Objectives. Internal Medicine Board Review Asthma. Emily DiMango, MD. Asthma Is Prevalent: Significant Morbidity and Mortality

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1 Internal Medicine Board Review Asthma Emily DiMango, MD Director John Edsall/John Wood Asthma Center Columbia University Medical Center Objectives Review asthma epidemiology Asthma pathophysiology/definition NIH National Asthma Education and Prevention Program (NAEPP) Guidelines Treatment Novel therapies Asthma prevalence (Increased from 7.3% in 2001 to 8.2% in 2009) Asthma Is Prevalent: Significant Morbidity and Mortality 32.6 Million People Have Had an Asthma Diagnosis in Their Lifetime 25 Million People Are Currently Diagnosed With Asthma 12.2 Million People Suffer From Asthma Attacks Annually Approximately 3500 Asthma- Related Deaths Occur Annually Approximately 11 People Die From Asthma Each Day Center for Disease Control, MMWR 2011 Available at: Accessed 2011 Risk factors for development of asthma -Family history -Sensitization to common allergens early in life -Maternal smoking -Obesity -Western lifestyle?? Diet, pollution Busse, W., NEJM 2001; 344:5

2 Percentage of Children with Asthma According to the Number of Older Siblings and the Age at Entry into Day Care Asthma - Definition Chronic inflammatory disorder of the airways, (eosinophil and lymphocyte mediated) Usually associated with atopy (IgE mediated) Obstruction to airflow (bronchospasm) which is reversible (either spontaneously or with use of medications). Airway hyperresponsiveness and narrowing in response to a variety of environmental stimuli. Ball M NEJM 2000 Airway inflammation - Early and late Response Airway inflammatory changes Accelerated decline in lung function among asthmatics Lange, et al, NEJM 1998

3 Diagnostic Criteria For Asthma Cough, dyspnea, wheeze, chest tightness Waxing and waning symptoms Heightened airway reactivity exacerbations upon exposure to stimuli Episodic airflow limitation in response to antigenic triggers. Physiologic features of asthma Reduced FEV1 and FEV1/FVC ratio (obstructive defect) Reversible airflow limitation with a significant (>12% or 200ml) increase in FEV1 in response to inhaled bronchodilator. response to bronchoprovocation testing - (methacholine, histamine, cold air) which provokes bronchial narrowing (decrease of 20%in FEV1) in sensitive individuals. (Clinical trials, professional athletes) Flow Volume loop appearance Airway obstruction Normal Pathologic targets in asthma Treatment Airway smooth muscle (b 2 agonists, anticholinergics, phosphodiesterase inhibitors) Airway inflammatory cells and mediators (glucocorticoids, leukotriene modifiers, anti-ige, phosphodiesterase inhibitors)

4 Reliever vs. controller medicines Inhaled glucocorticoids Reliever medicines Short acting bronchodilators (b 2 agonists, ipatropium) Controller medicines Inhaled corticosteroids Leukotriene modifiers (sythesis inhibitors and receptor antagonists) long acting beta agonists theophylline cromyln Omalizumab (Xolair) First line controller therapy for all but very mild asthma Reduce exacerbations, hospitalizations and death from asthma Improve lung function and quality of life? Prevent or delay airway remodeling Inhaled glucocorticoid use inversely correlates with asthma mortality Inhaled steroid use inversely correlates with asthma exacerbation Busse, W, NEJM 2001; 344: 5 Williams LK, JACI 2011 Time Course of Improvements in ACQ and MiniAQLQ Scores and Peak Expiratory Flow over a 2-Year Period in Patients with Asthma. b 2 -agonists Most effective bronchodilator for asthma bind to b 2 receptors on airway smooth muscle cells useful as rescue for acute symptom relief Side effects are due to overlap b 1 activity in other organs (cardiac) and activation of non-airway b 2 receptors (skeletal muscle, metabolic) no effect on inflammation Polymorphisms in b2-receptor gene may modify response????? Price D et al. N Engl J Med 2011;364:

