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1、Asthma: Immune PhenotypesPatricia W. Finn, MD Professor and Chair Department of Medicine University of Illinois at ChicagoPresident, American Thoracic Society 2013-2014Disclosures Research (funds paid to University of Illinois at Chicago) NIH Other sources of support: American Thoracic SocietyAsthma
2、 Asthma is clinically defined as a syndrome with episodic wheezing, shortness of breath, cough and sputum production The constant features are airway irritability (hyperresponsiveness) and inflammationAsthma: Epidemiology Between 150-300 million patients worldwide 15-25 million in the U.S. Most comm
3、on chronic disease of childhood Over 500,000 E.R. visits per year 25,000 ICU admissions 5-6,000 deaths in U.S. On the increaseAllergic Asthma: PathwaysIgEIgEIL -13EosinophilsIL-5IL-5ILIL -1313Th2Th2Th1Th1Mast CellB-cellIL-4IL-4TCRMHC IIT Lymphocyte APCCD80CD86 CD28Generation of Allergic AdaptiveImmu
4、ne ResponsesSevere Asthma Definition Phenotypes - Pathologic/Clinical Therapeutic OptionsInflammation and Remodeling in AsthmaCourtesy of Marllyn Glassberg, MDApproach to Management/Contributing Factors/Co -Morbid ConditionsExamine for concomitant medical disorders, i.e. sinusitis, OSA, VCD GERD - a
5、cid and non-acid reflux Environmental control Alternative diagnoses Incorporate objective measures into management Written action plan Review medication techniqueSevere Asthma ClustersMoore et al. AJRCCM 2010;181:315- 323Asthma Clusters Cluster 1: early onset, atopic, nl lung fxn 2 controllers, nl l
6、ung fxn, significant health care utilization Cluster 3: adult onset, obese woman with low lung fxn, high medication requirement and healthcare utilization Cluster 4: early onset, atopic, severe obstruction with some reversibility (FEV1: 57% to 76% pred), high healthcare utilization Cluster 5: early
7、onset, severe obstruction, 66% atopic; less reversibility ( FEV1: 43% to 58%), high health care utilizationMoore et al. AJRCCM 2010;181:315-323Asthma Phenotypes:Heterogeneous DiseaseClinical:Pathologic: Fixed obstructionEosinophilic ObeseNon-eosinophilic Adult onsetPauci-granulocytic Exacerbation pr
8、one Treatment resistantTriggers: Occupational Aspirin Exercise MensesPathological Phenotypes Eosinophilic/TH2 (IL-4, IL-5 and IL-13) Non-eosinophilic (sputum eos 2%, or peripheral blood eos 200/l)Clinical Features of Asthmatics with “High” and “Low” IL-13 Gene SignaturesWoodruff, et al. AJRCCM 2009;
9、 180:388-395Woodruff et al Am J Respir Crit Care Med 180:3888-95, 2009Th2 “high” vs. “low” signature results in different clinical characteristics and response to ICSInterleukin-13 and Non-Interleukin-13 Inflammatory Pathways in AsthmaKraft M. N Engl J Med 2011;365:1141Biomarkers to identify the Th2
10、 phenotype Sputum eosinophils Exhaled nitric oxide Circulating eosinophils Periostin IgE Allergen skin testingSevere Asthma: Periostin correlates with sputum and tissue eosinophilsJia et al. JACI 2012;130:647Eosinophilic Phenotype:Some Treatment OptionsEosinophilic Phenotype: Rationale for Zileuton
11、(Leukotriene Inhibitor) Anti-eosinophil and anti-mast cell effects Decreased BAL eos in nocturnal asthma (Wenzel ARRD 1995) Decreased mast cell tryptase following ASA challenge (Israel, ARRD 1993) Broader effect than montelukast Inhibits activation of multiple cysLT receptors Blocks LTB4 Blocks othe
12、r 5 LO metabolites Eosinophils Phenotype: Omalizumab (anti-IgE) reduces submucosal EosinophilsEosinophils (cells/mm2)BaselinePosttreatment020608080602004040BaselinePosttreatment8.0 1.56.36.4Placebo (n=14)Omalizumab (n=14)P0.001P=0.81P=0.033Djukanovic et al. AJRCCM 2004Lung Function: Inhibition of IL
13、-13Corren et al. NEJM 2011; 365:1088Non-eosinophilic AsthmaEosinophilic and non-eosinophilic asthma: pathologic comparisonBerry et al. Thorax 2007;62:1043Inhaled Corticosteroids: Airways HyperresponsivenessBerry et al. Thorax 2007;62:1043Inhaled Corticosteroids: Quality of Life Berry et al. Thorax 2
14、007;62:1043Non-eosinophilic asthma: other mediators?Wang, Curr Opin Immun 2008; 20:697-702Increased Membrane Bound TNF- in Refractory AsthmaBerry, et al. NEJM 2006; 354:697-708BAL TNF- Levels are Increased in The Lungs of Obese Asthmatics*p0.001, *p0.01, #p0.05 Lugogo et al. AJRCCM 2012; 864:404Non-
15、eosinophilic phenotype: treatment options?Asthma Phenotypes and Macrolides Brusselle et al. recruited 109 subjects with asthma, on combination therapy (Thorax 2013;177:148) Subjects were “exacerbation prone” as they were required to have had two exacerbations requiring oral corticosteroids or LTRI r
16、equiring antibiotics in the previous 12 months Azithromycin vs. placebo added to combination therapy for 6 months in a double-blind fashion Primary outcome was the rate of exacerbations and LTRI requiring antibioticsAsthma Phenotypes and Macrolides- Results in the Entire CohortBrusselle et al. Thorax 2013;177:148Nonoesinophilic Asthma: Only (defined as blood eos 2
