COPD in Smoking and Non-Smoking Community Members Exposed to the World Trade Center Dust and Fumes.

Background: The characteristics of community members exposed to World Trade Center (WTC) dust and fumes with Chronic Obstructive Pulmonary Disease (COPD) can provide insight into mechanisms of airflow obstruction in response to an environmental insult, with potential implications for interventions. Methods: We performed a baseline assessment of respiratory symptoms, spirometry, small airway lung function measures using respiratory impulse oscillometry (IOS), and blood biomarkers. COPD was defined by the 2019 GOLD criteria for COPD. Patients in the WTC Environmental Health Center with <5 or ≥5 pack year smoking history were classified as nonsmoker-COPD (ns-COPD) or smoker-COPD (sm-COPD), respectively. Main Results: Between August 2005 and March 2018, 467 of the 3430 evaluated patients (13.6%) fit criteria for COPD. Among patients with COPD, 248 (53.1%) were ns-COPD. Patients with ns-COPD had measures of large airway function (FEV1) and small airway measures (R5−20, AX) that were less abnormal than those with sm-COPD. More ns-COPD compared to sm-COPD had a bronchodilator (BD) response measured by spirometry (24 vs. 14%, p = 0.008) or by IOS (36 vs. 21%, p = 0.002). Blood eosinophils did not differ between ns-COPD and sm-COPD, but blood neutrophils were higher in sm-COPD compared to ns-COPD (p < 0.001). Those with sm-COPD were more likely to be WTC local residents than ns-COPD (p = 0.007). Conclusions: Spirometry findings and small airway measures, as well as inflammatory markers, differed between patients with ns-COPD and sm-COPD. These findings suggest potential for differing mechanisms of airway injury in patients with WTC environmental exposures and have potential therapeutic implications.

Characterization of Persistent Uncontrolled Asthma Symptoms in Community Members Exposed to World Trade Center Dust and Fumes.

The destruction of the World Trade Center (WTC) towers on the 11th of September, 2001 released a vast amount of aerosolized dust and smoke resulting in acute and chronic exposures to community members as well as responders. The WTC Environmental Health Center (WTC EHC) is a surveillance and treatment program for a diverse population of community members, including local residents and local workers with WTC dust exposure. Many of these patients have reported persistent lower respiratory symptoms (LRS) despite treatment for presumed asthma. Our goal was to identify conditions associated with persistent uncontrolled LRS despite standard asthma management. We recruited 60 patients who were uncontrolled at enrollment and, after a three-month run-in period on high-dose inhaled corticosteroid and long acting bronchodilator, reassessed their status as Uncontrolled or Controlled based on a score from the Asthma Control Test (ACT). Despite this treatment, only 11 participants (18%) gained Controlled status as defined by the ACT. We compared conditions associated with Uncontrolled and Controlled status. Those with Uncontrolled symptoms had higher rates of upper airway symptoms. Many patients had persistent bronchial hyper-reactivity (BHR) and upper airway hyper-reactivity as measured by paradoxical vocal fold movement (PVFM). We found a significant increasing trend in the percentage of Controlled with respect to the presence of BHR and PVFM. We were unable to identify significant differences in lung function or inflammatory markers in this small group. Our findings suggest persistent upper and lower airway hyper-reactivity that may respond to standard asthma treatment, whereas others with persistent LRS necessitate additional diagnostic evaluation, including a focus on the upper airway.

Clinical Evaluation of Sarcoidosis in Community Members with World Trade Center Dust Exposure.

