Asthma What is Asthma ? V1.0 1997 Merck & .

What is Asthma? 1952 Definition: “The presence of widespread narrowing of the airways which alters in severity either spontaneously or as a result of treatment” Asthma

What is Asthma? Chronic inflammatory disorder of the airways Inflammation associated with Airways hyperresponsiveness Airflow limitation (at least partially reversible) Respiratory symptoms (wheeze, cough, tight chest) Airway inflammation can be present even in mild disease Asthma is a chronic inflammatory disease of the airways. Airway inflammation in patients with asthma is associated with airway hyperresponsiveness, airflow limitation which is partly reversible, and respiratory symptoms including wheezing, breathlessness, cough, chest tightness and nocturnal awakenings. Studies have also demonstrated that airway inflammation can be present even in mild disease, suggesting that controller therapy should be used in patients with mild persistent disease even when they are asymptomatic. Beasley et al., Am Rev Respir Dis 1989;139:806-817 - Airway inflammation exists in patients with mild disease Asthma National Asthma Education and Prevention Panel, Expert Panel Report II “NAEPP Guidelines”, National Institutes of Health, 1997

The “Tip” of the Iceberg TITANIC Symptoms Airflow obstruction Bronchial hyperresponsiveness With asthma, what we see is the tip of the iceberg, the symptoms. At the base of the iceberg is the airway inflammation. This inflammation underlies the bronchial hyperresponsiveness of asthma. Airflow obstruction results from bronchoconstriction, bronchial edema, mucus hypersecretion and inflammatory cell recruitment including eosinophils, a key inflammatory cell. The culmination of the inflammatory process is the tip of the iceberg, the symptoms. Airway inflammation Asthma

Symptoms of Asthma Wheeze, cough, chest tightness (“dyspnea”) Nocturnal awakenings Recurrent attacks related to specific triggers Asthma 24

Special Aspects of Asthma • Allergic (or extrinsic) asthma • Nocturnal asthma • Exercise-induced bronchoconstriction (EIB) • Aspirin-sensitive • Cough-variant • Occupational Asthma

Asthma Prevalence by Age 37% 40% 30% 35% 10% 15-19y 30% 21% 25% Asthmatic Population Percentage of 20% 12% 19% 6-14y 15% 10% 5% 8% < 6y 0% 0-19y 20-39y 40-59y 60+y AGE (years) Asthma

Burden of Asthma …on society V1.0 1997 Merck & .

Asthma in the United States -- a growing problem 17.4 million Americans have asthma Prevalence rose 75% 1980-1994 Prevalence rose more in children (160% in 0–4 y.o.’s) 1.9 million ER visits (in 1995) and 466,000 hospitalizations (in 1993) Office Visits doubled (from 1975 to 1995) 3 per 10,000 asthmatic patients die (1994) Deaths doubled (for 5–24 y.o.’s from 1980 to 1993) Asthma from National Center for Health Statistics 4

Asthma is the Most Common Chronic Illness of Childhood 13 million physician visits/year 87% of asthmatic children had unscheduled physician visits in the prior year Third-ranking cause of hospitalization in children <15 and the highest-ranking cause among chronic conditions 200,000 hospitalizations/year Most common chronic illness resulting in school absences 10.1 million lost school days a year On average: 1 week absent per asthmatic child Asthma is the Most Common Chronic Illness of Childhood. The prevalence in the U.S. ranges from 3 to 7%, resulting in 13 million physician visits per year (Lozano et al., Pediatrics 1997;99:757-764). It is the third-ranking cause of hospitalization in children under the age of 15 and highest-ranking cause among chronic conditions, with 200,000 hospitalizations per year (Lozano et al., Pediatrics 1997;99:757-764). Asthma is the most common chronic illness resulting in school absences. Over ten million school days are lost each year , this is an average of 1 week per child asthmatic child (Weiss KB et al. N Engl J of Med 1992;326:862-866). It is not surprising that children with asthma have 3 times the school absences of children without asthma (Lozano et al., Pediatrics 1997;99:757-764). Total direct cost for asthma in 1994 were 1.9 billion dollars, with hospitalization and outpatient treatment accounting for 54% and 21% of that total, respectively (Weiss KB et al. N Engl J of Med 1992;326:862-866). Asthma

