Adult Asthma for UPCM LU4Aileen David – Wang MD MSc FPCCP Clinical Associate Professor Learning Objectives At the end of the session, the student should be able to: • define asthma • describe the local prevalence, epidemiology, and natural history of asthma • recognize the risk factors for asthma development and persistence • recognize its characteristic symptomatology Learning Objectives At the end of the session, the student should be ble to: recognize diseases that may mimic asthma enumerate and interpret laboratory tests that support or confirm the diagnosis of asthma classify asthmatics according to their level of chronic severity and control, and give recommendations on the appropriate drug therap become familiar with asthma pharmacotherapy Re e As c nt thm Guide a line s Global Initiative for Asthma (GINA) Update December 2008 www. ginasthma .org NAEPP Expert Panel Report Update by US NHLBI NIH Publication No. 02 -5075; July 2007 www.nhlbi.nih.gov/guidelines/asthma Philippine Consensus Report on the Mx of Asthma Dx and 2004 Evidence -Based Update; 2009 Update soon to be released Definition of Asthma Definition of Asthma • Asthma, irrespective of the severity, is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. • The chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to airflow limitation and respiratory symptoms Global Initiative for Asthma (GINA 2004) Mechanisms behind Asthma Symptoms Environmental Risk Factors (Causes) Bronchial HyperResponsiveness Airflow Limitation TRIGGERS Symptoms Bronchial Hyperresponsiveness (BHR) or Airway Hyperresponsiveness (AHR) Airways narrow too easily and too much in response to exogenous or endogenous stimuli Allergens Sensitizers Viruses Air pollutants c wi t S h ” “on Genetically Predispose d Airway Hyperresponsiveness Triggers: Allergens Exercise Cold air SO2 Particulates Chronic Inflammat ion Symptoms: cough dyspnea wheezing Adapted from: Peter J. Barnes, MD Laitinen 1992 Airway Inflammation in Asthma Normal Asthmatic P Jeffery, in: Asthma, Academic Press 1998 Normal Denuded mucosa Thickened basement membrane Inflammatory cells Wall edema Hypertrophied airway sm muscles Airflow Limitation in Asthma TRIGGER BHR 1. Acute bronchoconstriction/spasm 2. Swelling of the airway wall 3. Chronic mucus plug formation 4. Airway wall remodelling Airflow Limitation in Asthma TRIGGER BHR Widespread, variable and often reversible Asthma AECOPD • • • • Hypoventilation Respiratory acidosis Pneumothorax Hypotension Severe Asthma Exacerbation Asthma Inflammation: Cells and Mediators Source: Peter J. Barnes, MD Inflammatory Mediator Soup in Asthma Source: Peter J. Barnes, MD Asthma Symptoms Inflammation Airway Hyperresponsiveness Airway Remodeling Prevalence and Natural Hx of Asthma Asthma Epidemiology Asthma is a very common disease Found in all countries Prevalence seems to be increasing Occurs at all ages but predominantly in early life About half develop before age 10 and another 1/3 before age 40 Asthma Epidemiology Can begin in the elderly In childhood, 2:1 male/female preponderance; difference disappears after age 10 During puberty and thereafter, more females develop asthma than males Asthma Epidemiology Disappears in 30 to 50% of children at puberty, but often reappears in adult life In a recent survey of Filipinos living in urban communities, about 22% of adults, 33% of adolescents and 27% of children aged 6 to 7 years have asthma and asthma-like symptoms National Asthma Epidemiology Study: Urban Focus 2003 Risk Factors for Asthma Factors that Influence Asthma Development and Expression Host Factors Genetic - ATOPY - BHR Gender Obesity Race/ Ethnicity Environmental Factors Indoor allergens Outdoor allergens Occupational sensitizers Tobacco smoke Air Pollution Respiratory Infections Diet Factors Severe Respiratory Infection Allergy Family History Father Mother Other Relatives Risk Odds Ratio 1.81 4.92 3.74 4.27 4.12 95% C.I. 1.17 - 2.80 2.81 - 8.62 2.49 - 5.61 2.33 - 7.82 2.21 - 7.70 pvalue 0.007 <0.001 <0.001 <0.001 <0.001 0.002 Smoker in the household when the child was 1-3 years old 2.07 1.29 – 3.31 Note: Gender and breastfeeding were not significant Risk Factors for Persistence of Asthma Symptoms (Triggers) House Dust Mite (Dermatophagoides