5 Long acting beta agonists Inhaled salmeterol (component of Advair ) and formoterol (Symbicort );duration of action 12 hours Delayed onset of action (30 minutes) for salmeterol, rapid onset for formoterol Efficacious in moderate to severe asthma In patients not well controlled on ICS, addition of LABA is more effective than increasing steroid dose. Use of LABA may be associated with increased asthma risk. Preferred add-on therapy in patients not adequately controlled on inhaled corticosteroids (STEROID SPARING). Not monotherapy Black box warning: Increased mortality and serious events in some patients taking long acting beta agonists, particularly African Americans Salmeterol Multi-center Research Trial (SMART) Initiated week safety study comparing salmeterol (Serevent ) and placebo in addition to usual asthma therapy in the treatment of asthma. (47% of patients enrolled were taking inhaled steroids) Primary endpoint: number of respiratory-related deaths and life-threatening events (intubations) interim analysis performed once half of the patients (25,800) were recruited. Occurrence of asthma-related deaths by phase and study year Nelson, H. S. et al. Chest 2006;129:15-26 Are Long Acting Beta agonists dangerous in some people with asthma? Improve asthma control Improve lung function Reduce exacerbations Some individuals may be at increased risk for asthma related deaths and asthma related events such as intubation. NOT CLEAR YET Question A 78 year old woman with glaucoma and osteopenia has been treated with fluticasone 110mcg, two puffs bid. She reports asthma symptoms and need for short acting bronchodilators 5 times per week and awakens once per week with asthma symptoms. All of the following are acceptable changes in treatment EXCEPT: Possible answers a. Increase fluticasone to 220mcg, two puffs bid b. Change medication to combination fluticasone/salmeterol 250mcg/50mcg, one puff bid. c. No change in therapy is necessary d. Discuss environmental triggers with patient

6 Monoclonal Ab IgE (omalizumab, xolair ) Approved for treatment of moderate and severe atopic asthma (positive skin test or RAST), dose is weight and IgE dependent. Elevated IgE not necessary. Effect of treatment with anti-ige on corticosteroid requirement Effective in reducing asthma exacerbation rate and reducing required corticosteroid dose Subcutaneous injections 1-2x/month BLACK BOX: Associated with anaphylaxis, even with long term use, requires 2 hour observation Milgrom H NEJM 1999 NAEPP GUIDELINES FOR DIAGNOSIS AND TREATMENT OF ASTHMA 2007 Assessment of asthma severity in initiation of therapy Consider level of asthma impairment and risk Assessment of asthma impairment and risk during office visits Nocturnal awakenings from asthma symptoms Days per week with symptoms Need for rescue bronchodilators Activity limitation because of asthma Peak flow variability > 20% Frequency of exacerbations, loss of lung function,urgent care visits to assess risk NAEPP Severity classification Mild intermittent: symptoms < 2x/week, nocturnal symptoms < 2x/month, normal FEV 1 Mild persistent: symptoms 3-6x/week, 3-4 awakenings/month, normal FEV 1 Moderate persistent: daily symptoms, >5 nocturnal awakenings, FEV % Severe persistent: continual symptoms, FEV 1 < 60%