Asthma Mortality Higher risk of death from asthma African Americans Males Rate of Asthma Deaths (per 1,000,000) African Americans and males are at higher risk of death from asthma. This graph illustrates data from the CDC showing the asthma death rate for African Americans versus Caucasian Americans (categorized in the CDC data as “Black” and “White”, respectively). As shown, the rate is considerably higher for African Americans, and has risen more quickly over the past 20 years than in Caucasians. CDC. Surveillance for Asthma--United States, 1960-1995 (CDC Surveillance Summaries). MMWR. 1998;47(SS-1):1-26 Asthma

Pediatric Asthma Mortality Asthma deaths have more than doubled for 0- to 14-year-olds from 1979 to 19951 Number of Asthma Deaths Asthma deaths have doubled for 0- to 14-year-olds from 1979 to 1995, with the 5 to 14 year olds driving the rise in mortality1. In a population-based study by Robertson and colleagues2, the majority of patients aged 0 to 20 years who died due to asthma could not be classified as “high risk”: Of 51 deaths: 33% were judged to have had a history of trivial or mild asthma 32% had no previous hospital admission for asthma. Death occurred outside the hospital in 78% of subjects. Thus, some of the patients who died had apparently mild disease, though many were felt in retrospect to have had inadequate assessment or therapy of prior asthma. 1CDC. Surveillance for Asthma--United States, 1960-1995 (CDC Surveillance Summaries). MMWR. 1998;47(SS-1):1-26 2Robertson et al., Pediatric asthma deaths in Victoria: The mild are at risk. Pediatr Pulmonol 1992;13:95-100. Most patients who died – not seen as “high risk”2 Some patients who died had mild disease Asthma

Burden of Asthma …on the patient V1.0 1997 Merck & .

Asthma’s Impact The highest-ranking chronic condition causing hospitalization in children The most common chronic illness of childhood Children with asthma have 3x the school absences of children without asthma 40% of children with asthma have sleep disturbances, 1 to 2 nights/week even if the child is not absent from school, he or she may have reduced school performance due to sleep disturbances Asthma

Asthma’s Impact 23% of adults with asthma missed work during the prior year due to asthma 36% of parents of asthmatics missed work in the prior year 50% of parents and 49% of patients say asthma limits the range of activities a family can do together 78% of parents of asthmatics report that asthma has a negative impact on the family Asthma

Asthma Diagnosis V1.0 1997 Merck & .

Diagnosis of Asthma Symptoms Wheeze, cough, chest tightness (“dyspnea”) Nocturnal awakenings Recurrent attacks related to specific triggers Response to asthma-specific therapy Asthma 24

Diagnosis of Asthma Lung Function Measurements • Changes in lung function over time (Spontaneously or in response to therapy) - Spirometry (FEV1) - Peak expiratory flow rate (PEFR or “peak flow”) • Airway hyperresponsiveness to stimuli - Methacholine challenge test - Exercise challenge test Asthma

Bronchial Provocation A 20 B FEV1 % fall from baseline C Low PD20 High PD20 High BHR Low BHR Increasing dose of methacholine Asthma

The Early and Late Asthmatic Response 100 LAR 75 FEV1 (% predicted) 50 AAR 25 AAR = Acute asthmatic response LAR = Late asthmatic response 1 2 3 4 5 6 7 8 9 10 11 12 Inhaled Time (hours) allergen Asthma

Spirometry FEV1 post-bronchodilator FEV1 pre-bronchodilator 4 3 Exhaled volume (L) 2 FVC After bronchodilator 1 Before bronchodilator 1 2 3 4 5 6 Time (seconds) Asthma

