robert kruklitis, md, phd chief, pulmonary medicine...
TRANSCRIPT
Correlation of a Asthma pathophyisology with basic science
ó Asthma – (Physiology) ó Bronchodilators – (Organic and Biochemistry) ó Xolair – (Immunology) ó Heliox – (Physics of Airflow) ó Bronchothermoplasty – (Clinical Trials)
Centers for Disease Control and Prevention National Center for Health Statistics, National Health Statistics Report: Asthma Prevalence, Health Care Use, and Mortality: United States, 2005–2009: http://www.cdc.gov/nchs/data/nhsr/nhsr032.pdf
Approximately 9 People Die From Asthma Each Day in the U.S.
Annual incidence, based on 2007 data
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
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Asthma: Overview ó 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 ó Smooth muscle hyperplasia ó Excessive mucus ó Inflammation
History and Symptoms Physical Exam Chest X-ray Blood Tests Pulmonary Function Tests
Measurement of Airflow ó Spirometry
Forced Expiratory Volume 1 Forced Vital Capacity
Asthmatic Non-Asthmatic
Obstructive Airway Disease ó In Asthmatics ó FEV1: Decreased ó FVC: Normal ó FEV1/FVC ratio: Decreased
ó FEV1/FVC <70% defines Obstruction
ó Asthmatics have an Obstructive Pattern on Spirometry
Short-acting Beta2-agonists
Low-dose Inhaled Corticosteroids (ICS)
Low-dose ICS + Long-acting Beta2-agonists (LABA)
or Medium-dose ICS
Medium-dose ICS + LABA
High-dose ICS + LABA and Consider Omalizumab
High-dose ICS + LABA + Oral Corticosteroids
and Consider Omalizumab
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. 07-4051, Revised August 2007.
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6 Alternatives Needed
Stepwise Approach for Managing Asthma
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Bronchconstriction ó Smooth Muscle surrounding airways constrict
resulting in airway narrowing. ó Bronchodilators: Medicine that relax airways ó Adrenergic Agonists – Medications that stimulate
Adrenergic receptors
Fight or Flight
Adrenergic Agonists ó Fight or Flight Response ó Adrenal Gland Releases Epinepherine (Adrenaline) ó Epinepherine stimulate a1, a2, b1, b2, b3 receptors ó Clinical Effects ó Racing heart ó Dilated pupils ó Pale sweaty skin ó Nausea ó Improved breathing
ó Can we use Epinepherine to improve Asthma?
Epinepherine for Asthma ó Benefits
ó Bronchodilation
ó Side Effects ó Tachycardia ó Tremors ó Nausea
ó How do we maximize effectiveness while minimizing side effects? ó Epinepherine stimulate a1, a2, b1, b2, b3 receptors
Adrenergic Receptors
Target b receptors ó Alupent
Epinepherine
b2 Agonist
Albuterol: Short Acting b-2 agonist Levalbuterol (R-isomer)
Selective stimulation of adrenergic (b-2) receptors in bronchial tree results in bronchodilation
albuterol ó Beta(2)-adrenergic
agonist ó Binding to receptors
increases cAMP production ó Increased cAMP
activates protein kinase that inhibits phosporation of myosin ó Result is smooth muscle
relaxation
FEV1 after Albuterol
ó Improved FEV1 = less shortness of breath and wheezing
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. 07-4051, Revised August 2007.