Background: Sarcoidosis is a granulomatous disease involving intrathoracic and extrathoracic organs. Genetic and environmental factors, such as exposure to World-Trade Center (WTC) dust after 9/11, may play a role in clinical presentation. Characterization of sarcoidosis in community members with exposure to the WTC dust can provide further insight into the relationship between environmental exposure and sarcoidosis. Methods: Patients with documented sarcoidosis were identified in the WTC Environmental Health Center (EHC), a treatment program for community members. Demographic and clinical data were collected from standardized questionnaires and chart review. Organ involvement was assessed with a standard instrument. Results: Among patients in the WTC EHC, 87 were identified with sarcoidosis after 9/11. Sarcoidosis cases were more likely African-American, local workers, and had more respiratory symptoms, compared with non-sarcoidosis WTC EHC patients. Many (46%) had ≥ Scadding stage 3 on chest imaging, and had reduced lung function measures. Extrathoracic involvement was identified in 33/87 (38%) with a diversity of organs involved. Conclusions: WTC-exposed sarcoidosis in community members is often characterized by severe pulmonary disease and a high rate of diverse extrathoracic involvement. Further analysis is required to characterize the course of disease progression or resolution.

Paresthesias Among Community Members Exposed to the World Trade Center Disaster.

OBJECTIVE: Paresthesias can result from metabolic disorders, nerve entrapment following repetitive motions, hyperventilation pursuant to anxiety, or exposure to neurotoxins. We analyzed data from community members exposed to the World Trade Center (WTC) disaster of September 11, 2001, to evaluate whether exposure to the disaster was associated with paresthesias. METHODS: Analysis of data from 3141 patients of the WTC Environmental Health Center. RESULTS: Fifty-six percent of patients reported paresthesias at enrollment 7 to 15 years following the WTC disaster. After controlling for potential confounders, paresthesias were associated with severity of exposure to the WTC dust cloud and working in a job requiring cleaning of WTC dust. CONCLUSIONS: This study suggests that paresthesias were commonly associated with WTC-related exposures or post-WTC cleaning work. Further studies should objectively characterize these paresthesias and seek to identify relevant neurotoxins or paresthesia-inducing activities.

Elevated C-reactive protein and posttraumatic stress pathology among survivors of the 9/11 World Trade Center attacks.

BACKGROUND: Systemic inflammation has emerged as a promising marker and potential mechanism underlying post-traumatic stress disorder (PTSD). The relationship between posttraumatic stress pathology and systemic inflammation has not, however, been consistently replicated and is potentially confounded by comorbid illness or injury, common complications of trauma exposure. METHODS: We analyzed a large naturalistic cohort sharing a discrete physical and mental health trauma from the destruction of the World Trade Center (WTC) towers on September 11, 2001 (n = 641). We evaluated the relationship between multiple physical and mental health related indices collected through routine evaluations at the WTC Environmental Health Center (WTC EHC), a treatment program for community members exposed to the disaster. C-Reactive Protein (CRP), a marker of systemic inflammation, was examined in relation to scores for PTSD, PTSD symptom clusters (re-experiencing, avoidance, negative cognitions/mood, arousal), depression and anxiety, while controlling for WTC exposures, lower respiratory symptoms, age, sex, BMI and smoking as potential risks or confounders. RESULTS: CRP was positively associated with PTSD severity (p < 0.001), trending toward association with depression (p = 0.06), but not with anxiety (p = 0.27). CRP was positively associated with re-experiencing (p < 0.001) and avoidance (p < 0.05) symptom clusters, and trended toward associations with negative cognitions/mood (p = 0.06) and arousal (p = 0.08). CONCLUSIONS: In this large study of the relationship between CRP and posttraumatic stress pathology, we demonstrated an association between systemic inflammation and stress pathology (PTSD; trending with depression), which remained after adjusting for potentially confounding variables. These results contribute to research findings suggesting a salient relationship between inflammation and posttraumatic stress pathology.

Isolated small airway reactivity during bronchoprovocation as a mechanism for respiratory symptoms in WTC dust-exposed community members.