Uses of Daily Peak Flow Monitoring Acutely: • Assess severity of exacerbations Short term: • Evaluate therapy • Establish temporal relationship to triggers Long-term: • Detect changes in disease status • Evaluate treatment • Provide patient with a written action plan Asthma

PEFR recorded twice-daily over 2 weeks Circadian Changes in PEFR PEFR recorded twice-daily over 2 weeks Normal Asthma 100% 100% PEFR (%Predicted) 50% 50% Evening peak flow Morning peak flow Asthma

Diagnosis …per the guidelines Asthma Diagnosis …per the guidelines V1.0 1997 Merck & .

Asthma Guidelines: Recent evolution NAEPP Guidelines 1997 National Asthma Education and Prevention Panel, Expert Panel Report II, National Institutes of Health (“NIH”), National Heart, Lung, and Blood Institute (NHLBI)) GINA Guidelines 1998 Global INitiative for Asthma, Asthma Management and Prevention Report, NHLBI and World Health Organization (WHO) Pediatric Asthma: Promoting Best Practices 1999 American Academy of Allergy, Asthma & Immunology (AAAAI), American Academy of Pediatrics (AAP), National Heart, Lung, and Blood Institute (NHLBI), NAEPP, etc The pediatric asthma guidelines establish a four-step classification system for asthma severity: mild intermittent, mild persistent, moderate persistent, and severe persistent. The severity is classified before therapy begins. Pediatric Asthma: Promoting Best Practice, Guide for Managing Asthma in Children. Milwaukee, WI: American Academy of Allergy, Asthma and Immunology (with AAP, NAEPP / NHLBI / NIH), 1999. Asthma

NAEPP and GINA Guidelines Asthma severity: Classified the same Classified by: 3 4 2 1 Severe Persistent Moderate Persistent Mild Persistent Mild Intermittent Symptoms • Activity levels • Exacerbations • FEV1/PEFR • PEFR variability The pediatric asthma guidelines establish a four-step classification system for asthma severity: mild intermittent, mild persistent, moderate persistent, and severe persistent. The severity is classified before therapy begins. Pediatric Asthma: Promoting Best Practice, Guide for Managing Asthma in Children. Milwaukee, WI: American Academy of Allergy, Asthma and Immunology (with AAP, NAEPP / NHLBI / NIH), 1999. Severity is classified before therapy begins Severity is classified before therapy begins Asthma

Asthma Guidelines Severity: Mild Intermittent Clinical features before treatment Symptoms < 2x per week Brief exacerbations Nighttime symptoms < 2x per month Asymptomatic with normal lung function between exacerbations FEV1 and PEF > 80% predicted PEF variability < 20% 1 Mild Intermittent Asthma

Asthma Guidelines Severity: Mild Persistent Clinical features before treatment Symptoms > 2x per week but <1x per day Exacerbations may affect activity Nighttime asthma symptoms > 2x per month FEV1 and PEF > 80% predicted PEF variability 20 - 30% 2 Mild Persistent Asthma

Asthma Guidelines Severity: Moderate Persistent Clinical features before treatment Daily symptoms Exacerbations > 2x per week affect activity Nighttime asthma symptoms > 1x per week Daily use of short-acting ß agonist FEV1 and PEF > 60% and < 80% predicted PEF variability > 30% 3 Moderate Persistent Asthma

Asthma Guidelines Severity: Severe Persistent 4 Clinical features before treatment Continuous symptoms Frequent exacerbations Frequent nighttime symptoms Limited activity FEV1 and PEF < 60% predicted PEF variability > 30% Asthma

Management of Asthma Assessment and monitoring Control of factors contributing to asthma severity Pharmacotherapy Education Asthma

Inflammatory Cell-Derived Mediators Mast cells Eosinophils Histamine Leukotrienes Mediators Prostaglandins Mast cell tryptase Eosinophil cationic protein Cytokines (IL-4, IL-5) many other cells T lymphocytes Asthma

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