Short-acting Beta2-agonists
Low-dose Inhaled Corticosteroids (ICS)
Low-dose ICS + Long-acting Beta2-agonists (LABA)
or Medium-dose ICS
Medium-dose ICS + LABA
High-dose ICS + LABA and Consider Omalizumab
High-dose ICS + LABA + Oral Corticosteroids
and Consider Omalizumab
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2
3
4
5
6 Alternatives Needed
Stepwise Approach for Managing Asthma
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b2 agonists
Albuterol - Short acting Salmeterol – Long Acting
Albuterol vs. LABA Clinical Significance
Allergen exposure
Allergen Exposure ó Plasma Cells ó WBCs that produce
antibodies (immunoglobulin)
ó IgE ó Antibody ó Impt in allergic disease
ó Mast Cell Degranulation ó Histamines ó Prostaglandins ó Leukotrienes
Therapeutic Options Targeting IgE pathway ó Histamines
ó AntiHistamines (e.g. Benadryl, Zyrtec)
ó Prostaglandins ó Steroids (e.g. Prednisone)
ó Leukotrienes ó Leukotriene Inhibators
(e.g. Singular)
ó IgE ó Anti-IgE (e.g. Xolair)
IgE significantly elevated in asthmatics ó The predictive value of
IgE as a biomarker in Asthma ó IgE: 554 IU/ml in
Asthmatics ó IgE: 69 IU/ml in non-
Asthmatic ó J. Asthma 2008 45: 654-63
Xolair: Monoclonal anti-IgE
Second Generation anti-IgE?
ó Xolair ó Requires injection ó Potentially severe side effects ó Costly
Wheezing and Work of Breathing óWhat is Wheezing? ó How can we minimize Wheezing?
Physics of Airflow
ó Turbulent ó Laminar ó Reynolds Number (Re) ó Increased Re favors
turbulent airflow ó Turbulent airflow
dependent upon density, velocity and radius
rV Re a r2
óWheezing = Turbulent Flow ó Turbulent Flow = increased work of breathing
ó How can we decease wheezing and decease WOB?
rV Re a r2
Heliox ó 70% He: 30% O2 ó Density ó Heliox =0.5 g/l ó Air = 1.25 g/l
ó Increased tendency to laminar flow with Heliox ó Decreased Wheezing
and WOB
ó Cumbersome (lg tanks)
Smooth Muscle Hypertropy ó Adrenergic Agonists – Medications that stimulate
Adrenergic receptors ó Bronchial Thermoplasty – Treatment that
physically reduces hypertrophied muscle
Asthmatic Airway
Role of Airway Smooth Muscle on Asthma
Normal Airway Asthma Attack 38
Bronchial Thermoplasty – ASM Treatment Approach
Reduces Airway Smooth Muscle (ASM)
Reduces Bronchoconstriction
Reduces Asthma Exacerbations
Improves Asthma Quality of Life
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What is Bronchial Thermoplasty?
ó 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
ó Outpatient hospital procedure performed over 3 treatment sessions, routinely under moderate sedation, by a trained pulmonologist
ó Complementary treatment, and not a replacement, to current asthma reliever and controller medications
ó A treatment option shown to increase the level of asthma control and improve quality of life in patients with severe asthma
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The Alair® Bronchial Thermoplasty System
ó Alair Catheter – a flexible tube with an expandable wire array at the tip (introduced into the lungs through a standard bronchoscope)
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UNTREATED
Ciliated Epithelium ASM
Parenchyma Parenchyma
Ciliated Epithelium ASM Reduced
TREATED
Masson’s Trichrome stain
Reduced Airway Smooth Muscle ó 3 years post-treatment (canine model)
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Health Care Utilization for Respiratory Symptoms During Post-Treatment Period1
ó 6 weeks after the last bronchoscopy procedure to 12 month follow-up
0.7
0.36
0.43
0.13
0.48
0.28
0.07 0.04 0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Severe Exacerbations (Steroid)
Unscheduled Physician Office Visits
Emergency Room Visits Hospitalizations
Even
ts /
Subj
ect/
Year
Sham BT
**
* Posterior Probability of Superiority = 95.6% ** Posterior Probability of Superiority = 99.9%
73% decrease over Sham
84% decrease over Sham
32% decrease over Sham
22% decrease over Sham
*
BT = Bronchial Thermoplasty
1. Castro, Am J Respir Crit Care Med. 2010;181(2):116-24 45
Summary ó Bronchodilators
ó Selectively activate b2 receptors ó Modified to minimize side effects and last longer
ó Immunology of Asthma ó Anti IgE treatment
ó Heliox ó Decreased density promotes laminar airflow ó Less wheezing and less work of breathing
ó Bronchial Thermoplasty ó Physically altering the enlarged smooth muscle ó Less bronchoconstriction and improved quality of life