INTRODUCTION: Small airway dysfunction occurs following WTC dust exposure, but its role in producing symptoms is unclear. METHODS: Methacholine challenge (MCT) was used to assess the relationship between onset of respiratory symptoms and small airway abnormalities in 166 symptomatic WTC dust-exposed patients. Forced oscillation testing (FOT) and respiratory symptoms were assessed during MCT. FOT parameters included resistance at 5 and 20 Hz (R5 and R20 ) and the R5 minus R20 (R5-20 ). RESULTS: Baseline spirometry was normal in all (mean FEV1 100 + 13% predicted, mean FEV1 /FVC 80 + 4%). MCT revealed bronchial hyperreactivity by spirometry in 67 patients. An additional 24 patients became symptomatic despite minimal FEV1 change (<5%); symptom onset coincided with increased R5 and R5-20 (P > 0.001 vs. baseline). The dose-response of FOT (reactivity) was greater compared with subjects that remained asymptomatic (P < 0.05). CONCLUSIONS: FOT during MCT uncovered reactivity in small airways as a mechanism for respiratory symptoms in subjects with inhalational lung injury. Am. J. Ind. Med. 59:767-776, 2016. © 2016 Wiley Periodicals, Inc.

Improvement in severe lower respiratory symptoms and small airway function in World Trade Center dust exposed community members.

OBJECTIVE: Longitudinal assessment of lower respiratory symptoms (LRS) in community members with World Trade Center (WTC) exposures. METHODS: Adult members of a treatment program with complete standardized visits were evaluated (n = 798). Association of demographic characteristics, mental health symptoms and lung function with trajectory of LRS between initial and monitoring visit was evaluated. RESULTS: Severe LRS were present in 70% at initial and 63% at monitoring visit. Initial severe LRS were associated with WTC dust cloud exposure and mental health symptoms. Spirometry measures were not associated with LRS severity or trajectory; improvement in LRS was associated with improved lung function measured with forced oscillometry techniques. CONCLUSION: Many community patients in a WTC treatment program had severe LRS associated with exposures and mental health symptoms. Improvement in LRS was associated with improvement in measures of small airway function. Am. J. Ind. Med. 59:777-787, 2016. © 2016 Wiley Periodicals, Inc.

Systemic Inflammation Associated With World Trade Center Dust Exposures and Airway Abnormalities in the Local Community.

BACKGROUND: Destruction of the World Trade Center (WTC) towers on September 11, 2001, released massive dust, gas, and fumes with environmental exposures for community members. Many community members have lower respiratory symptoms (LRSs) that began after September 11, 2001, and remain persistent. We evaluated whether systemic inflammation measured by C-reactive protein was associated with WTC dust exposures, persistent LRS, and lung function. METHODS: Community members self-referred for the treatment of symptoms related to September 11, 2001. C-reactive protein and lung function measurements, including spirometry and forced oscillation tests (impulse oscillometry system), were included as routine analyses in patients (2007 to 2012). RESULTS: Increased C-reactive protein levels were associated with the type of WTC dust exposure, LRS, reduced spirometry, and increased forced oscillation measurements (n = 724). CONCLUSIONS: Ongoing systemic inflammation measured years after the event was associated with WTC dust exposures, persistent LRS, and abnormal lung function in a community cohort. These findings have implications for treatment and surveillance.

Coexpression of type 2 immune targets in sputum-derived epithelial and dendritic cells from asthmatic subjects.

