Current Asthma Therapy: Little Need to Phenotype. Phenotypes of Severe Asthma. Cellular Phenotypes 12/7/2012

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1 Subbasement Membrane Thickness(µm) 12/7/212 Current Asthma Therapy: Little Need to Phenotype Phenotypes of Severe Asthma Most mild and to some degree moderate asthmatics respond well to currently available therapies Implies mild asthma homogeneous disease and/or therapies quite nonspecific Rohit Katial, MD, FAAAAI, FACP Professor of Medicine Program Director, Allergy & Immunology Director, Weinberg Clinical Research Unit Director, A/I Clinical Services ATS-ERS Task Force on Outcomes: Start with Difficult Asthma DIFFICULT ASTHMA (i.e. requiring high intensity treatment) Good control only if on high intensity Rx Poor control despite high intensity Rx NO ASTHMA (VCD, Obesity, malingering Initial Subtyping features underlying phenotype A features underlying phenotype B Potentially treatmentresponsive e.g. poor compliance, persisting allergen exposure, smoking etc Adapted from Taylor DR ERJ 28 Persistent co-morbidities e.g. persistent sinusitis, psychosocial problems, obesity Treating GERD phenotype of? impact Treatment-resistant (sometimes called refractory asthma ) Cellular Phenotypes SBM Thickness Associated With Eosinophilic Phenotype Eosinophilic 2 p<.5 p<.5 Neutrophilic 15 Pauciimmune 1 5 Normal Mild Moderate Severe Eos (-) Severe Eos (+) Wenzel, AJRCCM, 1999;16:11 1

2 Percent Neutrophils (%) 12/7/212 Eosinophils Associated With Increased Symptoms*, Near Fatal Events FE NO Identifies Persistent Eosinophilia In Severe Asthma EARLY ONSET LATE ONSET 8 6 p=.1 p=.2 p=.3 p= p=.14 p=.4 p=.11 p=.82 p=.36 p= Cough Wheeze Chest Shortness Tightness Breath Sleep Disturbance Cough Wheeze Chest Shortness Tightness Breath Sleep Disturbance Eos Eos No Eos No Eos *Symptoms most or all of the time Early onset eosinophilic asthma: Higher % intubated (56% vs 22%) J Allergy Clin Immunol 24;113;11-8 SA SA Mod. Mild EOS+ EOS- asthma asthma Silkoff, Lent, Katial, et al J ACI 25;116: Normal subjects Neutrophils Increase In Sputum As Asthma Severity Increases 1 75 * * Sputum Cell Counts Average cell counts (partial data subset of baseline samples from each group): Non-asthmatic controls Total cell counts (million) Eos percent Neut percent % 44.4% 5 Well-controlled asthmatics % 19.1% 25 Normal Mild Moderate Severe Jatakanon, et al.am J Respir Crit Care Med 1999 Not wellcontrolled asthmatics Poorly controlled asthmatics % 4.8% % 74.8% Characteristics of Non-Eos Asthma Distinct Phenotype Absence of remodelling Absence of Eos Poor response to corticosteroids Berry M, et al. Thorax 27;62: 143 Neutrophilic Asthma Consistently associated with CS use and low FEV1 Lesser response to CSs Green, Thorax 22 More airway wall thickening and air trapping on CT Gupta Chest 29, Busacker Chest 29 SARP clusters suggested most severe and poorly reversible (to normal) late onset cluster also the most neutophilic Some neutrophilic asthma may be just CS treated allergic/th2 asthma 2

3 12/7/212 Th2 vs Th2-Lo asthma Since inception of Th1/Th2 concept, asthma thought of as Th2, primarily allergic, disease features underlying phenotype A features underlying phenotype B Vast majority of animal models use some variation of Th2 immunity Classic allergic asthma likely makes up bulk of asthma or dominant phenotype. Driven partially by Th2 cytokines IL-4, IL-5, IL-13 Molecular phenotyping supports a Th2/atopic phenotype Cytokine Profile Woodruff P, et al AJRCCM 29 3 genes expressed in vitro in epithelial cells in response to IL-13 applied to ex vivo epithelial cells with: More BHR, atopy, eosinophils Identified by increases in epithelial periostin in particular Woodruff P, et al AJRCCM 29 Features of Molecular Phenotypes Both Th2 High and Low has: Decrements in FEV1 Th2 High has greater: AHR Th2 Hi: Thick SBM and Robust CS Response Bronchodilator responsiveness Skin Prcik test reactivity IgE Blood and BAL Eosinophilia Woodruff P, et al AJRCCM 29 3

