source population consisted of 9,598 male firefighters who were actively employed by the FDNY on 9/11, first arrived at the WTC between 9/11–9/24/2001, and had ≥3 post-9/11 forced expiratory volume at one second (FEV₁) measurements from routine medical monitoring PFTs taken at FDNY.⁵ A subset of this population received at least one clinically-indicated BD-PFT performed according to American Thoracic Society (ATS) standards¹⁵ at a hospital-based pulmonary function laboratory between 9/11/2001 and 9/10/2017. We excluded 57 participants whose BD-PFT occurred before their first post-9/11 medical monitoring examination. The final study population included 2,137 firefighters (Figure 1). Participants provided written informed consent. The Montefiore Medical Center (FWA #00002558)/Albert Einstein College of Medicine (FWA #00023382) Institutional Review Board approved this study.

Figure 1. Firefighters who participated in the Asthma/COPD overlap study.

Shown is the source population of male firefighters who were employed by the Fire Department of the City of New York (FDNY) on 9/11/2001, present at the World Trade Center (WTC) site between 9/11/2001 and 9/24/2001, and had at least three routine monitoring pulmonary function tests (PFTs) taken between 9/11/2001 and 9/10/2017 for forced expiratory volume at one second (FEV₁) slope measurement. The final study population included those who had received a post-9/11/2001 clinically-indicated PFT with bronchodilator measurement. The serum biomarker population was a subgroup who had biomarkers measured on serum drawn between 10/2001 and 2/2002.

Baseline Characteristics

Demographic data were retrieved from the FDNY employee database. Participants’ height, weight, self-reported smoking status (current, former or never-smoker) and time of initial arrival at the WTC site were assessed during routine medical monitoring examinations at FDNY; both active duty firefighters and WTC-exposed retirees are scheduled to have a monitoring exam once every 12–18 months. We classified individuals as having high (morning of 9/11), moderate (afternoon on 9/11–9/12) or low (9/13–9/24) WTC exposure based on their WTC site arrival time.⁴ Current and former smokers were grouped together as ever-smokers in our analyses. Those who consistently self-reported no cigarette smoking were classified as never-smokers.

Blood and Serum Biomarkers

Eosinophil concentration was measured from blood drawn shortly after 9/11, during the first post-9/11 monitoring examination. The median first post-9/11 blood draw date was 1/10/2002 (interquartile range: 11/26/2001–12/27/2002). We also had pre-9/11 blood data (eosinophil concentration) for the 1,008 participants who had blood drawn at a pre-9/11 monitoring exam. Serum biomarkers from the first post-9/11 blood draw, including IgE and cytokines, were available for a subgroup of the study cohort (N=215). Serum was stored at −80°C; IL-4 and IFN- γ were assayed with EMD Milipore HSTCMAG28SPMX21 and IgE with HGAMMAG-303E.

Pulmonary Function

Participants’ most recent BD-PFT from the 9/11/2001–9/10/2017 period provided the pre- and post-bronchodilator FEV₁ and forced vital capacity (FVC) measurements used to define our main outcome. A bronchodilator response of a >12% and 200 ml increase from baseline FEV₁ diagnosed asthma.¹⁶ COPD was defined according to the GOLD criteria, which requires FEV₁/FVC ratio<0.7 on a post-bronchodilator PFT.⁷ We classified individuals who had a bronchodilator response and FEV1/FVC≥0.7 as having isolated-asthma, and those who had FEV1/FVC<0.7 and no bronchodilator response as having isolated-COPD. Individuals who met the criteria for both asthma and COPD had asthma/COPD overlap. Total lung capacity (TLC) and residual volume (RV) measurements were also available from the BD-PFT data; these were measured prior to bronchodilator administration. We used spirometric measurements from 22,737 routine monitoring PFTs (always done without BD) taken between 9/11/2001 and 9/10/2017 to assess post-9/11 FEV₁ trajectories. FEV₁ values from post-9/11 monitoring PFTs that occurred prior to the BD-PFT were used to determine whether patients with asthma and/or COPD had accelerated (>64 ml/year) or expected (≤64 ml/year) FEV₁ decline post-9/11, but prior to our outcome determination; for individuals who had neither diagnosis, all post-9/11 FEV₁ values were included in the FEV₁ decline rate calculation. Pre-9/11 FEV₁ and FVC measurements were available from 1,265 spirometries performed at FDNY monitoring in the year prior to 9/11 (9/11/2000–9/10/2001).

