Faculty Bibliography

INTRODUCTION: Impulse oscillometry (IOS) has been used to demonstrate distal airway dysfunction in symptomatic WTC exposed patients despite normal spirometry. However, it remains to be determined whether the respiratory symptoms can be attributed to the observed functional abnormalities. The present study was designed to assess the simultaneous relationship between the onset of respiratory symptoms and IOS abnormalities in patients undergoing bronchoprovocation for diagnostic evaluation. METHODS: Methacholine challenge testing (MCT) was performed in 113 symptomatic WTC dust exposed patients with normal spirometry that were enrolled WTC Environmental Health Center treatment program. In addition to spirometry, the MCT protocol included performance of IOS and assessment of respiratory symptoms (cough, dyspnea, chest tightness). IOS parameters included resistance at 5 and 20Hz (R⁵ and R₂₀) and frequency dependence of resistance assessed as the difference between these parameters (R_5-20). The PC20 for FEV₁, was used to categorize bronchial hyperreactivity (BHR) as negative (>16mg/ml), borderline (4-16mg/ml) or positive (<4mg/ml). RESULTS: The cohort was 58% female with mean age 49+/-12yr and BMI 29+/-5 kg/m². Baseline spirometry was within normal limits (FEV₁ 98+/-13% predicted, FEV₁/FVC 80+/-4%). Approximately 58% demonstrated abnormal baseline R₅ or R_5-20 indicating respiratory dysfunction despite normal spirometry. MCT revealed BHR, as assessed by spirometry, in 49/113 patients (43%). An additional 27 patients became symptomatic at methacholine doses <4mg/ml despite minimal change in FEV₁ (<5% decrement). All of these patients demonstrated increased R₅, R₂₀ and R_5-20 that coincided with onset of symptoms; median (IQR) increases were 23% (16-41), 13% (7-20), and 92% (39-138), respectively. Following bronchodilator administration, respiratory symptoms resolved and IOS parameters returned towards baseline. CONCLUSIONS: During bronchoprovocation, development of symptoms may coincide with development of distal airway dysfunction as assessed by IOS, even in absence of change in FEV₁. Findings reversed with bronchodilator administration reinforcing the link between symptoms and distal airway dysfunction

Air pollution contributes to acute exacerbations of asthma and the development of asthma in children and adults. Airway epithelial cells interface innate and adaptive immune responses, and have been proposed to regulate much of the response to pollutants. Thymic stromal lymphopoietin (TSLP) is a pivotal cytokine linking innate and Th2 adaptive immune disorders, and is upregulated by environmental pollutants, including ambient particulate matter (PM) and diesel exhaust particles (DEP). We show that DEP and ambient fine PM upregulate TSLP mRNA and human microRNA (hsa-miR)-375 in primary human bronchial epithelial cells (pHBEC). Moreover, transfection of pHBEC with anti-hsa-miR-375 reduced TSLP mRNA in DEP but not TNF-alpha-treated cells. In silico pathway evaluation suggested the aryl hydrocarbon receptor (AhR) as one possible target of miR-375. DEP and ambient fine PM (3 mug/cm(2)) downregulated AhR mRNA. Transfection of mimic-hsa-miR-375 resulted in a small downregulation of AhR mRNA compared with resting AhR mRNA. AhR mRNA was increased in pHBEC treated with DEP after transfection with anti-hsa-miR-375. Our data show that two pollutants, DEP and ambient PM, upregulate TSLP in human bronchial epithelial cells by a mechanism that includes hsa-miR-375 with complex regulatory effects on AhR mRNA. The absence of this pathway in TNF-alpha-treated cells suggests multiple regulatory pathways for TSLP expression in these cells.