pteronyssinus) Risk Factors for Persistence of Asthma Symptoms (Triggers) Risk Factors for Persistence of Asthma Symptoms (Triggers) Indoor Allergens – house dust mite, cockroach, animal allergens (cats, dogs), fungi, molds, yeasts Outdoor Allergens- Pollens Tobacco Smoke Air Pollution Factors that Precipitate Asthma Exacerbations Respiratory Infections esp. viral- most common Weather changes Indoor and outdoor allergens/ air pollutants Exercise Drugs – aspirin, beta-blockers, coloring agents Food Irritants- household sprays, paints, fumes Extreme emotional expression/ stress- laughter Diagnosis of Asthma Who is unlikely to be an asthmatic? A. 18 y.o./F, on and off dyspnea and chest tightness for the past 10 years B. 50 y.o./F, sole complaint of on and off cough for the past 2 years, treated with various antibiotics C. 15 y.o. athlete who develops SOB after running D. 48 y.o. smoker with progressive SOB x 4 y and recent active hemoptysis E. All can be considered asthmatics Triad of Asthma • Dyspnea • Cough • Wheeze Pulmonary Pearls: Diagnosis of Asthma Episodic or Intermittent Symptoms Usually triggered by exogenous factors Seasonal variability Typical early morning symptoms Typical atopic history Family history of asthma Positive response to bronchodilators Is it Asthma? Recurrent episodes of wheezing Troublesome cough at night Cough or wheeze after exercise Cough, wheeze or chest tightness after exposure to airborne allergens or pollutants Colds “go to the chest” or take more than 10 days to clear Pulmonary Pearls: Diagnosis of Asthma No pathognomic manifestation “Not all that wheezes is asthma, not all asthma wheezes” Differential Diagnosis of Asthma Foreign body aspiration esp. in children Tracheal, laryngeal and bronchial lesions/ tumors Extrinsic obstruction of the airways Other chronic obstructive airways diseases – COPD, bronchiectasis, diffuse panbronchiolitis, cystic fibrosis Pulmonary embolism “Cardiac asthma” – CHF, mitral stenosis Vocal cord dysfunction Confirmatory Tests for Asthma Measurements of airflow limitation, its reversibility and its variability are critical in establishing a clear diagnosis Bronchoprovocation Test measures non-specific BHR Methacholine/ Histamine Inhalation Challenge high sensitivity but low specificity a negative test can be useful to exclude a diagnosis of persistent asthma Can be positive in recent viral URTI, COPD, bronchiectasis, allergic rhinitis, etc. 0 Bronchoprovocation Test Normal % Fall FEV1 5 10 15 20 25 30 35 0 0.125 0.25 0.5 Asthma b PC2 Concentration0of Methacholine (mg/ml) 1 2 4 8 16 32 PC20 PC20 FEV1 – concentration of bronchoprovoking agent that causes the FEV1 to fall by 20% Confirmatory Tests for Asthma Spirometry FEV1/FVC < 75% Obstructive Airways Disease Acute Bronchodilator Response (Reversibility): > 12 % increase + absolute increase of 200 ml in FEV1 and/or FVC GINA 2004 Forced expiratory volume in 1 second (FEV1) – 4.0 L Forced vital capacity (FVC) – 5.0 L FEV1/FVC = 80% FEV1 FVC Since asthma is an episodic disease, the spirometry can be normal during a mild or asymptomatic perio 0 L 1 i t e r 2 s F E V 1 Asthma: FEV1 > 12% COPD: Obstructive < 12% FEV1 pattern 3 Normal Asthma 2 3 4 COPD 4 4 1 6 Seconds Confirmatory Tests for Asthma Bronchodilator % = post-BD FEV1 - pre-BD FEV1 pre-BD FEV1 Reversibility x 100 GINA 2004 Confirmatory Tests for Asthma Peak Flow Monitoring Acute BD Response: > 15% increase in PEF Diurnal variability > 10% (if no BD) or > 20% (if on BD) Drop of >15% with 6-minute running/exercise GINA 2004 Confirmatory Tests for Asthma > 20% DV = 100 PEFevening - PEFmrning o Peak Flow Diurnal Variability x ½ (PEFevening + PEFmrning ) o GINA 2004 Other Laboratory Tests in Asthma Chest Radiograph no role in making a diagnosis of asthma usually normal, but may show hyperinflation useful in excluding other causes of wheezing and detecting complications of asthma exacerbations (e.g., pneumothorax) and concomitant conditions (e.g., pneumonia) Sputum/ Blood Eosinophilia } Allergy skin tests/ IgE } Not specific for asthma Asthma Pharmacotherapy Drugs Available for Asthma A T M M D A IO S S H A E IC T N T IG E R GR B R H C N R LLE O TO R (M aintenance) R LIE E E VR (A N ed) s eed Current Asthma Medications Relievers Short acting Beta