Statistical Analyses

Demographic and other characteristics of the study population and serum biomarker subgroup were assessed as proportions and means (±SD), with independent sample t-tests or chi square tests used to evaluate differences, as appropriate. Longitudinal FEV₁ % predicted, FEV₁/FVC ratio and post-9/11 rate of FEV₁ change were estimated in four subsets of the population defined by outcome (isolated-asthma, isolated-COPD, asthma/COPD overlap, or neither condition) using linear mixed effects models with random intercepts. Participants’ age on 9/11, height and race were included as fixed effects in the models with absolute FEV₁ or FEV₁/FVC ratio as the outcome. Mean FEV₁ % predicted and FEV₁/FVC ratio values in the four groups were estimated for each one-year period between 9/11/2000 and 9/10/2017, and mean rates of FEV₁ change were determined using the post-9/11 spirometry data.

We performed log-rank Mantel-Cox tests to examine the univariable associations of post-9/11 FEV₁ trajectory (accelerated vs. expected FEV₁ decline), eosinophil concentration and smoking status with incident asthma/COPD overlap, followed by multivariable marginal Cox regression models for multiple events to evaluate shared and distinct risk factors for isolated-asthma, isolated-COPD, and asthma/COPD overlap. Censoring occurred at the time of the BD-PFT. Blood eosinophil concentration was assessed first as a binary (≥300 cells/μl vs. <300 cells/μl) and then as a continuous variable. We carried out two sensitivity analyses: one that excluded individuals with FEV₁/FVC ratio<0.7 on a pre-9/11 monitoring PFT (N=69), and another that examined the relationship between pre-9/11 eosinophil concentration and the outcomes of interest (N=1,008). Absolute change in eosinophil concentration from pre- to post-9/11 was also investigated. A multivariable-adjusted Cox regression analysis for multiple events data was also performed in the serum biomarker subpopulation (N=215) in order to determine whether log₂ transformed serum IgE and 21 cytokines were associated with isolated-asthma, isolated-COPD, or asthma/COPD overlap. After Bonferroni correction, the significance cut-off for the serum biomarker analyses was set at a two-sided p-value of 0.0024. For all other analyses, reported p-values are two-sided and considered significant at the <0.05 level. Multivariable models included age, race, smoking status, WTC exposure, first post-9/11 FEV₁/FVC ratio and BMI as covariates. Covariates were selected based on theory. Data analyses were performed using SAS version 9.4. We created figures using Prism 7.

Results

Baseline Characteristics

Demographic and other characteristics of the 2,137 firefighters with clinically-indicated post-9/11 BD-PFT in the final study population (Figure 1) and those without BD-PFT are presented in Table 1. Compared with WTC-exposed firefighters who did not have a BD-PFT, the study population was slightly different in that it was older, had a higher BMI and post-9/11 blood eosinophil concentration, and a greater proportion of ever-smokers. These differences were more pronounced in those who would develop post-BD FEV₁/FVC ratio<0.70. The serum biomarker subgroup was similar to the study population, with the exception of having a smaller proportion of ever-smokers.

Table 1:

