Faculty Bibliography

There is an increasing awareness of the role of distal airways in the pathophysiology of obstructive lung diseases including asthma and chronic obstructive pulmonary disease. We hypothesize that during induced bronchoconstriction: 1) disparity between distal and proximal airway reactivity may occur; and 2) changes in distal airway function may explain symptom onset in subjects with minimal FEV(1) change. 185 subjects underwent methacholine challenge testing (MCT). In addition to spirometry, oscillometry was performed at baseline and after maximum dose of methacholine; 33/185 also underwent oscillometry after each dose. Oscillometric parameters included resistance at 5 and 20 Hz (R(5,) R(20)) and heterogeneity of distal airway mechanics assessed by frequency dependence of resistance 5-20 Hz (R(5-20)) and reactance area (AX). R(5) varied widely during MCT (range -0.8 - 11.3 cmH(2)O/L/s) and correlated poorly with change in FEV(1) (r = 0.17). Changes in R(5) reflected changes in both R(20) and R(5-20) (r = 0.59, p<0.05; r = 0.87, p<0.0001). However, R(20) increased only 0.3 cmH(2)O/L/s, while R(5-20) increased 0.7 cmH(2)O/L/s for every 1cmH(2)O/L/s change in R(5,) indicating predominant effect of distal airway mechanics. 9/33 subjects developed symptoms despite minimal FEV(1) change (<5%), while R(5) increased 42% due to increased distal airway heterogeneity. These data indicate disparate behavior of proximal airway resistance (FEV(1) and R(20)) and distal airway heterogeneity (R(5-20) and AX). Distal airway reactivity may be associated with methacholine-induced symptoms despite absence of change in FEV(1). This study highlights the importance of disparity between proximal and distal airway behavior, which has implications in understanding pathophysiology of obstructive pulmonary diseases and their response to treatment

OBJECTIVE: : To describe pathologic findings in symptomatic World Trade Center-exposed local workers, residents, and cleanup workers enrolled in a treatment program. METHODS: : Twelve patients underwent surgical lung biopsy for suspected interstitial lung disease (group 1, n = 6) or abnormal pulmonary function tests (group 2, n = 6). High-resolution computed axial tomography and pathologic findings were coded. Scanning electron microscopy with energy-dispersive x-ray spectroscopy was performed. RESULTS: : High-resolution computed axial tomography showed reticular findings (group 1) or normal or airway-related findings (group 2). Pulmonary function tests were predominantly restrictive. Interstitial fibrosis, emphysematous change, and small airway abnormalities were seen. All cases had opaque and birefringent particles within macrophages, and examined particles contained silica, aluminum silicates, titanium dioxide, talc, and metals. CONCLUSIONS: : In symptomatic World Trade Center-exposed individuals, pathologic findings suggest a common exposure resulting in alveolar loss and a diverse response to injury

RATIONALE: Residents and area workers who inhaled dust and fumes from the World Trade Center disaster reported lower respiratory symptoms in two World Trade Center Health Registry surveys (2003-2004 and 2006-2007), but lung function data were lacking. OBJECTIVES: To examine the relationship between persistent respiratory symptoms and pulmonary function in a nested case-control study of exposed adult residents and area workers 7-8 years post-9/11/2001. METHODS: Registrants reporting post-9/11 onset of a lower respiratory symptom in the first survey and the same symptom in the second survey were solicited as potential cases. Registrants without lower respiratory symptoms in either Registry survey were solicited as potential controls. Final case-control status was determined by lower respiratory symptoms at a third interview (the study), when spirometry and impulse oscillometry were also performed. MAIN RESULTS: We identified 180 cases and 473 controls. Cases were more likely than controls to have abnormal spirometry (19% versus 11%, P<0.05), and impulse oscillometry measurements of elevated airway resistance, R5 (68% versus 27%, P<0.0001) and frequency dependence of resistance, R5-20 (36% versus 7%, P<0.0001). When spirometry was normal, cases were more likely than controls to have elevated R5 and R5-20 (62% versus 25% and 27% versus 6% respectively, both P<0.0001). Associations between symptoms and oscillometry held when factors significant in bivariate comparisons (BMI, spirometry, exposures) were analyzed using logistic regression. CONCLUSIONS: This study links persistent respiratory symptoms and oscillometric abnormalities in WTC-exposed residents and area workers. Elevated R5 and R5-20 in cases despite normal spirometry suggested distal airway dysfunction as a mechanism for symptoms