agonist + Anti – cholinergics Systemic Controllers Cromolyn Sodium Nedocromil Na Steroids Short acting Theophyllines Corticosteroids Long Acting Theophylline Long Acting Beta agonists Anti-Leukotrienes Anti-IgE Inhalational is superior to oral therapy. Relievers • • • • quick relief bronchodilators “rescue” medicine use as-needed relieve bronchoconstriction and the accompanying symptoms • no effect on airway inflammation and BHR • frequent need for rescue is a sign of poor asthma control Short Acting Beta2 Agonists • drug of choice for treatment of acute asthma exa’s and episodes • useful as prophylaxis against EIA • stimulate beta-adrenergic receptors and activate G proteins to produce cAMP • decrease release of mediators • improve mucociliary transport • Salbutamol (Albuterol), Levalbuter Terbutaline, Fenoterol Anticholinergics • slower in onset and of modest potency compared to SABAs • reliever of choice for betablocker induced asthma • additive effect when combined with SABA • Ipratropium bromide Controllers • used daily on a long-term basis to achieve and maintain control of persistent asthma • act on airway inflammation and BHR Controllers: Inhaled Steroids • Most potent and most effective anti-inflammatory medications currently available • Budesonide, Fluticasone, Beclomethasone, Flunisolide, Triamcinolone • Preferred Rx for all levels of persistent asthma • Most common side effects: dysphonia, oral thrush gargle after use Clinical Effects of Inhaled Corticosteroids on Asthma improved BHR reduced symptoms reduced frequency and severity of exacerbations reduced oral steroid rescues reduced prn SABA use improved lung function decreased ER visits and hospitalization improved quality of life reduced relapse after an acute attack (GINA 2006) LEVEL OF EVIDENCE: A Effects of Corticosteroids on istopathologic Histopathologic Characteristics in Asthma • Decreased cellularity usually resulting from decreases in eosinophils, mast cells, and lymphocytes • Decreased numbers of dendritic cells and HLA-DR expression • Decreased numbers of cells expressing mRNA for IL-4 and IL-5 γ • Increased numbers of cells expressing mRNA for IFN• Increased area of ciliated epithelium • Decreased thickness of basement membrane • Decreased tenasein in basement membrane Fish. J Allergy Clin Immunol 1999; 104: 509-516 Systemic Steroids • Considered as “relievers” for treatment of moderate to severe exacerbations, in short-courses of moderate to high daily dose • Onset of action > 4 -6 h • Also used as “controllers” for chronic severe asthma, in low dose daily or alternate-day therapy • Long term use is limited by systemic side effects including adrenal suppression Inhaled Long Acting Beta2 Agonists (LABA) Same effects as SABAs May modulate mediator release from mast cells and basophils Activity persists for > 12 h Provide long-term protection against bronchoconstrictor stimuli and for EIA The preferred add-on therapy for asthmatics who remain symptomatic despite the use of inhaled steroid Should never be used as sole controller in asthma Inhaled Long Acting Beta2 Agonists (LABA) Formoterol – onset of action similar to Salbutamol Salmeterol Fixed dose combination inhaled steroid – LABA are now available Budesonide – Formoterol (Symbicort) Fluticasone – Salmeterol (Seretide) Theophylline and derivatives As a bronchodilator: Weak phosphodiesterase inhibition, adenosine antagonism Use as add-on therapy in moderate to severe As a controller: Weak Anti - Inflammatory Properties asthma esp. nocturnal symptoms Eosinophil infiltration of airways T - lymphocytes in alveolar epithelium mucociliary clearance Alternative but not preferred controller in mild persistent asthma (Philippine Guidelines) Oral preparation 2002 NHLBI guidelines Anti-Leukotrienes Arachidonic Acid 5-LO Inhibitor e.g. Zileuton 5-Lipoxygenase FLAP Cysteinyl-LT Antagonist e.g. Zafirlukast, Montelukast LTA4 LTB4 Chemotaxis Immunomodulation LTC4 LTD4 LTE4 Bronchoconstriction Mucus secretion Oedema Hyperresponsiveness Eosinophilia Anti-Leukotrienes Monotherapy as alternative first-line controller Second-Line Controller Add-On Steroid Sparing Effect Drug of choice for aspirin induced asthma Cromones Mast cell stabilizers: inhibit degranulation Alternative but not