Population characteristics and longitudinal lung function

		Bronchodilator PFT Study Population N=2,137
Variable	WTCd-exposed No Bronchodilator PFTa N=7,404	Post- Bronchodilator FEV1/FVC ≥ 0.7 N=1,823	Post- Bronchodilator FEV1/FVC< 0.7 N=314	Subpopulation with serum biomarkers N=215	Pr
Age on 9/11b	39.9 ± 7.6	40.5 ± 6.7	44.0 ± 6.8	41.0 ± 6.8	<0.001
BMIbc	28.7 ± 3.4	29.2 ± 3.5	28.5 ± 3.3	28.7 ± 3.3	<0.001
Smoking status, N (%)c
Never	5,031 (67.9)	1,229 (67.4)	142 (45.2)	185 (86.0)
Former	2,143 (28.9)	542 (29.7)	148 (47.1)	22 (10.2)	<0.001
Current	230 (3.1)	52 (2.9)	24 (7.6)	8 (3.7)
Race, N (%)
White	6,971 (94.2)	1,719 (94.3)	299 (95.2)	208 (96.7)
Black	174 (2.3)	36 (2.0)	10 (3.2)	4 (1.9)	<0.001
Hispanic	234 (3.2)	66 (3.6)	5 (1.6)	3 (1.4)
Other	25 (0.3)	2 (0.1)	0	0
WTCd Arrival Time, N (%)
Morning of 9/11	1,129 (15.3)	366 (20.1)	52 (16.6)	37 (17.2)
Afternoon on 9/11–9/12	5,322 (71.9)	1,295 (71.0)	223 (71.0)	168 (78.1)	<0.001
9/13–9/24	953 (12.9)	162 (8.9)	39 (12.4)	10 (4.7)
Pre-9/11 Spirometry
FEV1e (L)b	4.43 ± 0.68g	4.38 ± 0.69j	3.94 ± 0.74jm	4.32 ± 0.69p	<0.001
FEV1 % predictedb	105.9 ± 13.3g	104.3 ± 13.7j	95.2 ± 15.4jm	103.3 ± 14.2p	<0.001
FEV1/FVCf	0.85 ± 0.05g	0.85 ± 0.05j	0.78 ± 0.07jm	0.84 ± 0.05p	<0.001
Post-9/11 Spirometry
FEV1 (L)bc	4.05 ± 0.65	3.96 ± 0.65	3.46 ± 0.73	3.92 ± 0.70	<0.001
FEV1 % predictedbc	97.8 ± 12.9	95.4 ± 13.5	85.2 ± 15.3	94.4 ± 14.4	<0.001
FEV1/FVC	0.84 ± 0.05	0.84 ± 0.05	0.74 ± 0.07	0.83 ± 0.06	<0.001
Post-9/11 FEV1 slope (ml/yr)b	−35.1 ± 30.8	−37.8 ± 32.4	−47.5 ± 36.3	−41.1 ± 37.0	<0.001
Blood eosinophil concentration
Pre-9/11 eos/μl	154 ± 109h	162 ± 117k	186 ± 144n	153 ± 104q	<0.001
Post-9/11 eos/μlbc	184 ± 1.26i	194 ± 1.36l	231 ± 1.75o	198 ± 132	<0.001

^aPulmonary function test

^bMean ± standard deviation

^cValue on first post-9/11 monitoring exam

^dWorld Trade Center

^eForced expiratory volume in one second

^fForced vital capacity

^gN=6,836

^hN=3,295

ⁱN=7,388

^jN=1,686

^kN=857

^lN=1,780

^mN=285

ⁿN=151

^oN=304

^pN=209

^qN=109

^rANOVA or chi square test comparing values in first three columns

Lung Function on Monitoring and BD-PFTs

Clinically-indicated BD-PFT diagnosed isolated-asthma in 202 individuals (9.4%), isolated-COPD in 215 (10.1%), and asthma/COPD overlap in 99 (4.6%) (Figure 2). At the time of BD-PFT, the asthma/COPD overlap subgroup had a lower pre-BD FEV₁ % predicted, lower pre-BD FEV₁/FVC ratio and higher RV/TLC ratio than any other diagnostic category (Table 2). Bronchodilator response was similar in asthma/COPD overlap and isolated-asthma patients (22.6±13.3% vs. 19.9±12.8% increase in FEV₁, respectively, p=0.09).

Figure 2. Asthma/COPD overlap in WTC-exposed firefighters who had a bronchodilator PFT.

The Venn diagram demonstrates abnormalities on bronchodilator PFTs obtained via the WTC treatment program. Isolated-asthma was diagnosed in 202 individuals who had FEV₁ bronchodilator response of greater than 12% and 200 ml. Isolated-COPD was diagnosed in 215 individuals who had a post-bronchodilator FEV₁ /FVC ratio <0.70. Asthma COPD/overlap was diagnosed in 99 who had both a FEV₁ bronchodilator response >12% and 200 ml, and a FEV₁/FVC ratio <0.70. The remainder of the study population (1,621) did not have a bronchodilator response or airflow limitation.

