1. ©2014 MFMER | slide-1 Acute Asthma An update Robert Vassallo, MD Mayo Clinic, Rochester, MN, USA. Kuwait congress – Update in Internal Medicine February 2014

2. ©2014 MFMER | slide-2 Disclosures I have nothing to disclose with respect to this presentation.

3. ©2014 MFMER | slide-3 Abbreviations used in this presentation SABA - short acting beta agonist LABA - long acting beta agonist NO – nitric oxide IL-5 - Interleukin-5 IL-13 – Interleukin-13 Th – T-helper cell

4. ©2014 MFMER | slide-4 Outline of this presentation Advances in asthma pathophysiology Overview of current therapy and acute management in hospitalized patients. Use of biomarkers to monitor therapy Safety concerns with long acting beta-antagonists A paradigm shift: anti-cholinergic therapy in asthma Treatment of severe asthma: Omalizumab (Xolair) Anti-IL-13 Therapy (Lebrikizumab) Bronchial thermoplasty

5. ©2014 MFMER | slide-5 Asthma pathophysiology Key components: inflammation, bronchial hyper- reactivity, airway remodeling 1970’s 1980’s 1990’s present Bronchospasm + Inflammation Bronchospasm + Inflammation + Remodeling CHEST 2013; 144(3):1026–1032. T cell Eosinophil Th-2 IL-5 / IL-13 Th17 Dendritic cells

6. ©2014 MFMER | slide-6 All of the following cause obstructive lung disease except: A) Obliterative bronchiolitis B) Bronchiectasis C) Asthma D) Marked obesity E) Chronic Obstructive Pulmonary Disease (COPD)

7. ©2014 MFMER | slide-7 Establishing the diagnosis Not all that wheezes is asthma The medical history! Pulmonary function testing with bronchodilator Reversibility: 12% AND 200 cc change in FEV 1 Obstructive physiology on pulmonary function test (FEV 1 reduced much more than FVC) Bronchoprovocation testing Methacholine, histamine, exercise Exhaled nitric oxide (NO)

8. ©2014 MFMER | slide-8 Nitric Oxide Exhaled NO Exhaled nitric oxide is a biological marker that correlates with eosinophilic inflammation in asthma. Exhaled NO measurement can provide diagnostic and predictive value for a corticosteroid response. More longitudinal studies are required to clarify the clinical significance of exhaled NO in asthma. Kim et al, Curr Opin Allergy Clin Immunol 2014,14:49–54

9. ©2014 MFMER | slide-9 Treatment of acute severe asthma requiring hospitalization Why do patients develop respiratory failure with severe asthma attacks? NHLBI Asthma web educ resources Air trapping Mucus plugging Increased work of breathing

10. ©2014 MFMER | slide-10 Acute Asthma Initial Assessment and Management History Physical Exam Peak flow determination Up to 2 treatments 20 minutes apart Normal peak flow Consider brief trial of oral corticosteroids Peak flow 50- 80% predicted Start oral corticosteroids Contact primary MD Peak flow <50% predicted Start oral corticosteroids Contact primary MD ER Admit Modified from NHLBI EPR3 2007

11. ©2014 MFMER | slide-11 Acute Asthma Management Clinical and Laboratory Assessment Assess clinically – accessory muscle use, tachypnea, tachycardia, diaphoresis, pulsus paradoxus, exhaustion. Assess airflow limitation – peak flow measurement. Assess oxygenation – pulse oximetry. Assess for hypercapnia – selected patients especially if somnolent, fatigued, difficulty with speech, elderly, concomitant use of sedatives. Imaging – chest X ray Blood work – CBC, glucose.

12. ©2014 MFMER | slide-12 Treatment of Acute Severe Asthma Principles and Primary Goals of care Relieve airflow limitation: bronchodilator therapy Treat airway inflammation: steroids. Treat hypoxemia or hypercapnia if present. Non-invasive ventilation / mechanical ventilation in severe cases (clinical judgment). Selected therapies: magnesium sulphate and heliox. Limited or no role for antibiotics and methylxanthines.

13. ©2014 MFMER | slide-13 In the treatment of severe asthma, corticosteroid therapy would be expected to cause all of the following, except: A) Corticosteroids enhance efficacy of β2-adrenergic agonists (bronchodilator). B) Corticosteroids may decrease hospital admission rates in acute asthma if administered early. C) High dose parenteral steroids may cause hyperglycemia. D) Corticosteroids enhance edema in the acute asthmatic airway.

14. ©2014 MFMER | slide-14 Treatment of Acute Asthma Bronchodilator therapy Albuterol (or salbutamol) provides rapid, dose- dependent bronchodilation. Continuous administration may be more effective in severe exacerbations. Levalbuterol is the R-isomer of albuterol. Ipratropium bromide is an anticholinergic bronchodilator with a slow onset of action and peak effectiveness at 60 to 90 minutes.

