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.

Objectives. We assessed associations between new-onset (post-September 11, 2001 [9/11]) lower respiratory symptoms reported on 2 surveys, administered 3 years apart, and acute and chronic 9/11-related exposures among New York City World Trade Center-area residents and workers enrolled in the World Trade Center Health Registry. Methods. World Trade Center-area residents and workers were categorized as case participants or control participants on the basis of lower respiratory symptoms reported in surveys administered 2 to 3 and 5 to 6 years after 9/11. We created composite exposure scales after principal components analyses of detailed exposure histories obtained during face-to-face interviews. We used multivariate logistic regression models to determine associations between lower respiratory symptoms and composite exposure scales. Results. Both acute and chronic exposures to the events of 9/11 were independently associated, often in a dose-dependent manner, with lower respiratory symptoms among individuals who lived and worked in the area of the World Trade Center. Conclusions. Study findings argue for detailed assessments of exposure during and after events in the future from which potentially toxic materials may be released and for rapid interventions to minimize exposures and screen for potential adverse health effects.

PURPOSE OF REVIEW: Guidelines suggest that asthma medication should be reduced once asthma control is sustained. Moderate-dose inhaled corticosteroids (ICS) can typically be reduced, but questions remain about the lowest effective ICS dose and the role of non-ICS controllers in treatment reduction. Long-acting beta agonist (LABA) safety concerns have created controversy about how to step down patients on ICS/LABA therapy. This review will focus on the current status of these issues. RECENT FINDINGS: Intermittent ICS treatment, often in fixed combination with short-acting beta agonist, is an emerging strategy for control of mild asthma. Addition of leukotriene modifiers, LABAs, and omalizumab to ICS can allow for reduced ICS dosing. Doses of ICS that control symptoms may be inadequate to control exacerbations. Reducing ICS dose before discontinuing LABAs may be the more effective approach for patients on combination therapy. SUMMARY: Use of non-ICS controllers allows for ICS dose reduction with superior outcomes. Tapering of ICS prior to LABA discontinuation may be the favored approach for patients on ICS/LABA therapy, but an understanding of long-term outcomes and further safety data are required. The lowest ICS dose that adequately controls both asthma impairment and risk remains to be determined

Introduction: Mouse RELMalpha is a member of the resistin family of adipokines and is expressed by many cell types including intestinal and airway epithelial cells, macrophages activated in the course of Th2 responses (alternatively activated macrophages), dendritic cells and white adipose tissue. This molecule is also known as Found in Inflammatory Zone (FIZZ) and Hypoxia Induced Mitogenic Factor (HIMF). The human homologue, RELMbeta, is expressed at increased levels in the pulmonary artery in pulmonary arterial hypertension and is a mitogen for human vascular smooth muscle cells. Methods: Our studies focused on the role of RELMalpha in severe pulmonary arterial remodeling induced by a T helper 2 (Th2) response to antigen. We studied wild type and RELMalpha deficient mice following immunization with Ovalbumin (OVA) complexed to Alum and exposure to soluble OVA alone or in combination with respirable urban particulate matter. The urban particulate matter (PM2.5) was collected from the air in New York City. Results: The study showed that the number of cells that stain positively for RELMalpha by immunohistochemistry was significantly correlated with the severity of pulmonary arterial remodeling. Furthermore, our studies demonstrated a significant exacerbation of pulmonary arterial remodeling in antigen primed wild type mice exposed to a combination of antigen and urban particulate matter. RELMalpha deficient mice, in contrast, failed to show the exacerbation and developed pulmonary arterial thickening to exposure with antigen and respirable urban particulate matter to a significantly smaller degree relative to wild type. The severity of inflammation and the type of the immune response in the RELMalpha deficient mice challenged with antigen or the combination of antigen and urban particulate matter was not significantly different from the responses in wild type mice. Conclusion: RELMalpha is known to have a critical role in hypoxia induced pulmonary arterial remodeling; and combustion of fossil fuels releases airborne metals that can mimic hypoxia induced cell signaling. Therefore, our data suggest the idea that hypoxia-mimetic metals contained within urban particulate matter exacerbate pulmonary arterial remodeling induced by a Th2 response to antigen via synergistic augmentation of RELMalpha expression

Rationale: Ambient pollutants upregulate cytokines involved in mucosal immune responses. We recently demonstrated that diesel exhaust particle (DEP)-treated human bronchial epithelial cells (HBEC) upregulated myeloid dendritic cell (mDC) maturation and promoted DC that support Th2 polarization via HBEC-derived thymic stromal lymphopoietin (TSLP). IL-33 is an IL-1 like cytokine that signals via a heterodimer (IL-1RL1, ST2 and IL-1R accessory protein; IL-1RAcP). Genetic variants of IL-33 and ST2 are associated with asthma. Since IL-33/ST2 signaling acts in synergy with TSLP to induce Th2 responses, we hypothesized that DEP-treated HBEC up-regulate expression and release of IL-33 and support mDC maturation. Methods: Primary culture HBEC (pHBEC) were treated with PBS (resting), PMA (5ng/ml), or DEP (3mug/cm²) and total RNA (6h) or supernatant (18h) isolated. Immature mDC isolated from peripheral blood (magnetic selection, BDCA-1) were exposed to resting or treated pHBEC (48h). mDC function was determined by the ability to support an allogeneic mixed lymphocyte reaction (aMLR) after rescue from pHBEC co-culture by FACS sorting. T cell proliferation was measured by BrdU-incorporation. Results: DEP-treated pHBEC upregulated IL-33 mRNA (2.5+/-0.5 fold induction, n=3; mean +/- SEM; p<0.05). Soluble IL-33 was undetected from resting pHBEC but was increased by DEP treatment (7.2+/-0.2pg/ml; n=3, p<0.05). mDC expressed ST2 and IL-1RacP (FACS analysis) but neither DEP nor DEP-treated pHBEC changed their expression. As previously reported, DEP-treated pHBEC upregulated mDC function (aMLR). Anti-IL-33 pAb reduced DEP-treated pHBEC-dependent functional maturation of mDC, (26+/-7% reduction; n=3; p<0.05). The reduction observed was less than that with anti-TSLP pAb (48+/-8% reduction; n=3; p<0.05). Conclusion: DEP-treated pHBEC upregulated IL-33 transcription and supernatant protein and upregulation was associated with functional mDC maturation. Our data suggest that DEP upregulated Il-33 and TSLP in pHBEC, and these may act in concert to induce mDC regulated Th2 immune-responses at mucosal sites