Asthma

1. Asthma J.B. Handler, M.D. Physician Assistant Program University of New England

2. SOB-shortness of breath ASA- aspirin P.E.- physical exam EOS- eosinophils RR- respiratory rate ABG- arterial blood gas Nl- normal CxR- chest x-ray SaO2- saturation of oxygen OP- out patient V/Q- ventilation/perfusion DM- diabetes mellitus ß- beta EIA-exercise induced asthma PRN- as needed HTN- hypertension D/C- discontinue SO2- sulfate NO2- nitrate GERD- gastroesophageal reflux disease PO- by mouth Alt- alternative NSAID- non-steroidal anti-inflammatory drug Abbreviations

3. Definition • A clinical syndrome of unknown etiology with three components:1. Recurrent episodes of airway obstruction that resolve spontaneously or following treatment.2. Exaggerated bronchoconstrictor response to stimuli that have little/no effect on non-asthmatics.3. Inflammation of the airways.

4. Case 1 • A 45 y/o white male presents with paroxysms of severe coughing lasting up to 1 hour, resolving spontaneously. He had a recent URI. No prior history of pulmonary problems. No hx of smoking. Currently feels well. • P.E: Healthy appearing male, NAD; Vesicular breath sounds throughout both lung fields without wheezing, ronchi or crackles. • What is your differential diagnosis?

5. Differential Diagnosis • New/superimposed respiratory infection- bronchitis, pertussis, etc. • Asthma • Allergies • Toxin or pollutant exposure • Early signs of new disease • Psychogenic cough – dx only of exclusion

6. Epidemiology • 5% of child/adult U.S. population • Can develop any time in life (often <25 y.o.) • 500,000 hospitalizations, 5,000 deaths/yr. • 15 million OP visits/yr. • >6 billion dollars/annually

7. Pathogenesis • Genetic predisposition. • Inflammatory infiltrates (lymphocytes, neutrophils, eosinophils, mast cells). • Injury to airway epithelium; denudation. • Thickened airway wall from: • Inflammation, collagen deposition, smooth muscle hypertrophy. • Hypertrophy and hyperplasia of airway glands. • Airway hyperresponsiveness.

8. Pathogenesis • Episodic airway narrowing: smooth muscle constriction, thickening of airway epithelium and mucus secretion into the airway lumen; mucus inspissates. • Local release of bioactive mediators or neurotransmitters during attacks contributes to airway constriction. • End result is acute, reversible obstruction of the airway lumen to airflow.

9. Pathophysiology • Airway resistance; medium and small airwayswork of breathing. • Diffuse airway obstruction. • Airway reactivity to variety of stimuli. • V/Q mismatch: low V/Q contributes to hypoxemia when present. • Tachypnea results in PCO2. If PCO2, ominous sign of ventilatory failure.

10. Airway Obstruction AllRefer Health

11. Asthma Microscopic Images.google.com

12. Asthma: Mucous Plugging

13. Mediators: Acute Response • Acetylcholine: neurotransmitter released via intrapulmonary branches of vagus nerve increases bronchial smooth muscle contraction bronchoconstriction. • Histamine: endogenous bronchoconstrictor in mast cells, basophils, lungs. Vasodilator properties promote capillary leakage in presence of inflammation.

14. Mediators: Acute Response • Kinins- bradykinin activated by enzymes (kallikreins) released by mast cells- bronchoconstrictor. • Leukotrienes: biochemical mediators released by mast cells, EOS and macrophages-potent smooth muscle constriction; increase mucus secretion and activate airway inflammatory cells.

15. Asthma Triggers • “Atopy” association of allergies- inhaled allergens can trigger attacks- dust mites, cats, seasonal pollens, hay fever, etc. • Single largest risk factor for developing asthma. • Non-specific triggers: URI’s, sinusitis, tobacco smoke, ozone, GERD, weather, stress, exercise, SO2, NO2, and others. • Aspirin allergy- cross reactivity with other NSAIDs, but not selective COX-2 agents. • Absence of triggers not unusual as well.

