Robert Kruklitis, MD, PhD Chief, Pulmonary Medicine Lehigh Valley Health Network
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1 Robert Kruklitis, MD, PhD Chief, Pulmonary Medicine Lehigh Valley Health Network
2 Correlation of a Asthma pathophyisology with basic science Asthma (Physiology) Bronchodilators (Organic and Biochemistry) Xolair (Immunology) Heliox (Physics of Airflow) Bronchothermoplasty (Clinical Trials)
3 Asthma Overview: Prevalence, Morbidity and Mortality 24.6 million People diagnosed with asthma 12.8 million People experience asthma attacks 1.8 million Emergency room visits 456,000 Hospitalizations 3,447 Asthma-related deaths Annual incidence, based on 2007 data Approximately 9 People Die From Asthma Each Day in the U.S. Centers for Disease Control and Prevention National Center for Health Statistics, National Health Statistics Report: Asthma Prevalence, Health Care Use, and Mortality: United States, : 3
4 Asthma: Overview Asthma is a disorder that causes the airways of the lungs to swell and narrow, leading to wheezing, shortness of breath, chest tightness, and coughing Smooth muscle hyperplasia Excessive mucus Inflammation
5 History and Symptoms Physical Exam Chest X-ray Blood Tests Pulmonary Function Tests
6 Measurement of Airflow Spirometry Forced Expiratory Volume 1 Forced Vital Capacity
7 Asthmatic Non-Asthmatic
8 Obstructive Airway Disease In Asthmatics FEV1: Decreased FVC: Normal FEV1/FVC ratio: Decreased FEV1/FVC <70% defines Obstruction Asthmatics have an Obstructive Pattern on Spirometry
9
10 Stepwise Approach for Managing Asthma 6 High-dose ICS + LABA + Oral Corticosteroids and Consider Omalizumab Alternatives Needed 5 High-dose ICS + LABA and Consider Omalizumab 4 Medium-dose ICS + LABA 3 Low-dose ICS + Long-acting Beta 2 -agonists (LABA) or Medium-dose ICS 2 Low-dose Inhaled Corticosteroids (ICS) 1 Short-acting Beta 2 -agonists Adapted from National Asthma Education and Prevention Program (NAEPP) Guidelines. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute, NIH Publication No , Revised August
11
12 Bronchconstriction Smooth Muscle surrounding airways constrict resulting in airway narrowing. Bronchodilators: Medicine that relax airways Adrenergic Agonists Medications that stimulate Adrenergic receptors
13 Fight or Flight
14 Adrenergic Agonists Fight or Flight Response Adrenal Gland Releases Epinepherine (Adrenaline) Epinepherine stimulate a1, a2, b1, b2, b3 receptors Clinical Effects Racing heart Dilated pupils Pale sweaty skin Nausea Improved breathing Can we use Epinepherine to improve Asthma?
15 Epinepherine for Asthma Benefits Bronchodilation Side Effects Tachycardia Tremors Nausea How do we maximize effectiveness while minimizing side effects? Epinepherine stimulate a1, a2, b1, b2, b3 receptors
16 Adrenergic Receptors
17 Target b receptors Alupent Epinepherine
18 b2 Agonist Albuterol: Short Acting b-2 agonist Levalbuterol (R-isomer) Selective stimulation of adrenergic (b-2) receptors in bronchial tree results in bronchodilation
19 albuterol Beta(2)-adrenergic agonist Binding to receptors increases camp production Increased camp activates protein kinase that inhibits phosporation of myosin Result is smooth muscle relaxation
20 FEV1 after Albuterol Improved FEV1 = less shortness of breath and wheezing
21 Stepwise Approach for Managing Asthma 6 High-dose ICS + LABA + Oral Corticosteroids and Consider Omalizumab Alternatives Needed 5 High-dose ICS + LABA and Consider Omalizumab 4 Medium-dose ICS + LABA 3 Low-dose ICS + Long-acting Beta 2 -agonists (LABA) or Medium-dose ICS 2 Low-dose Inhaled Corticosteroids (ICS) 1 Short-acting Beta 2 -agonists Adapted from National Asthma Education and Prevention Program (NAEPP) Guidelines. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute, NIH Publication No , Revised August
22 b2 agonists Albuterol - Short acting Salmeterol Long Acting
23 Albuterol vs. LABA Clinical Significance
24
25 Allergen exposure
26 Allergen Exposure Plasma Cells IgE WBCs that produce antibodies (immunoglobulin) Antibody Impt in allergic disease Mast Cell Degranulation Histamines Prostaglandins Leukotrienes
27 Therapeutic Options Targeting IgE pathway Histamines AntiHistamines (e.g. Benadryl, Zyrtec) Prostaglandins Steroids (e.g. Prednisone) Leukotrienes IgE Leukotriene Inhibators (e.g. Singular) Anti-IgE (e.g. Xolair)
28 IgE significantly elevated in asthmatics The predictive value of IgE as a biomarker in Asthma IgE: 554 IU/ml in Asthmatics IgE: 69 IU/ml in non- Asthmatic J. Asthma :
