ASTHMA PATHOPHYSIOLOGY ASTHMA OVERVIEW Presented by Michelle Harkins

ASTHMA PATHOPHYSIOLOGY ASTHMA OVERVIEW Presented by: Michelle Harkins, MD University of New Mexico

This session will cover • • • Review asthma statistics Define asthma Outline key pathophysiologic features Review signs and symptoms of asthma Reference to NAEPP – EPR-3: asthma severity classification system-including impairment and risk domains • Diagnosing asthma

Prevalence vs Incidence • Prevalence - the proportion or percentage of a population that has disease at a specific point or period of time • Incidence – the number of new cases of disease that develop in a population of individuals at risk during a specific point or period of time

• 1980 -1996 prevalence of asthma in US increased • Since 1999, mortality and hospitalization due to asthma have decreased

Asthma – Current Prevalence by Age, 2011 CURRENT PREVALENCE RATE PER 1, 000 120 105. 5 94. 9 100 79. 9 80 86. 7 79. 4 68. 5 60 40 20 0 Under 5 5 -17 <18 18 -44 Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012. 45 -64 65+

Asthma – Current Prevalence by Sex and Age, 2011 Male Female Current Prevalence per 1, 000 120 97. 3 100 80 101. 7 100. 1 87. 8 71. 9 61. 8 60 40 20 0 Total Under 18 Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012. 18 and Over

Asthma – Current Prevalence by Race, 2011 Whites 350 Blacks 314. 2 287. 9 Current Prevalence per 1, 000 300 238 250 200 147. 3 150 100 118 80. 4 50 0 Total Under 18 Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012. 18 and Over

New Mexico BRFSS Results for 2010: Current Prevalence: Percent of New Mexico Children who Currently Have Asthma by Various Demographic Characteristics Race/Ethnicity: White, Non-Hispanic Native American 8. 1% 7. 4% 13. 1% SOURCE: Centers for Disease Control and Prevention (CDC). Behavioral Risk Factor Surveillance System Survey Data. Atlanta, Georgia: U. S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2009

Asthma – Attack Prevalence by Age and Race, 2011 White Black 100 ATTACK PREVALENCE per 1, 000 90 80 70 60 50 40 30 20 10 0 Total <5 5 -17 18 -44 Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012. 45 -64 65+

Asthma – First-Listed Hospital Discharges by Race, 2010 Total White Black All Other 28. 5 30 DISCHARGES PER 10, 000 25 20 15 14. 3 11. 6 10 9 5 0 Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012.

Asthma age-adjusted hospitalization rates per 10, 000 standard population by county, New Mexico, 2007 -2011 average

Asthma hospitalization rates per 10, 000 standard population among youth (0 -14 years) by county, New Mexico, 2007 -2011 average

Asthma – Crude Death Rate by Age Group, 2009 CRUDE DEATH RATE PER 100, 000 12 10 8 6 4 2 0 1 -4 5 -14 15 -24 25 -34 35 -44 45 -54 Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012. 55 -64 65 -74 75 -84 85+

Asthma – Age-Adjusted Death Rates by Sex and Race, 2009 Male Female AGE-ADJUSTED DEATH RATE PER 100, 000 3 2. 5 2 1. 5 1 0. 5 0 Total White Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012. Black Hispanic

Asthma Age-Adjusted Death Rates Based on the 1940 and 2000 Standard populations, 1979 -2005 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 1940 0. 9 1. 0 1. 2 1. 1 1. 2 1. 3 1. 4 1. 5 1. 4 1. 2 1. 1 1. 0 0. 9 2000 1. 3 1. 4 1. 5 1. 7 1. 6 1. 8 1. 9 2. 0 2. 1 2. 2 2. 1 2. 0 1. 7 1. 6 1. 5 1. 4 1. 3