Table 2:

Bronchodilator pulmonary function test results

Variable	Asthma COPD overlap, mean ± SD	Isolated-asthma, mean ± SD	Isolated-COPD, mean ± SD	Neither diagnosis, mean ± SD
Pre-BDa FEV1b % predicted	67.3±14.8	80.9±13.5f	82.3±15.2f	96.9±13.2f
Post-BD FEV1 % predicted	81.3±14.5	96.2±13.7f	85.9±15.0f	100.5±13.5f
Pre-BD FVCc % predicted	93.3±15.8	87.1±13.9f	101.2±15.1f	98.3±12.9f
Post-BD FVC % predicted	101.8±14.0	96.0±13.3f	103.4±15.1	98.5±12.9f
Pre-BD FEV1/FVC	0.56±0.08	0.73±0.07f	0.62±0.07f	0.77±0.05f
Post-BD FEV1/FVC	0.62±0.07	0.78±0.05f	0.64±0.06f	0.80±0.05f
Pre-BD RVd/TLCe	0.40±0.10	0.33±0.09f	0.33±0.08f	0.28±0.07f

^aBronchodilator

^bForced expiratory volume in one second

^cForced vital capacity

^dResidual volume

^eTotal lung capacity

^fp<0.05 vs. Asthma/COPD overlap subgroup

Both the pre-9/11 and first post-9/11 FEV₁ % predicted in each subgroup were on average ≥80% on monitoring PFTs, but were lowest in those who went on to develop asthma/COPD overlap (Figure 3A). FEV₁/FVC ratio on the first post-9/11 monitoring PFT was also lowest in this subgroup (Figure 3B). The annual post-9/11 FEV₁ loss in individuals with asthma/COPD overlap was similar to that of the COPD subgroup (47.6 ml/year, 95% CI: 43.5–51.6, and 47.2 ml/year, 95% CI: 44.7–49.6, respectively), and greater than the rate of FEV₁ loss in those with isolated-asthma (43.4 ml/year, 95% CI: 40.7–46.2) or neither outcome (36.8 ml/year, 95% CI: 35.9–37.6).

Figure 3. Lung function over time.

Panel A shows the mean (±SEM; SEM not shown if it is smaller than the size of the symbol) FEV₁ % predicted in each year between 9/11/2000 and 9/10/2017 in the asthma/COPD overlap (purple), isolated COPD (red), isolated asthma (blue) and asthma-free and COPD-free (black) groups. The vertical line at 0 represents 9/11/2001. The number of spirometries per year is shown below the x axis. Panel B shows the mean FEV₁/FVC ratio in the above groups in each year, adjusted for race, height and age, using the same number of spirometries per year as shown in panel A.

Risk Factors for Asthma/COPD Overlap

Univariable analyses showed that the incidence of asthma/COPD overlap was elevated in participants with post-9/11 eosinophil concentration ≥300 cells/μl (HR: 1.69, 95% CI: 1.00–2.81, p<0.05) (Figure 4A), those with a history of smoking (HR: 1.67, 95% CI: 1.11–2.50, p=0.02) (Figure 4B) and those experiencing post-9/11 accelerated FEV₁ decline (HR: 2.05, 95% CI: 1.22–3.43, p=0.006) (Figure 4C). In multivariable marginal Cox regression models for multiple events, asthma/COPD overlap was predicted by eosinophil concentration ≥300 cells/μl (Table 3a). Eosinophil concentration was not significantly associated with isolated-asthma or isolated-COPD. When isolated-asthma and asthma/COPD overlap were compared directly, asthma/COPD overlap was still associated with elevated eosinophils (Table 3b). Results were similar if analyses were restricted to those who had eosinophils measured less than 15 months after 9/11 (data not shown). A unique risk factor for isolated-asthma was high intensity WTC exposure, and for isolated-COPD was ever-smoking. Post-9/11 accelerated FEV₁ decline was associated with all three outcomes. The observed associations did not change when eosinophil concentration was assessed as a continuous variable (data not shown).

Figure 4. Cumulative incidence of asthma/COPD overlap in WTC-exposed firefighters who had a bronchodilator PFT.

Panel A shows the cumulative incidence of asthma/COPD overlap in participants with blood eosinophil concentration ≥300 cells/μl (orange) and <300 cells/μl on first post-9/11 medical monitoring exam. The level of significance shown in each panel was determined by the log rank test. Panel B shows the cumulative incidence in those who reported ever smoking (orange) and never smoking (green). Panel C shows the cumulative incidence in participants who had an accelerated rate of post-9/11 FEV₁ decline >64 ml/year (orange) and those with expected FEV₁ decline ≤64 ml/year (green).