BACKGROUND: Noninvasive sputum sampling has enabled the identification of biomarkers in asthmatic patients. Studies of discrete cell populations in sputum can enhance measurements compared with whole sputum in which changes in rare cells and cell-cell interactions can be masked. OBJECTIVE: We sought to enrich for sputum-derived human bronchial epithelial cells (sHBECs) and sputum-derived myeloid type 1 dendritic cells (sDCs) to describe transcriptional coexpression of targets associated with a type 2 immune response. METHODS: A case-control study was conducted with patients with mild asthma (asthmatic cases) and healthy control subjects. Induced sputum was obtained for simultaneous enrichment of sHBECs and sDCs by using flow cytometry. Quantitative PCR was used to measure mRNA for sHBEC thymic stromal lymphopoietin (TSLP), IL33, POSTN, and IL25 and downstream targets in sDCs (OX40 ligand [OX40L], CCL17, PPP1R14A, CD1E, CD1b, CD80, and CD86). RESULTS: Final analyses for the study sample were based on 11 control subjects and 13 asthmatic cases. Expression of TSLP, IL33, and POSTN mRNA was increased in sHBECs in asthmatic cases (P = .001, P = .05, and P = .04, respectively). Expression of sDC OX40L and CCL17 mRNA was increased in asthmatic cases (P = .003 and P = .0001, respectively). sHBEC TSLP mRNA expression was strongly associated with sDC OX40L mRNA expression (R = 0.65, P = .001) and less strongly with sDC CCL17 mRNA expression. sHBEC IL33 mRNA expression was associated with sDC OX40L mRNA expression (R = 0.42, P = .04) but not sDC CCL17 mRNA expression. CONCLUSIONS: Noninvasive sampling and enrichment of select cell populations from sputum can further our understanding of cell-cell interactions in asthmatic patients with the potential to enhance endotyping of asthmatic patients.

Oscillometry complements spirometry in evaluation of subjects following toxic inhalation.

The World Trade Center (WTC) destruction released dust and fumes into the environment. Although many community members developed respiratory symptoms, screening spirometry was usually normal. We hypothesised that forced oscillation testing would identify functional abnormalities undetected by spirometry and that symptom severity would relate to magnitude of abnormalities measured by oscillometry. A symptomatic cohort (n=848) from the Bellevue Hospital WTC Environmental Health Center was evaluated and compared to an asymptomatic cohort (n=475) from the New York City Department of Health WTC Health Registry. Spirometry and oscillometry were performed. Oscillometry measurements included resistance (R5) and frequency dependence of resistance (R5-20). Spirometry was normal for the majority of subjects (73.2% symptomatic versus 87.6% asymptomatic, p<0.0001). In subjects with normal spirometry, R5 and R5-20 were higher in symptomatic versus asymptomatic subjects (median (interquartile range) R5 0.436 (0.206) versus 0.314 (0.129) kPa·L-1·s-1, p<0.001; R5-20 0.075 (0.085) versus 0.004 (0.042) kPa·L-1·s-1, p<0.0001). In symptomatic subjects, R5 and R5-20 increased with increasing severity and frequency of wheeze (p<0.05). Measurement of R5-20 correlated with the presence and severity of symptoms even when spirometry was within normal limits. These findings are in accord with small airway abnormalities as a potential explanation of the respiratory symptoms.

MicroRNA-375 regulation of thymic stromal lymphopoietin by diesel exhaust particles and ambient particulate matter in human bronchial epithelial cells.

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-α-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 µg/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-α-treated cells suggests multiple regulatory pathways for TSLP expression in these cells.

Elevated peripheral eosinophils are associated with new-onset and persistent wheeze and airflow obstruction in world trade center-exposed individuals.

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.

Application of the asthma phenotype algorithm from the Severe Asthma Research Program to an urban population.

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.

Longitudinal spirometry among patients in a treatment program for community members with World Trade Center-related illness.

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.

Cigarette smoking induces overexpression of a fat-depleting gene AZGP1 in the human.