15. ©2014 MFMER | slide-15 Treatment of Acute Asthma Corticosteroid therapy Oral administration of prednisone is often equivalent to iv methylprednisolone unless there is nausea. Give a 5- to 10-day course. Current evidence is insufficient to permit conclusions about using inhaled corticosteroids in acute asthma. For severe exacerbations unresponsive to the albuterol and corticosteroid therapy, adjunctive treatments may be used: iv magnesium sulphate or heliox. Expert Panel Report 3: National Heart Lung and Blood Institute 2007 https://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf

16. ©2014 MFMER | slide-16 Treatment of Acute Asthma Heliox Heliox is a mixture of helium and oxygen (usually a 70:30 helium to oxygen ratio) that is less viscous than ambient air. Heliox improves delivery and deposition of nebulized albuterol.

17. ©2014 MFMER | slide-17 Challenges in severe asthma Why do patients get hospitalized? Patient non-adherence to medication. Continued exposure to triggers (pets etc) or exposure to second-hand smoke. Incomplete assessment of co-morbidities like sleep apnea or GERD. Inadequate follow-up Pharmacogenomics and individualized patient responses to medication. Aldington S, Beasley R. Thorax 2007; 62: 447-458

18. ©2014 MFMER | slide-18 Asthma management Post-hospital follow up of severe asthma 1) Identify triggers 2) Control inflammation 3) Provide bronchodilator for relief 4) Assess response 5) Modify (escalate/ de-escalate as appropriate) and educate. Assess for risk factors associated with higher mortality. Corticosteroid therapy Leukotriene inhibitors Anti-IgE therapy Thermoplasty Short acting beta-agonists Long acting beta-agonists Long acting anti-muscarinic Symptom diary, pulmonary function testing, exhaled NO

19. ©2014 MFMER | slide-19 Risk Factors Associated with Higher Mortality in Acute Asthma Previous severe exacerbation (e.g., ICU admission). Two or more hospitalizations for asthma. Three or more ED visits for asthma in the past year. Using >2 canisters of SABA per month. Difficulty perceiving asthma symptoms or severity of exacerbations. Other risk factors: sensitivity to Alternaria low socioeconomic status or inner-city residence illicit drug use major psychosocial problems comorbidities like cardiovascular disease, etc.

20. ©2014 MFMER | slide-20 Expert Panel Report 3: National Heart Lung and Blood Institute 2007 https://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf

21. ©2014 MFMER | slide-21 Treatment of severe asthma Anti-IgE Therapy Biologic antibody therapy (Omalizumab; Xolair) binds IgE in the circulation and prevents it from activating mast cells and basophils. In moderate to severe asthma, anti-IgE therapy reduced exacerbation rate and reduced steroid dose needed. Anti IgE therapy is recommended as an add-on to optimized standard therapy in asthmatics 12 years and older who need continuous or frequent treatment with oral corticosteroids. Elevated serum IgE 1.Ann Intern Med. 2011 3;154(9):573-82 2.Lancet Respir Med. 2013;1(3):189-90. 3.Cochrane Database Syst Rev. 2014 13;1

22. ©2014 MFMER | slide-22 Tiotropium Recent double blind trial in asthmatic patients Addition of tiotropium compared with: Doubling inhaled steroid Addition of salmeterol Tiotropium increased am peak flows more than doubling inhaled steroids and equivalent to salmeterol. Most secondary outcomes favored tiotropium N Eng J Med 2010;363:1715-26

23. ©2014 MFMER | slide-23 Risks with LABA monotherapy Meta-analyses have shown that LABAs are associated with increased risk of overall death when used as monotherapy. The use of LABAs concomitantly with inhaled corticosteroids significantly reduces asthma hospitalizations and is not associated with life- threatening events and asthma-related deaths. The evidence appears to support the use of LABAs plus inhaled steroids in a single inhaler device for patients with moderate to severe asthma. Thorax 2012;67:342-349

24. ©2014 MFMER | slide-24 Bronchial Thermoplasty Am J Respir Crit Care Med. 2012 Apr 1;185(7):709-14. Am J Respir Crit Care Med. 2010 Jan 15;181(2):116-24.

25. ©2014 MFMER | slide-25 Treatments for severe asthma in the pipeline

26. ©2014 MFMER | slide-26 New and Emerging Therapies Being Evaluated for Asthma. Wechsler ME. N Engl J Med 2013;368:2511-2513.

27. ©2014 MFMER | slide-27 Anti-IL-13 Therapy (Lebrikizumab) N Engl J Med. 2011 Sep 22;365(12):1088-98. Bottom line: more studies needed

28. ©2014 MFMER | slide-28 Thank you for your attention. The Nobel Prize in Physiology or Medicine 1950. Nobelprize.org. Nobel Media AB 2013. Web. 30 Jan 2014. "In our opinion, the awards we received belong truly to all the men and women of the Mayo Clinic because it was the spirit of cooperative endeavor, the fundamental credo of the institution, which made possible the work which resulted in our trip to Stockholm.“ Dr Philip Hench, MD.