Asthma: Immune Phenotypes,Asthma,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 inflammation,Asthma: Epidemiology,Between 150-300 million patients worldwide 15-25 million in the U.S. Most common 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 increase,Allergic Asthma: Pathways,IgE,IL,-,13,Eosinophils,IL-5,IL,-,13,Th2,Th1,Mast Cell,B-cell,IL-4,TCR,MHC II,T Lymphocyte,CD80,CD86,CD28,Generation of Allergic Adaptive Immune Responses,Severe Asthma,Definition Phenotypes - Pathologic/Clinical Therapeutic Options,Inflammation and Remodeling in Asthma,Courtesy of Marllyn Glassberg, MD,Approach to Management/Contributing Factors/Co-Morbid Conditions,Examine for concomitant medical disorders, i.e. sinusitis, OSA, VCD GERD - acid and non-acid reflux Environmental control Alternative diagnoses Incorporate objective measures into management Written action plan Review medication technique,Severe Asthma Clusters,Moore et al. AJRCCM 2010;181:315-323,Asthma Clusters,Cluster 1: early onset, atopic, nl lung fxn 2 controllers, nl lung 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 onset, severe obstruction, 66% atopic; less reversibility ( FEV1: 43% to 58%), high health care utilization,Moore et al. AJRCCM 2010;181:315-323,Asthma Phenotypes: Heterogeneous Disease,Clinical: Pathologic: Fixed obstruction Eosinophilic Obese Non-eosinophilic Adult onset Pauci-granulocytic Exacerbation prone Treatment resistant Triggers: Occupational Aspirin Exercise Menses,Pathological 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 Signatures,Woodruff, et al. AJRCCM 2009; 180:388-395,Woodruff et al Am J Respir Crit Care Med 180:3888-95, 2009,Th2 “high” vs. “low” signature results in different clinical characteristics and response to ICS,Interleukin-13 and Non-Interleukin-13 Inflammatory Pathways in Asthma,Kraft M. N Engl J Med 2011;365:1141,Biomarkers to identify the Th2 phenotype,Sputum eosinophils Exhaled nitric oxide Circulating eosinophils Periostin IgE Allergen skin testing,Severe Asthma: Periostin correlates with sputum and tissue eosinophils,Jia et al. JACI 2012;130:647,Eosinophilic Phenotype: Some Treatment Options,Eosinophilic Phenotype: Rationale for Zileuton (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 other 5 LO metabolites,Eosinophils Phenotype: Omalizumab (anti-IgE) reduces submucosal Eosinophils,Eosinophils (cells/mm2),Baseline,Posttreatment,0,20,60,80,80,60,20,0,40,40,Baseline,Posttreatment,8.0,1.5,6.3,6.4,Placebo (n=14),Omalizumab (n=14),P0.001,P=0.81,P=0.033,Djukanovic et al. AJRCCM 2004,Lung Function: Inhibition of IL-13,Corren et al. NEJM 2011; 365:1088,Non-eosinophilic Asthma,Eosinophilic and non-eosinophilic asthma: pathologic comparison,Berry et al. Thorax 2007;62:1043,Inhaled Corticosteroids: Airways Hyperresponsiveness,Berry et al. Thorax 2007;62:1043,Inhaled Corticosteroids: Quality of Life,Berry et al. Thorax 2007;62:1043,Non-eosinophilic asthma: other mediators?,Wang, Curr Opin Immun 2008; 20:697-702,Increased Membrane Bound TNF- in Refractory Asthma,Berry, et al. NEJM 2006; 354:697-708,BAL TNF- Levels are Increased in The Lungs of Obese Asthmatics,*p0.001, *p0.01, #p0.05,Lugogo et al. AJRCCM 2012; 864:404,Non-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 requiring 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 antibiotics,Asthma Phenotypes and Macrolides- Results in the Entire Cohort,Brusselle et al. Thorax 2013;177:148,Nonoesinophilic Asthma: Only (defined as blood eos 200/l),Brusselle et al. Thorax 2013;177:148,Severe Asthma: Tiotropium,Kerstjens et al. NEJM 2012,Environment and immunity: impact on asthma pathogenesis?,NEJM 347:911, 2002,Epidemiological trends in infections and chronic diseases,Innate and Adaptive Immunity,Innate Antigen indepen