BACKGROUND: Smokers weigh less and have less body fat than nonsmokers. Increased body fat and weight gain are observed following smoking cessation. To assess a possible molecular mechanism underlying the inverse association between smoking and body weight, we hypothesized that smoking may induce the expression of a fat-depleting gene in the airway epithelium, the cell population that takes the brunt of the stress of cigarette smoke. METHODS: To assess whether smoking up-regulates expression in the airway epithelium of genes associated with weight loss, microarray analysis was used to evaluate genes associated with fat depletion in large airway epithelial samples obtained by fiberoptic bronchoscopy from healthy smokers and healthy nonsmokers. As a candidate gene we further evaluated the expression of alpha(2)-zinc-glycoprotein 1 (AZGP1), a soluble protein that stimulates lipolysis, induces a reduction in body fat in mice, is associated with the cachexia related to cancer, and is known to be expressed in secretory cells of lung epithelium. AZGP1 protein expression was assessed by Western analysis and localization in the large airway epithelium by immunohistochemistry. RESULTS: Both microarray and TaqMan analysis demonstrated that AZGP1 messenger RNA levels were higher in the large airway epithelium of healthy smokers compared to healthy nonsmokers (p < 0.05, all comparisons). Western analysis of airway biopsy specimens from smokers compared with those from nonsmokers demonstrated up-regulation of AZGP1 at the protein level, and immunohistochemical analysis demonstrated up-regulation of AZGP1 in secretory as well as neuroendocrine cells of smokers. CONCLUSIONS: In the context that AZGP1 is involved in lipolysis and fat loss, its overexpression in the airway epithelium of chronic smokers may represent one mechanism for the weight difference in smokers vs nonsmokers.

Invasive size is an independent predictor of survival in pulmonary adenocarcinoma.

Current classification of pulmonary adenocarcinoma includes noninvasive bronchioloalveolar carcinoma, mixed subtype adenocarcinoma, and several patterns of invasive carcinoma. The extent of invasion in mixed subtype adenocarcinoma is variable, and prior studies suggest that estimates of extent of desmoplasia or invasion and gross tumor size are predictors of survival. Pathologic review of 178 consecutive primary lung adenocarcinoma resections from 1997 to 2000 was performed blinded to outcome. Lymph node metastases were not present in adenocarcinomas with less then 0.6 cm of invasion. In multivariate analysis and in strata adjusted for stage, measurement of linear extent of invasion was significantly associated with survival whereas gross size measurement alone was not. Significant differences in median survival were observed when patients were divided into noninvasive, microinvasive (<0.6 cm invasion), and invasive subcategories. In conclusion, among lung adenocarcinomas, histologic assessment of invasive growth may provide valuable prognostic information, and tumors with invasion under 0.6 cm have a more indolent clinical course after resection.

Overexpression of apoptotic cell removal receptor MERTK in alveolar macrophages of cigarette smokers.

Mononuclear phagocytes play an important role in the removal of apoptotic cells by expressing cell surface receptors that recognize and remove apoptotic cells. Based on the knowledge that cigarette smoking is associated with increased lung cell turnover, we hypothesized that alveolar macrophages (AMs) of normal cigarette smokers may exhibit enhanced expression of apoptotic cell removal receptor genes. AMs obtained by bronchoalveolar lavage of normal nonsmokers (n = 11) and phenotypic normal smokers (n = 13; 36 +/- 6 pack-years) were screened for mRNA expression of all known apoptotic cell removal receptors using Affymetrix HG-U133 Plus 2.0 microarray chips with TaqMan RT-PCR confirmation. Of the 14 known apoptotic receptors expressed, only MER tyrosine kinase (MERTK), a transmembrane tyrosine kinase receptor, was significantly up-regulated in smokers. MERTK expression was then assessed in AMs of smokers versus nonsmokers by TaqMan RT-PCR, immunocytochemistry, Western analysis, and flow analysis. Smoker AMs had up-regulation of MERTK mRNA levels (smoker vs. nonsmoker: 3.6-fold by microarray, P < 0.003; 9.5-fold by TaqMan RT-PCR, P < 0.02). Immunocytochemistry demonstrated a qualitative increase in MERTK protein expression on AMs of smokers. Increased protein expression of MERTK on AMs of smokers was confirmed by Western and flow analyses (P < 0.007 and P < 0.0002, respectively). MERTK, a cell surface receptor that recognizes apoptotic cells, is expressed on human AMs, and its expression is up-regulated in AMs of cigarette smokers. This up-regulation of MERTK may reflect an increased demand for removal of apoptotic cells in smokers, an observation with implications for the development of chronic obstructive pulmonary disease, a disorder associated with dysregulated apoptosis of lung parenchymal cells.