7 Classification of Control Well controlled Not well controlled Very poorly controlled Well controlled asthma Symptoms < 2 days per week < 2 nocturnal awakenings per month FEV1 > 80% predicted 0-1 exacerbations per year Overview of Guidelines - Classify asthma severity to initiate therapy (assess impairment and risk) Assess control to monitor and adjust therapy (every 1-6 months) STEP UP OR DOWN. Patient education, environmental control and management of comorbidities (rhinitis, sinusitis, allergies) at every visit Consider asthma specialist if more than medium dose ICS is needed for control Consider subcutaneous allergen immunotherapy for patients who have moderate to severe allergic asthma. Re-assess patients every 1-6 months, PFTs once yearly Long term control of asthma Symptoms occurring more than twice per week is an indication for daily antiinflammatory therapy (ICS preferred). Well-controlled Step up anti-inflammatory therapy or add second controller based on need for bronchodilators and frequency of symptoms (LABAs are preferred add-on, though increase in ICS now being recommended because of risk issues for LABAs) Intermittent Sx < 2x/week <2 awaken/mo FEV1 > 80% Step 1 Preferred: SABA prn Stepwise Approach for Managing Asthma NAEPP 2007 Mild Persistent Sx 3-6x/week Awaken 3-4x FEV1 > 80% Step 2 Preferred: Low-Dose ICS Alternative: Cromolyn, Nedocromil, LTRA, or Theophylline Moderate Persistent Sx daily Awaken > 5x FEV % Step 3 Preferred: Medium-Dose ICS or Low-Dose ICS + LABA Alternative: Low-Dose ICS and either LTRA, Theophylline, or Zileuton Step 4 Preferred: Medium-Dose ICS + LABA Alternative: Medium-Dose ICS and either LTRA, Theophylline, or Zileuton Continual sx Frequent awakening FEV1 < 60% Severe Persistent Step 6 Step 5 Preferred: Preferred: High-Dose ICS + High-Dose ICS + LABA LABA + Oral Corticosteroid and Consider Omalizumab for Patients Who Have Allergies (>12 yrs) and Consider Omalizumab for Patients Who Have Allergies Add LTRA, theophylline Time to asthma exacerbation based on symptom based, FeNO based or guideline based controller therapy Calhoun, W JAMA 2012

8 Mean monthly dose of ICS based on different treatment strategies Tiotropium versus salmeterol or doubling dose of ICS Guideline based 1610 ug/ml Biomarker (FeNO) based: 1,617 ug/ml Symptom based: 832 ug/ml (p < compared with guideline and biomarker based). Peters, S, NEJM 2010 Tiotropium versus salmeterol or doubling dose of ICS Guidelines for treatment of asthma in pregnancy Inadequate control of asthma is a greater risk to the fetus than is use of asthma medications (premature birth, low birth weight). Monthly evaluations during pregnancy including asthma history and lung function (PF or spirometry) Albuterol is the preferred bronchodilator Peters, S, NEJM 2010 Budesonide is the preferred ICS no risk to fetus Guiding asthma management during pregnancy using exhaled nitric oxide Case 2 58 year old woman with asthma since age 42, usually treated with budesonide two puffs bid. Comorbidities: osteoporosis, early cataracts URI 4 days ago, now with persistent cough, using albuterol 5 times per day, short of breath climbing stairs in her home Past two nights has awakened with asthma symptoms requiring use of rescue therapy Powell; Lancet 2011 WHAT IS THE BEST TREATMENT?

9 Treatment Options A. Increase budesonide to four puffs bid B. Add a long acting beta agonist C. Add a leukotriene modifier D. Treat with oral corticosteroids for 10 days. E. Trial of anti-reflux medication Bronchial thermoplasty -performed in bronchoscopy suite -thermal energy to destroy bronchial smooth muscle cells in airways -improves asthma quality of life, reduces exacerbations. Thermoplasty improves asthma related quality of life Asthma Triggers Effect of high fat versus low fat diet on bronchodilator response What s new in Asthma treatment Macrolides not effective Bronchial thermoplasty Tiotropium as add-on controller Wood LG, JACI 2011 Prn rather than regular use of ICS Attention to pragmatic (CER) study results

10 Summary Asthma prevalence is high and increasing Asthma mortality is slowly decreasing Clinical diagnosis with PFTs as confirmatory Rescue versus controller medication Goal of treatment is very well controlled (same as mild intermittent symptoms) ICS first line for all but mild intermittent READING Busse, W., NEJM 2001; 344:5 (Review article) Fanta, C., NEJM 2009 (Review of asthma medication) Badrul A. NEJM 2010 (discussion of FDA warning on LABAs) Eder, W, etal NEJM 2007 (Changing asthma epidemiology) Boushey, H etal, NEJM 2005 (asthma therapies) Milgrom H NEJM 1999 (anti-ige) Nelson, H. S. et al. Chest 2006;129:15-26 (safety of LABA) Castro, M. Am J Respir Crit Care Med 2010 (thermoplasty) Peters, S, etal. NEJM 2010 (tiotropium)