Asthma Impact – Economic Burden • Childhood asthma accounts for 14. 4 million days missed from school annually – The number-one chronic condition causing children to be absent from school and the third highest ranked cause of pediatric hospitalizations in the United States – On average, a child with asthma will miss one full week of school each year due to the disease

Asthma Impact – Economic Burden • Adult asthma accounts for 14. 2 million missed workdays annually • 4 th leading cause of missed work days

National Burden of Asthma $19. 7 billion annually • $14. 7 billion in direct costs (prescription medications, hospital care, and physician services) • $5 billion in indirect costs (lost productivity due to missed work or school and premature mortality)

DEFINE ASTHMA Develop a collaborative working definition of asthma

Evolution of the Definition of Asthma 1962 American Thoracic Society, 1962. • Episodic disease characterized by: – Reversible airway constriction – Increased airway responsiveness 2007 NAEPP, EPR 3, 2007. • Chronic disease characterized by: – Chronic airway inflammation – At least partially reversible airway obstruction – Increased airway responsiveness

3 M Resource Cards Doctors Designers 11 -96

3 M Resource Cards Doctors Designers 11/96

3 M Resource Cards Doctors Designers 11 -96

Pathophysiology of Asthma

Epithelial Damage in Asthma Normal Asthmatic

Asthma: Pathophysiology • Inflammatory cell infiltrate consists of mainly of eosinophils and lymphocytes • “Sudden death” asthma associated with an infiltrate of neutrophils • Denudation of airway epithelium • Mucus gland hyperplasia and hypersecretion • Smooth muscle cell hyperplasia • Submucosal edema and vascular dilatation • Fibrin deposition/airway remodeling

Multiple Mechanisms Contribute to Asthma: Inflammatory Mediators • • • Mast Cells Macrophages Eosinophils T-Lymphocytes Epithelial Cells Platelets Neutrophils Myofibroblasts Basophils Bronchoconstriction Mediator Soup Histamine Lipid Mediators* Peptides† Cytokines‡ Growth Factors *For example, prostaglandins and leukotrienes. †For example, bradykinin and tachykinin. ‡For example, tumor necrosis factor (TNF). Adapted with permission from Barnes PJ. In: Barnes PJ et al, eds. Asthma: Basic Mechanisms and Clinical Management. 3 rd ed. Academic Press; 1998: 487 -506. Microvascular Leakage Mucus Hypersecretion Airway Hyperresponsiveness

FACTORS LIMITING AIRFLOW IN ACUTE AND PERSISTENT ASTHMA NAEPP, EPR-3, pg. 15.

Inflammation in Asthma Allergen/Trigger Mast cell T-cell Macrophage Histamine Cytokines Eosinophil Airway Inflammation Ig. E = immunoglobulin E. National Asthma Education and Prevention Program Guidelines, 1997. Busse WW et al. N Engl J Med. 2001; 344: 350 -362. Bousquet J et al. Am J Resp Crit Care Med. 2000; 161: 1720 -1745. B-cell Ig. E

Aftermath of Inflammation • Reversibility – Occurs in most asthma episodes – Airway returns to normal caliber – Flow of air through airways returns to normal “speed” • Remodeling – Airway lining builds up persistent fibrotic changes – Airway caliber remains abnormal – Air flow is decreased – Permanent changes appear to begin in childhood, but become recognizable in adults

Asthma is a Chronic Inflammatory Disease: Pathophysiologic Changes Normal Architecture Disrupted Architecture Bronchial Mucosa From a Subject Without Asthma Bronchial Mucosa From a Subject With Mild Asthma Hematoxylin and eosin stain. Photographs courtesy of Nizar N. Jarjour, MD, University of Wisconsin.

Consequences of Persistent Asthma: Subepithelial Collagen Deposition Lumen Epithelium Subepithelial Collagen Deposition Reprinted with permission from Holloway L et al. In: Busse WW, Holgate ST, eds. Asthma and Rhinitis. Blackwell Scientific Publications; 1995: 109 -118.

