Faculty Bibliography

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.

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

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

Asthma in the elderly is underdiagnosed and undertreated, and there is a paucity of knowledge on the subject. The National Institute on Aging convened this workshop to identify what is known and what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of asthma in the elderly. Asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger patients, but comorbid illnesses and the psychosocial effects of aging might affect the diagnosis, clinical presentation, and care of asthma in this population. At least 2 phenotypes exist among elderly patients with asthma; those with longstanding asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. Many challenges exist in the recognition and treatment of asthma in the elderly. Furthermore, the pathophysiologic mechanisms of asthma in the elderly are likely to be different from those seen in young asthmatic patients, and these differences might influence the clinical course and outcomes of asthma in this population.

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

The attack on the World Trade Center (WTC) on 9/11/2001 produced a massive dust cloud with acute exposure, and the rubble pile burning over 3 months exposed more than 300,000 residents, rescue workers, and clean-up workers. Firefighters in the New York City Fire Department had significant respiratory symptoms characterized by cough, dyspnea, gastroesophageal reflux, and nasal stuffiness with a significant 1-year decline in FVC and FEV(1). Bronchial hyperreactivity measured by methacholine challenge correlated with bronchial wall thickening on CT scans. Compared with the NHANES III data for FVC and FEV(1), 32% of 2,000 WTC dust-exposed residents and clean-up workers were below the lower 5th percentile. The most common abnormality was a low FVC pattern, a finding similar to that also described for individuals in rescue and recovery activities. Among those complaining of respiratory symptoms and normal spirometry, almost half had abnormalities detected with impedance oscillometry consistent with distal airways' disease. Follow-up with the WTC Health Registry and the WTC Environmental Health Center will help discern whether treatment with anti-inflammatory medications or bronchodilators in those with respiratory symptoms may prevent the development of chronic obstructive pulmonary disease