Background. Exposure to World Trade Center (WTC) dust and fumes is associated with the onset of asthma-like respiratory symptoms in rescue and recovery workers and exposed community members. Eosinophilic inflammation with increased lung and peripheral eosinophils has been described in subpopulations with asthma. We hypothesized that persistent asthma-like symptoms in WTC-exposed individuals would be associated with systemic inflammation characterized by peripheral eosinophils. Methods. The WTC Environmental Health Center (WTC EHC) is a treatment program for local residents, local workers, and cleanup workers with presumed WTC-related symptoms. Patients undergo a standardized evaluation including questionnaires and complete blood count. Between September 2005 and March 2009, 2462 individuals enrolled in the program and were available for analysis. Individuals with preexisting respiratory symptoms or lung disease diagnoses prior to September 2001 and current or significant tobacco use were excluded, Results. One thousand five hundred and seventeen individuals met the inclusion criteria. Patients had a mean age of 47 years, were mostly female (51%), and had a diverse race/ethnicity. Respiratory symptoms that developed after WTC dust/fume exposure and remained persistent included dyspnea on exertion (68%), cough (57%), chest tightness (47%), and wheeze (33%). A larger percentage of patients with wheeze had elevated peripheral eosinophils compared with those without wheeze (21% vs. 13%, p < .0001). Individuals with elevated peripheral eosinophils were more likely to have airflow obstruction on spirometry (16% vs. 7%, p = .0003). Conclusion. Peripheral eosinophils were associated with wheeze and airflow obstruction in a diverse WTC-exposed population. These data suggest that eosinophils may participate in lung inflammation in this population with symptoms consistent with WTC-related asthma.

Rationale: Exposure to World Trade Center (WTC) dust and fumes is associated with onset of asthma-like respiratory symptoms in exposed community members including local workers, residents and clean-up workers. Although abnormal spirometry measurements are often not detected in these patients, impulse oscillometry (IOS) suggests abnormalities localized to the smaller airways. Peripheral C-reactive protein (CRP) is a marker of systemic inflammation. Since an association between CRP and asthma has been reported, we hypothesized that levels of CRP would be associated with lung function abnormalities as assessed by spirometry and IOS measurements in community members exposed to WTC dust/fumes and gasses. Methods: The WTC Environmental Health Center (EHC) is a treatment program for community members, with presumed WTC-related symptoms. Patients undergo a standardized evaluation including questionnaires and routine blood work, spirometry and IOS measurements. Between 10/1/2009 and 9/29/2011, a measurement of CRP was included for patients undergoing standardized visits. Measurements of lung function were compared utilizing the Wilcoxon test between subjects with normal vs. elevated CRP and further analyzed using linear regression models with log(CRP) as a continuous predictor. Regression analyses were adjusted for potential confounding factors including Body mass index (BMI), exposure category, and smoking history. Results: 208 WTC-exposed individuals met inclusion criteria. Valid spirometry and IOS data were available in 204 and 189 patients, respectively. Mean age was 49 years, 53% were female. Exposure categories (local workers, clean-up workers, residents) were associated with normal/elevated CRP levels (P=0.01). Smokers had a larger portion of elevated CRP (P=0.048). BMI was higher among the high CRP group (Wilcoxon test, P<0.001). FEV₁ and FVC were lower for the high CRP group (P=0.016, P=0.033). However, CRP level was not associated with the ratio FEV₁/FVC (P=0.58). The IOS measurements (R₅, R_5-20, AX ) were higher (P=0.01, P=0.003, P=.001, respectively) among the high CRP group. Multiple regression analysis confirmed that log(CRP) values were inversely correlated with % of predicted FEV 1 (P=0.009) and positively correlated with log(R₅) (P=0.02) and log(AX) (P=0.0045) after adjustment for log(BMI). Conclusions: Peripheral CRP was negatively correlated with levels of FEV₁ and positively correlated with IOS measurements in community members with WTC dust/gas/fume exposure. These data suggest a relationship between systemic inflammation, as reflected by CRP, and both large and small airway abnormalities in a WTC- exposed population