Table 3:

Marginal Cox regression models predicting isolated-asthma, isolated-COPD, and asthma/COPD overlap^ab

Variables	Asthma/COPD Overlap vs. Neither			Isolated-Asthma vs. Neither			Isolated-COPD vs. Neither
	HR	95% CI	p	HR	95% CI	p	HR	95% CI	p
Eosinophils ≥ 300 cells/μlc	1.85	1.16–2.95	0.009	0.93	0.63–1.36	0.69	1.16	0.82–1.64	0.39
Accelerated FEV1 decline	2.17	1.40–3.35	<0.001	2.12	1.54–2.91	<0.001	2.18	1.59–2.99	<0.001
Ever smoker	0.92	0.58–1.44	0.70	0.77	0.56–1.05	0.09	1.60	1.18–2.17	0.003
WTC exposure morning of 9/11	1.40	0.84–2.32	0.19	1.58	1.14–2.20	0.006	0.86	0.59–1.26	0.44

Variables	Asthma/COPD Overlap vs. Isolated-Asthma			Asthma/COPD Overlap vs. Isolated-COPD
	HR	95% CI	p	HR	95% CI	p
Eosinophils ≥ 300 cells/μlc	2.00	1.11–3.62	0.02	1.60	0.89–2.85	0.12
Accelerated FEV1 decline	1.02	0.60–1.74	0.94	0.99	0.60–1.65	0.98
Ever smoker	1.19	0.69–2.05	0.52	0.57	0.34–0.98	0.04
WTC exposure morning of 9/11	0.88	0.49–1.61	0.68	1.62	0.88–3.01	0.12

^aN=2,124 due to missing covariates

^bAdjusted for age, race, BMI, first post-9/11 FEV₁/FVC

^cFirst post-9/11 measurement

To confirm that elevated post-9/11 eosinophil concentration and accelerated FEV₁ decline were associated with incident asthma/COPD overlap, we carried out a sensitivity analysis excluding patients with a pre-exposure PFT that showed a FEV₁/FVC ratio<0.7 (N=69). First post-9/11 eosinophil concentration ≥300 cells/μl and accelerated FEV₁ decline both remained significant predictors of asthma/COPD overlap (HR: 1.67, 95% CI: 1.03–2.71, p=0.03 and HR: 2.15, 95% CI: 1.35–3.43, p=0.001, respectively). To assess if pre-exposure blood eosinophil levels were indicative of a predisposition to asthma/COPD overlap, we performed another sensitivity analysis using pre-9/11 eosinophil concentration in place of the post-9/11 measurement. The subgroup of participants who had had a pre-9/11 blood draw (N=1,008) had baseline characteristics and lung function similar to those of the full study population (data not shown). We found that pre-9/11 eosinophil concentration ≥300 cells/μl was also associated with the outcome (HR: 1.42, 95% CI: 1.22–1.66, p<0.001). Change in eosinophil concentration from pre- to post-9/11 was not associated with asthma/COPD overlap (data not shown).

In order to gain further insight into the immunological pathways associated with isolated-asthma, isolated-COPD, and asthma/COPD overlap, we examined serum Th1, Th-17 and Th2 biomarkers obtained within six months of 9/11. A multivariable marginal Cox regression analysis for multiple events in the serum biomarker subpopulation (N=215) showed that higher early post-9/11 IgE was associated with incident asthma/COPD overlap, but this result was not significant after adjustment for multiple comparisons (Table 4). We found that elevated IL-4 predicted asthma/COPD overlap and elevated IL-21 predicted both isolated-asthma and isolated-COPD, while elevated IFN-γ was a protective factor for isolated-asthma and isolated-COPD. Early post-9/11 levels of IL-5, IL-13, IL-17, IL-23 and IL-6 were not associated with any of the three mutually exclusive outcomes (data not shown).