preferred controller in mild persistent asthma, esp. in children Also useful for EIA prophylaxis 4 to 6 week therapeutic trial may be required to determine efficacy Oral preparation Cromolyn sodium, Nedocromil sodium Classification of Asthma Classification of Asthma • Traditional classification into Endogenous vs Exogenous Asthma: classification clinically not useful • Classification Based on Chronic Severity Assessment vs. Control of asthma • Severity assessed at the initial consult • Control assessed on follow up Classification of Chronic Asthma Severity Clinical features before treatment Daytime Symptoms STEP 4 Severe persistent STEP 3 Moderate persistent STEP 2 Mild persistent STEP 1 Intermittent Continuous Limited physical activity, freq exa Daily symptoms and β 2-agonist use Attacks affect activity > 1 a week but <1 x a day <1 a week Asymptomatic and normal PEF between attacks Night-time symptoms Frequent PEF or FEV1 <60% predicted Variability >30% >60% - <80% predicted Variability >30% Meds to control Multiple Controllers b >1 X a week > 2 Controllers One Controller No Controllers Needed >2 X a month But < 1 x a week <2 X a month >80% predicted Variability 20-30% >80% predicted Variability <20% GINA, 2005 Asthma as an Evolving Concept: Shift in Paradigm of Asthma Treatment from Severity to Control AW Remodelling Airway Inflammation Bronchospasm 1975 1980 1985 1990 1995 2000 Asthma as an Evolving Concept: Shift in Paradigm of Asthma Treatment from Severity to Control • Asthma severity involves both the severity of the underlying disease AND its responsiveness to treatment • Asthma severity may change over months or years • Thus, for ongoing Mx of asthma, GINA 2007 classification by level of control is more relevant and GINA 2007 Asthma Management and Prevention Program Assess, Treat and Monitor Asthma The choice of treatment should be guided by: Level of asthma control treatment Current Pharmacological Economic properties and availability of the various forms of asthma treatment considerations Cultural preferences and differing health care systems need to be considered Characteristi c Daytime Sx’s Activity limitation Assessing Level of Asthma Control (GINA 2008) Controlled Partly controlled (Any present in any week) More than twice / week Any Any More than twice / week < 80% predicted or personal best (if known) on any day One or more / year (All of the following) None (2 or less / week) None None None (2 or less / week) Normal Uncontrolled Nocturnal Sx’s / awakening Need for “reliever” Rx 3 or more features of partly controlled asthma present in any week Lung function (PEF or FEV1) Exacerbation None 1 in any week* LEVEL OF CONTROL controlled partly controlled uncontrolled exacerbation REDUCE TREATMENT OF ACTION maintain and find lowest controlling step consider stepping up to gain control INCREASE step up until controlled treat as exacerbation REDUCE STEP STEP TREATMENT STEPS STEP INCREASE STEP STEP 1 2 3 4 5 Treating to Maintain Asthma Control When control has been achieved, ongoing monitoring is essential to: - maintain control - establish lowest step and least drug/dose treatment necessary to maintain control If control is maintained for at least 3 months, consider step down to the next lower step Asthma episode versus exacerbation Exacerbations of asthma (asthma attacks) are episodes of rapidly progressive (in minutes to hours to days) increase in shortness of breath, cough, wheezing, or chest tightness, or some combination of these symptoms. GINA 2004 Asthma Severity and Exacerbations Severe asthmatics tend to have the most severe and the most frequent exacerbations The more severe the underlying inflammation, the more difficult and dangerous the exacerbation Even mild asthmatics can have severe, life- threatening exacerbations! Acute Exacerbation of Asthma = Failure of Chronic Management + Trigger Acute Exacerbation of Asthma = Indicator of Poor Asthma Control Asthma Management and Prevention Program Component 4: Manage Asthma Exacerbations Primary therapies for exacerbations: Repetitive administration of rapid-acting inhaled β2agonist Early introduction of systemic glucocorticosteroids Oxygen supplementation Closely monitor response to treatment with serial measures of lung function