Consequences of Persistent Asthma: Progressive Decline in FEV 1 % Predicted 120 100 80 60 40 n = 89 r = -0. 47 P<. 001 20 0 10 20 30 Duration of Asthma (years) FEV 1 = forced expiratory volume in 1 second. Adapted with permission from Brown PJ et al. Thorax. 1984; 39: 131 -136. 40 50

Asthma is. . . 1. Chronic inflammatory disorder of the airways – Mast cells, eosinophils and lymphocytes infiltrate into airway lining – Airway hyperresponsiveness develops 2. Excessive reaction to “minor” irritants results in a host of deleterious airway changes – Bronchial wall edema – Smooth muscle contraction – Excess mucus production 3. Patchy, mostly reversible regions of airway narrowing cause asthma symptoms

Acute Reaction to Triggers 1. Irritated airways become more inflamed after exposure to stimuli 2. Muscle layers around airway constrict 3. Airway lining swells 4. Excess mucus builds up in lumen 5. Result: symptoms of cough, wheeze, shortness of breath, chest tightness

Risk Factors for Developing Asthma • • • Genetic predisposition Atopy Airway hyperresponsiveness Gender Race/Ethnicity

What Parameters Affect Disease ? • Intrinsic factors – Genetics – Duration of asthma – Severity of childhood asthma – Gender – Response to therapy • Extrinsic factors – Viral infections – Allergen exposure – Airway irritants – Exercise – Compliance – Season – Time of day – Occupational— 10 -15% of adult asthma – Western Lifestyle-obesity

Environmental Risk Factors for Development of Asthma • • • Indoor allergens Outdoor allergens Occupational sensitizers Tobacco smoke Air Pollution Respiratory Infections • Parasitic infections • Socioeconomic factors • Family size • Diet and drugs • Obesity • Hygiene hypothesis

Asthma & Airway Inflammation Genetic Risk Factors Environmental (for development of asthma) INFLAMMATION Bronchial Hyperresponsiveness Airflow Obstruction Symptoms Risk Factors (for exacerbations)

Multiple Triggers Can Stimulate Acute Reaction • Upper Respiratory Infections (URI’s) – Viral Respiratory infections are the #1 trigger behind asthma hospitalizations – Influenza vaccines are recommended for people with asthma • • • Allergens Irritants Sudden or extreme changes of weather Exercise Intense emotions

Exercise Induced Bronchospasm • Bronchospasm caused by activity – Some activity more likely than others to trigger it • Cold environment: skiing, ice hockey • Heavy exertion: Soccer, long distance running • Exercising when you have a viral cold

Exercise Induced Bronchospasm • Symptoms include – Coughing – Wheezing – Chest tightness • Symptoms may begin during activity and peak in severity 10 -20 minutes after stopping • Can spontaneously resolve 20 -30 minutes after its onset

Epidemiology • Prevalence 7 -20% of the general population • 80% of patients with asthma have some degree of EIB • Exercise is not a risk factor for asthma, rather a trigger • ? Exercise may help prevent onset of asthma in children – Decrease in physical activity may play a role in increased in asthma prevalence • JACI 2005 Lucas SR, Platts-Mills TA

Prevention of EIB • Use bronchodilator 10 -15 minutes before onset of activity • Do warm-up/cool down exercises • Check ozone/allergy warnings • Never encourage anyone to “tough it out”

Management • Increasing fitness: decreases minute ventilation needs with exercise • Less severe if inspired air is warmer, more humid (Evidence Class C) – Scarf or mask if cold weather – Warm-up period before exercise • Good asthma control: EIB more frequent in patients with poorly controlled disease (Class A) – Check for asthma control – Treating appropriately will reduce frequency and severity of EIB

Impairment and Risk Domains • Impairment-frequency and intensity of symptoms and functional limitations the patient is experiencing or has experienced • Risk-the likelihood of either asthma exacerbations, progressive decline in lung function or risk of adverse effects from medication NIH. NAEPP Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, October 2007.