Table 4:

Marginal Cox regression models predicting isolated-asthma, isolated-COPD, and asthma/COPD overlap in the subpopulation with serum drawn between 9/11/2001 and 3/10/2002^ab

Variables	Asthma/COPD Overlap vs. Neither			Isolated-Asthma vs. Neither			Isolated-COPD vs. Neither
	HR	95% CI	p	HR	95% CI	p	HR	95% CI	p
IgEc	2.31	1.14–4.67	0.02d	1.21	0.92–1.58	0.16	1.14	0.81–1.62	0.45
IFN-γc	0.42	0.22–0.81	0.01d	0.48	0.32–0.70	<0.001	0.45	0.28–0.70	<0.001
IL-21c	1.33	0.89–1.98	0.17	1.73	1.27–2.35	<0.001	2.06	1.31–3.23	0.002
IL-4 substituted for IL-21 in Marginal Cox regression model
IL-4c	1.51	1.17–1.95	0.002	1.68	1.08–2.61	0.02d	1.35	0.96–1.91	0.08

^aN=215;

^bAdjusted for age, race, BMI, smoking status, WTC exposure level, first post 9/11 FEV₁/FVC;

^cOne log₂ increase (doubling) of cytokine concentration.

^dA p value of 0.0024 was considered significant after bonferroni correction.

Discussion

The WTC-exposed FDNY firefighter population is a cohort comprised of previously healthy males. Importantly, asthma documented during pre-employment medical evaluation precludes employment as a FDNY firefighter. Those who develop reactive airways disease during their career are removed from active duty;¹⁷ therefore, the prevalence of pre-9/11 asthma in this cohort was low. The massive irritant exposure at the WTC site resulted in an acute drop in lung function, with rescue/recovery workers going on to experience air trapping as well as fixed and reversible airflow obstruction.^2–4 In this study, we observed that elevated early post-9/11 blood eosinophil concentration predicted irritant-associated asthma/COPD overlap, but not isolated-asthma or isolated-COPD. A sensitivity analysis observed pre-911 elevated eosinophils were a risk factor for asthma/COPD overlap. This suggests a pre-WTC exposure predisposition to irritant-associated fixed and reversible airway injury. While we found some overlapping biomarkers of these outcomes, the observation that there are unique biomarkers of vulnerability to asthma/COPD overlap, isolated-asthma and isolated-COPD suggests the potential for different pathological processes for these three diagnoses; this could be explored in future studies.

The FDNY WTC-exposed cohort has advantages for investigating irritant-associated airways disease. Data from a centralized post-WTC medical treatment program enabled explicit diagnostic criteria for incident isolated-asthma, isolated-COPD and asthma/COPD overlap. Pre-9/11 lung function and blood data were available for a large subset of the cohort, enabling assessment of early indicators of susceptibility to subsequent airway injury. Our observation that pre-exposure eosinophil concentration was associated with later asthma/COPD overlap suggests patient-intrinsic vulnerability to the damaging effects of WTC dust exposure. How much the exposure itself contributed to the presentation is limited because not every assessment was performed pre-exposure.

Compared with those who developed isolated-asthma or isolated-COPD, asthma/COPD overlap patients had lower post-exposure FEV₁ and FEV₁/FVC ratio. An investigation in a cohort without WTC exposure found that low lung function in childhood was a risk factor for subsequent asthma/COPD overlap,¹⁸ and so our observed associations between early lung function measurements and this outcome may be evidence of similar biological mechanism(s). Both the asthma/COPD overlap and isolated-COPD subgroups have progressive airway injury, with greater post-9/11 FEV₁ decline rates than individuals with isolated-asthma or neither diagnosis. The asthma/COPD overlap subgroup also experienced more air trapping, shown by higher RV/TLC at the time of BD-PFT. This is consistent with prior investigation of asthma/COPD overlap in never-smokers¹⁹ and could be evidence of the severity of small airways dysfunction associated with WTC exposure.²⁰

Eosinophils and IgE are two Th-2 mediators that have been extensively studied as risk factors for asthma, COPD and asthma/COPD overlap.^12,21–25 In this investigation, serum IgE was associated with asthma/COPD overlap but did not achieve significance after bonferroni adjustment for multiple comparisons. We did observe a significant association between serum levels of the Th-2 cytokine IL-4 and this outcome. IL-4 may be a biomarker on the causal pathway to irritant-iassociated asthma/COPD overlap, since inhibiting it with Dupilumab reduced asthma severity in non-WTC-exposed patients with or without high eosinophil levels.^26,27 Further investigation is required to assess the Th-2 pathway(s) that are associated with FEV₁ decline, airflow limitation and bronchodilator response following an intense irritant exposure.