29 Xolair: Monoclonal anti-ige
30 Second Generation anti-ige? Xolair Requires injection Potentially severe side effects Costly
31
32 Wheezing and Work of Breathing What is Wheezing? How can we minimize Wheezing?
33 Physics of Airflow Turbulent Laminar Reynolds Number (Re) Increased Re favors turbulent airflow Turbulent airflow dependent upon density, velocity and radius Re a rv r 2
34 rv Re a r 2 Wheezing = Turbulent Flow Turbulent Flow = increased work of breathing How can we decease wheezing and decease WOB?
35 Heliox 70% He: 30% O2 Density Heliox =0.5 g/l Air = 1.25 g/l Increased tendency to laminar flow with Heliox Decreased Wheezing and WOB Cumbersome (lg tanks)
36
37 Smooth Muscle Hypertropy Adrenergic Agonists Medications that stimulate Adrenergic receptors Bronchial Thermoplasty Treatment that physically reduces hypertrophied muscle
38 Role of Airway Smooth Muscle on Asthma Normal Airway Asthmatic Airway Asthma Attack 38
39 Bronchial Thermoplasty ASM Treatment Approach Reduces Airway Smooth Muscle (ASM) Reduces Bronchoconstriction Reduces Asthma Exacerbations Improves Asthma Quality of Life 39
40 What is Bronchial Thermoplasty? A procedure that delivers thermal energy to the airways via a bronchoscope to reduce excess airway smooth muscle and limit its ability to constrict the airways Outpatient hospital procedure performed over 3 treatment sessions, routinely under moderate sedation, by a trained pulmonologist Complementary treatment, and not a replacement, to current asthma reliever and controller medications A treatment option shown to increase the level of asthma control and improve quality of life in patients with severe asthma 40
41 The Alair Bronchial Thermoplasty System Alair Catheter a flexible tube with an expandable wire array at the tip (introduced into the lungs through a standard bronchoscope) 41
42
43 Reduced Airway Smooth Muscle 3 years post-treatment (canine model) Ciliated Epithelium ASM Reduced ASM Ciliated Epithelium Parenchyma Parenchyma UNTREATED TREATED Masson s Trichrome stain 43
44
45 Health Care Utilization for Respiratory Symptoms During Post-Treatment Period 1 6 weeks after the last bronchoscopy procedure to 12 month follow-up Events / Subject/ Year * 32% decrease over Sham 0.48 Severe Exacerbations (Steroid) % decrease over Sham 0.28 Unscheduled Physician Office Visits 0.43 * Posterior Probability of Superiority = 95.6% ** Posterior Probability of Superiority = 99.9% ** 84% decrease over Sham 0.07 Emergency Room Visits Sham 0.13 BT 0.04 Hospitalizations 73% decrease over Sham BT = Bronchial Thermoplasty 1. Castro, Am J Respir Crit Care Med. 2010;181(2):
46 Summary Bronchodilators Selectively activate b2 receptors Modified to minimize side effects and last longer Immunology of Asthma Heliox Anti IgE treatment Decreased density promotes laminar airflow Less wheezing and less work of breathing Bronchial Thermoplasty Physically altering the enlarged smooth muscle Less bronchoconstriction and improved quality of life
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