BACKGROUND: Thymic stromal lymphopoietin (TSLP), an IL7-like cytokine produced by bronchial epithelial cells is upregulated in asthma and induces dendritic cell maturation supporting a Th2 response. Environmental pollutants, including tobacco smoke and diesel exhaust particles upregulate TSLP suggesting that TSLP may be an interface between environmental pollution and immune responses in asthma. Since asthma is prevalent in urban communities, variants in the TSLP gene may be important in asthma susceptibility in these populations. OBJECTIVES: To determine whether genetic variants in TSLP are associated with asthma in an urban admixed population. METHODOLOGY AND MAIN RESULTS: Ten tag-SNPs in the TSLP gene were analyzed for association with asthma using 387 clinically diagnosed asthmatic cases and 212 healthy controls from an urban admixed population. One SNP (rs1898671) showed nominally significant association with asthma (odds ratio (OR) = 1.50; 95% confidence interval (95% CI): 1.09-2.05, p = 0.01) after adjusting for age, BMI, income, education and population stratification. Association results were consistent using two different approaches to adjust for population stratification. When stratified by smoking status, the same SNP showed a significantly increased risk associated with asthma in ex-smokers (OR = 2.00, 95% CI: 1.04-3.83, p = 0.04) but not significant in never-smokers (OR = 1.34; 95% CI: 0.93-1.94, p = 0.11). Haplotype-specific score test indicated that an elevated risk for asthma was associated with a specific haplotype of TSLP involving SNP rs1898671 (OR = 1.58, 95% CI: 1.10-2.27, p = 0.01). Association of this SNP with asthma was confirmed in an independent large population-based cohort consortium study (OR = 1.15, 95% CI: 1.07-1.23, p = 0.0003) and the results stratified by smoking status were also validated (ex-smokers: OR = 1.21, 95% CI: 1.08-1.34, p = 0.003; never-smokers: OR = 1.06, 95% CI: 0.94-1.17, p = 0.33). CONCLUSIONS: Genetic variants in TSLP may contribute to asthma susceptibility in admixed urban populations with a gene and environment interaction

Following a peak in asthma mortality in the late 1980s and early 1990s, we have been fortunate to see a substantial decrease in asthma deaths in recent years. Although most asthma deaths occur outside the hospital, near-fatal events are commonplace, with anywhere from 2-20% of patients with acute asthma admitted to intensive care, and 2-4% intubated for respiratory failure. Standard therapies for acute severe and near-fatal asthma include administration of systemic corticosteroids, and frequent or continuous inhaled beta agonists. Controversy remains regarding the optimal therapy of those who fail to respond to these initial treatments, those who remain at risk of acute respiratory failure, and patients requiring mechanical ventilation. There remain significant gaps in our knowledge regarding relative benefits of intravenous versus oral corticosteroids, intermittent versus continuous beta agonists, and the role of various adjunctive treatments including intravenous magnesium, systemic beta agonists, aminophylline, and helium-oxygen mixtures. Using models and radiolabeled aerosols, there is a greater understanding regarding effective administration of inhaled beta-agonists in ventilated patients. There is limited available evidence for treatment of near-fatal asthma, a fact reflected by the significant variability in asthma critical care practice. Much of the data guiding treatment in this setting has been generalized from studies of acute asthma in the ED and from general populations of hospitalized patients with acute asthma. This review will focus on pharmacologic approaches to life-threatening asthma by reviewing current guideline recommendations, reviewing the scientific basis of the guidelines, and highlighting gaps in our knowledge in treatment of refractory acute or near-fatal asthma

We investigated whether residents living near the World Trade Center (WTC) continued to experience respiratory problems several years after September 11, 2001 (9/11). Residents living within one mile of the WTC surveyed after 9/11 responded two and four years later to follow-up surveys that asked about lower respiratory symptoms (LRS), medical history, psychological stress, and indoor environmental characteristics. There were declines in the proportion of residents reporting LRS, new lower respiratory diagnoses, unplanned medical visits, and asthma medication use. However, the proportion of residents reporting any LRS in the affected area at follow-up remained higher than the original proportion in the control area; residents with multiple sources of potential 9/11-related exposures were at greatest risk for LRS at follow-up. Psychological stress, dust/odors, and moisture were significantly associated with LRS at follow-up. These data demonstrate that LRS continue to burden residents living in the areas affected by the WTC disaster