Risk Factors for Death from Asthma • • History of severe exacerbations Prior intubation for asthma Prior admission to Intensive Care Unit 2 or more hospital admissions in the past year 3 or more emergency room visits in the past year Hospital or emergency room visit past month Use of >2 canisters per month of inhaled shortacting beta 2 –agonist

Risk Factors for Death from Asthma • • Chronic use of systemic corticosteroids Poor perception of airflow obstruction or its severity Co-morbid conditions (other diseases) Serious psychiatric disease or psychosocial problems Low socioeconomic status and urban residence Illicit drug use Sensitivity to alternaria-mold Lack of written asthma action plan

Diagnosing Asthma • Recurrent episodes of coughing or wheeze • Asthma may be present without a wheeze cough may be the sole symptom • Shortness of breath or difficulty breathing • Chest Tightness • Wheezing does not always mean asthma • Absence of symptoms and physical findings at the time of the examination does not exclude asthma

Asthma • Diagnosis by history of wheeze, shortness of breath, cough, chest tightness • Spirometry can help define the severity of the disease, however may be normal if asthma is under control • Lack of bronchodilator response does not rule out asthma • Following Peak Flows may be useful

Measures of Assessment & Monitoring • Spirometry should be performed: – at initial assessment – after treatment is initiated and symptoms and PEFs have stabilized – at least every 1 -2 years to assess maintenance of airway function if well controlled – More often if poor asthma control

Measures of Assessment & Monitoring • Peak Flows may be performed: – In all moderate and severe persistent asthmatics • establish a personal best • useful in exacerbations and maintenance/ changes of therapy, • Can be helpful with ‘poor perceivers’

< 2 Years Old: When Is It Asthma? • Family history of asthma • Atopy, eczema • Perinatal exposure to Risk aeroallergens and Factors for irritants (e. g. , passive Developing smoke) Asthma • Wheezing triggered by factors other than upper respiratory infections

< 2 Years Old: When Is It Asthma? TWO GROUPS OF INFANTS WHEEZE ASTHMA NOT ASTHMA

Asthma Predictive Index In an infant or young child with > 3 episodes of wheezing in the past year 1 of 2 major criteria or 2 minor criteria • MAJOR CRITERIA – Atopic dermatitis – Parental Asthma • MINOR CRITERIA – Wheezing apart from colds – Allergic rhinitis – Blood eosinophilia > ¾ of children with a positive index had some active asthma symptoms between 6 and 13 years of age

• Present with symptoms of cough ± noisy or rapid breathing, usually before 5 years of age Adults Children Asthma: Children vs. Adults • Present with symptoms of cough, shortness of breath, chest pain, wheezing, often intermittent or nocturnal

Asthma Misdiagnosis Commonly Misdiagnosed in Children as: Commonly Misdiagnosed in Adults as: CHRONIC/WHEEZY BRONCHITIS RECURRENT CROUP RECURRENT UPPER RESPIRATORY INFECTION RECURRENT PNEUMONIA RECURRENT BRONCHITIS

Asthma Severity Assessments • < 6 year old often cannot perform reliable Pulmonary Function Test’s (PFT’s) or peak flow measurements • Older children with even severe symptoms often have fairly normal PFT’s between episodes • Severity assessment often focuses on symptoms more than lung function measurements • PFTs play more important role in assessment • PFT’s performed at diagnosis and routinely at least every 1 -2 years CHILDREN ADULTS

Long-Term Management of Asthma in Children: Initiation of Control Therapy • Symptoms > 2 x week • Severe exacerbations < 6 weeks apart • 2 or more burst of prednisone in 6 months for ages 0 -4 • 2 or more burst of prednisone in 1 year for ages 5 -11 • Positive Asthma Predictive Index

Questions?