The incident asthma observed in our study is a variant of irritant-induced asthma.²⁸ That it was associated with high-intensity WTC exposure but not eosinophil concentration suggests that airway reactivity in this cohort is a form of noneosinophilic asthma.²⁹ IFN-γ was a protective biomarker for this condition, and also for isolated-COPD. High IFN-γ is associated with low IL-4 in modulation of pulmonary lymphocyte-mediated innate immunity.³⁰ Furthermore, asthma is associated with blunted IFN-γ response.^31,32

The balance between Th-2 and Th-17 cytokines in airway inflammation is under active investigation.^33–35 IL-21, which was found to significantly predict isolated-asthma and isolated-COPD in our cohort, is a component of the Th-17 pathway that is produced by innate lymphoid cells that regulate airway inflammation.³⁶ Elevated levels are associated with airway inflammation in mouse models and humans.^37–39 The data from the WTC-exposed FDNY cohort is consistent with a Th-2 and Th-17 response predicting airway remodeling and reactivity. These data support further investigation of the innate Th-17 response to pulmonary irritants.

In univariable analyses, we found that in addition to high eosinophil concentration and accelerated FEV₁ decline, ever-smoking was associated with asthma/COPD overlap. After adjusting for confounders, such as post-9/11 lung function, smoking was a unique risk factor for isolated-COPD but not isolated-asthma or asthma/COPD overlap. Therefore, the relationship between smoking and asthma/COPD overlap in this cohort was confounded by the other covariates. High WTC exposure level was not associated with isolated-COPD or asthma/COPD overlap, which suggests that an intense but brief irritant exposure did not increase risk of airway remodeling. In this cohort, isolated-COPD was not associated with eosinophil levels. In a population with smoking-related COPD, however, elevated blood eosinophil concentration was a biomarker of increased exacerbation.⁴⁰ The variability of eosinophil effect reported in the literature may be related to the proportion of the study cohorts with an asthma component.^41,42

There are several limitations to this investigation. The FDNY firefighters are overwhelmingly white, male, and experienced a massive irritant exposure, potentially limiting generalizability of these findings; however, most findings from the FDNY cohort have been replicated in other WTC-exposed cohorts. Our definitions of isolated asthma, asthma/COPD overlap and isolated COPD depend on results from the most recent BD-PFT. It is possible that those with isolated COPD, defined as FEV1/FVC < 0.7 and no bronchodilator response in this study, have asthma/COPD overlap since we did not proceed to methacholine challenge testing in the subgroup. Similarly those with asthma/COPD overlap, defined as FEV1/FVC < 0.7 and a bronchodilator response, may not have persistent with FEV1/FVC < 0.7 with permanent airway remodeling. A third limitation may be the use of eosinophils ≥300 or <300 cells/μl in our analyses. We modeled post-9/11 eosinophils as a continuous variable and still observed a significant association with asthma/COPD overlap. This suggests cut-point selection did not drive the analyses. Lastly, this study was vulnerable to selection bias. The study population with clinically-indicated BD-PFT was systematically different from those without BD-PFT, with more intense WTC exposure, higher eosinophil levels and post-WTC exposure lower lung function. This precludes assessment of rates of asthma/COPD overlap in the entire cohort, since undiagnosed cases are likely. Nevertheless, analyses within the BD-PFT population provide a valid assessment of risk factors for specific diagnoses within a symptomatic subgroup.

The data from the FDNY WTC Health Program is a valuable resource for understanding irritant-associated airways disease in a previously healthy population. High eosinophil concentrations, uniquely associated with asthma/COPD overlap in this population, may reflect biological pathways that predispose one to exaggerated inflammation and/or poor counter-regulatory responses to inflammation, leading to reversible and fixed airflow obstruction. There may be potential for early interventions that involve targeting specific inflammatory pathways in an attempt to improve lung function outcomes.

Abbreviation list

ATS

American Thoracic Society

BD

Bronchodilator

BMI

Body mass index

CI

Confidence interval

COPD

Chronic obstructive pulmonary disease

FDNY

Fire Department of the City of New York

FEV₁

Forced expiratory volume at one second

FVC

Forced vital capacity

GOLD

Global Initiative for Obstructive Lung Disease

HR

Hazard ratio

μl

Microliter

ml

Milliliter

PFT

Pulmonary function test

RV

Residual volume

SD

Standard deviation

SEM

Standard error

TLC

Total lung capacity

WTC

World Trade Center