INTRODUCTION: We have previously shown improvement in spirometry parameters in symptomatic WTC dust exposed community members enrolled in the WTC Environmental Health Center treatment program. Additionally, impulse oscillometry (IOS) has demonstrated evidence for distal lung injury not apparent on spirometry. We hypothesize that longitudinal change of spirometry will differ based on presence or absence of distal airway injury and its response to bronchodilator at baseline. METHODS: 810 patients were identified with more than one spirometry and IOS assessment. IOS parameters included resistance at 5 and 20Hz (R₅ and R₂₀) and frequency dependence of resistance assessed as the difference between these parameters (R_5-20). Linear mixed effects modeling evaluated longitudinal changes in IOS parameters, FVC and FEV₁ for the entire population. Separate models were fit for subgroups categorized based on normal vs. abnormal baseline spirometry and normal vs. abnormal baseline IOS (R₅>3.96 cmH2O/L/s). Analyses were adjusted for confounding factors (age, gender, BMI, race/ethnicity, smoking, exposure category and dust cloud exposure). RESULTS: Mean age was 50yr. Patients were mostly female (52%) and had diverse race/ethnicity. At baseline, mean FVC was 91+/-17% predicted and FEV₁ was 88+/-18% predicted. A normal spirometry pattern was noted in the majority (67%; n=542). Despite normal spirometry, IOS revealed abnormalities in 67% (n=364). Longitudinal analysis of IOS parameters (R₅, R₂₀, R_5-20) over time revealed no significant trends for the entire population and for subgroups categorized by baseline spirometry pattern. In contrast, the longitudinal change in spirometry variables differed based on presence of IOS abnormality. In patients with normal spirometry, FEV₁ increased more rapidly in patients with abnormal baseline IOS compared to those with normal IOS (0.76 vs. 0.52 % predicted/yr; Table 1). For patients with abnormal baseline spirometry, FVC increased more rapidly in the abnormal vs. normal IOS patients (1.73 vs. 1.02 % predicted/yr). Patients with IOS response to bronchodilator (highest quartile for improvement of R₅ post bronchodilator) demonstrated a more rapid longitudinal increase in FEV₁ compared with patients without bronchodilator response (lowest quartile)(0.88 vs. 0.53 % predicted/yr,; Table 2). CONCLUSIONS: Spirometry parameters demonstrated improvement over time, while improvement in IOS parameters was not evident, suggesting potential irreversible injury in the distal lung. However, assessment of baseline distal airway function and its acute response to bronchodilator predicted longitudinal response of spirometry in patients enrolled in a treatment program. (Table Presented)

OBJECTIVE: : The course of lung function in community members exposed to World Trade Center (WTC) dust and fumes remains undefined. We studied longitudinal spirometry among patients in the WTC Environmental Health Center (WTCEHC) treatment program. METHODS: : Observational study of 946 WTCEHC patients with repeated spirometry measures analyzed on the population as a whole and stratified by smoking status, initial spirometry pattern, and WTC-related exposure category. RESULTS: : Improvement in forced vital capacity (54.4 mL/yr; 95% confidence interval, 45.0 to 63.8) and forced expiratory volume in 1 second (36.8 mL/yr; 95% confidence interval, 29.3 to 44.3) was noted for the population as a whole. Heavy smokers did not improve. Spirometry changes differed depending on initial spirometry pattern and exposure category. CONCLUSION: : These data demonstrate spirometry improvement in select populations suggesting reversibility in airway injury and reinforcing the importance of continued treatment.

RATIONALE: Identification and characterization of asthma phenotypes are challenging due to disease complexity and heterogeneity. The Severe Asthma Research Program (SARP) used unsupervised cluster analysis to define 5 phenotypically distinct asthma clusters that they replicated using 3 variables in a simplified algorithm. We evaluated whether this simplified SARP algorithm could be used in a separate and diverse urban asthma population to recreate these 5 phenotypic clusters. METHODS: The SARP simplified algorithm was applied to adults with asthma recruited to the New York University/Bellevue Asthma Registry (NYUBAR) to classify patients into five groups. The clinical phenotypes were summarized and compared. RESULTS: Asthma subjects in NYUBAR (n = 471) were predominantly women (70%) and Hispanic (57%), which were demographically different from the SARP population. The clinical phenotypes of the five groups generated by the simplified SARP algorithm were distinct across groups and distributed similarly to those described for the SARP population. Groups 1 and 2 (6 and 63%, respectively) had predominantly childhood onset atopic asthma. Groups 4 and 5 (20%) were older, with the longest duration of asthma, increased symptoms and exacerbations. Group 4 subjects were the most atopic and had the highest peripheral eosinophils. Group 3 (10%) had the least atopy, but included older obese women with adult-onset asthma, and increased exacerbations. CONCLUSIONS: Application of the simplified SARP algorithm to the NYUBAR yielded groups that were phenotypically distinct and useful to characterize disease heterogeneity. Differences across NYUBAR groups support phenotypic variation and support the use of the simplified SARP algorithm for classification of asthma phenotypes in future prospective studies to investigate treatment and outcome differences between these distinct groups. TRIAL REGISTRATION: Clinicaltrials.gov NCT00212537.