4 inos protein (relative to βactin) 12/7/212 Th2 Phenotyping & Treatment of Severe Asthma 2+ pts with moderate to severe asthma on mid to high dose ICS, most with LABA randomized to Rx with anti-il-13 vs placebo Anti-IL-13 modestly effective in improving FEV1 in all comers However, 2ndary analysis was to target Th2 Hi vs LO Corren, et al N Engl J Med 211 Serum Periostin Identifies Th2 Hi Phenotype Which Responds to Anti-IL-13 Patients divided by median split of periostin levels Those with hi periostin had the largest increase in FEV1 Hi FeNO as good or better than periostin Lack of inos response to high dose CS: Fe NO as biomarker for Th2 severe asthma Yamamoto, Clin Exp Allergy inos 13kDa Overall p=.3 p<.1 Not suppressed by CS Normal Mild Mild+ Moderate Severe +ICS Normal Normal Mild Mild+ICS Severe Severe PGD2 Receptor, CRTH2, Selectively Increased in Severe Asthma Confirmed at protein/ihc level as well Courtesy Wenzel, S Overall p<.1 Relative BAL cell mrna CRTH2 mrna * p<.5 * p<.5 * p<.5 Normal Mild: no ICS Mild/Mod: on ICS Severe Th2-Lo Asthma Defined as the apparent absence of Th2 Much less well defined that Th2-Hi Generally adult onset May include neutrophilic, obesity-related, post infectious, smoking related? All associated with poor CS response features underlying phenotype A features underlying phenotype B 4

5 Percent 12/7/212 Early onset asthma: Identifies an allergic /Th2 phenotype p=.4 EARLY LATE p=.7 p=.2 p=.7 Hx eczema (p=.7) Early 4% Late 4% Serum IgE (p=.12) Early 18 Late 56 SARP Cluster Analysis 25 House Furred Seasonal Dust Animals Pollen Allergic Symptoms (most or all of time) Atopy Family hx of asthma Early>late J Allergy Clin Immunol 24;113;11-8 Moore et al. Am J Respir Crit Care 21;181: SARP clusters: 5% of severe asthma late onset, less allergic Obese Asthmatics May Be a Distinct Subset Mild atopic asthma Mild to moderate atopic asthma (largest) Severe atopic asthma Late onset Nonatopic 1 o female 1 o late onset/females Severe obstruction/less atopy Highest HCU/lowest QOL Haldar P et al. Am J Respir Crit Care Med 28;178: Obesity Obesity and Airway Inflammation Controversial phenotype Studies suggest highly symptomatic and high HCU Diagnosis of asthma not clear in some cases Parkvale Chest 21 As a phenotype more strongly associated with late onset asthma Haldar AJRCCM 28, Moore AJRCCM 21, Holguin JACI 211 Beuther DA et al. Am J Respir Crit Care Med 26;174:

6 12/7/212 Mechanical Effects of Obesity Obesity and Asthma Key Clinical Observations 25, new asthma cases/year due to obesity BMI a differentiator of asthma phenotype Obesity reduces glucocorticoid sensitivity Obesity alters macrophage phenotype/function Vitamin D may be an important cofactor No specific recommendations in NAEPP or GINA regarding the treatment of obese asthmatics Beuther DA et al. Am J Respir Crit Care Med 26;174: Refractory Asthma: Importance of Bronchoscopy to Identify Phenotypes and Direct Therapy Different Degrees of Upper Airway Pathology 18 y/o, n = 58 12% improvement post BD or PC2 6 mg/ml Met ATS criteria for refractory asthma Exclusion Smoking history > 5 pack years Evidence of VCD by history or flow-volume loops compatible with VCD Normal SGI = 2 Moderate SGI = 16 Mild SGI = 6 Severe SGI = 22 Chest 212 Mar;141(3): Lower airway: Secretions Initial 2 Patients Intensified Standard vs Directed Treatment 25 1 * = No Secretions 1 = Mild ACT score FEV 1 % Pred. 3 = Severe = Moderate 5 Initial presentation After 4 mo intensified standard Tx Post-bronch directed therapy 6

7 Severity Th2 Allergic Asthma Allergy/Duration Non-Th2 besity-associated Smoking/neutrophilic Smooth muscle mediated paucigranulocytic 12/7/212 Th2 Non Th2 Infection? Th17? Neutrophil? Th2 High AERD Late onset eosinophilic Very Late onset women Little eos, no fibrosis, normal airway mucin expression IgE, AHR, Skin Test Th2 Low Incr. eos, increase fibrosis, incr mucin Th2 High IgE, AHR, Skin Test EIA Childhood Adult Adult Wenzel, Nature Medicine :: Age at onset 7