16. Clinical Presentation • History: “attacks” of coughing, wheezing, SOB, anxiety, chest tightness. Associations- allergies, irritants, ASA. Highly variable presentation. • Episodes often at night and early AM when airway reactivity is highest. • P.E*: P & RR, secretions, expiratory phase, wheezing, mucosal swelling. • Note: with severe asthma, wheezing may decrease or stopdecreased airflow. *During asthma episode/attack

17. Pulmonary Function Testing • Spirometry easily obtainable – FVC, FEV1, FEV1/FVC. • PEFR-Peak expiratory flow rate-(L/min)- varies with age, gender, height; hand-held device good for following asthma severity as an adjunct to PFT’s. • Spirometry or PEFR following bronchodilator: assess responsiveness to treatment.

18. Spirometry of Asthmatic • Lung volumes: TLC, FRC, RV; FVC normal or slightly • Lung flow:; FEV1, FEV1/FVC (<70% means obstruction), PEFR. • DLCO- normal • Spirometry in between asthmatic attacks may or may not be normal; depends on asthma severity/classification (see below).

19. Case 1 • One year ago, he had a similar episode which responded to antibiotics. • In the last year he has noted episodic coughing when using a dictaphone or speaking for extended periods of time. • Some episodes with exercise- no pattern. • PFT’s done on 2 occasions when asymptomatic have been entirely normal. • Symptoms rapidly respond to short courses of oral prednisone.

20. Pulmonary Testing • Provocative testing (If spirometry nl)- Methacholine challenge to induce Sx and decrease in FEV1 (by 20% or more). If negative, asthma very unlikely. • Arterial blood gases (ABG’s)- measure pH, PCO2, PO2. Respiratory Alkalosis with PCO2 is common during attack. If PCO2 is normal or high during an attack  impending respiratory failure. PO2 indicates severe V/Q mismatch. • CxR- Often normal vs hyperinflation.

21. Case 1 • During methacholine challenge testing, he has abrupt onset of severe coughing with a >20% drop in FEV1 and FEV1/FVC. • Treatment with inhaled ß-agonist aborts the attack. • PFT’s return to normal following albuterol.

22. Asthma Complications • Infection including pneumonia • Exhaustion, dehydration • Oxygenation failure • Ventilation failure – lose drive to inflate alveoli • Death

23. Classification of Severity • Applies to clinical features of chronic, stable asthma. • Mild intermittent asthma- Symptoms  2x/week- No symptoms and normal PEFR between attacks- Night symptoms  2x/month- FEV1 and PEFR  80% predicted*- PEFR variability 20% *In between attacks Current, Chapter 9

24. Mild persistent asthma- Symptoms > 2x/week, <1x/day- Night symptoms > 2x/month- FEV1 or PEFR  80% predicted*- PEFR variability 20-30% *In between attacks Current, Chapter 9

25. Moderate persistent asthma- Daily symptoms; daily use of inhaled short acting ß2 agonists - Night symptoms >1x/week- FEV1 or PEFR >60% to <80% * predicted - PEFR variability >30% *In between attacks Current, Chapter 9

26. Severe persistent asthma- Symptoms daily and frequent- may be continuous- Frequent night symptoms- FEV1 or PEFR 60% predicted*- PEFR variability >30% • Note: Exacerbations of symptoms are common in patients with asthma and often limit activities in moderate to severe forms. *In between attacks Current, Chapter 9

27. Long Term Treatment Goals • Minimize chronic symptoms that impair normal activity. • Minimize exacerbations/hospitalizations. • Limit side effects of medications. • Cornerstone treatment of persistentasthma- daily anti-inflammatory therapy with inhaled corticosteroids. • Stepped care approach (Current, table 9-3). • Long term control vs. quick relief meds.

28. Quick Relief: Beta Adrenergic Agents • Most efficacious brondchodilators for acute symptoms. • Also used to prevent exercise induced asthma (EIA). • 2 agonists selectively relax bronchial smooth muscle- bronchodilate while limiting cardiac stimulation.

29. Quick Relief: Beta Adrenergic Agents • Albuterol, others: Rapid onset of action (<5”); most effective agents for acute bronchospasm. Use of a spacer may improve delivery. • MDI 1-2 puffs (0.18mg) up to 6+ puffs q6hr; delivery may improve with spacer. • Nebulizer doses (2.5 mg) are 14x more potent than MDI (2 inhalations)- more effective for severe asthmatic exacerbations (ED, hospitalized).

30. Inhalers and Spacers AllRefer Health

31. Quick Relief: Anticholinergic Meds • Reverse vagally mediated bronchoconstriction and mucus production. • Ipratropium bromide (Atrovent) via inhaler 2-4 puffs (18mcg/puff) q6h as an alternative or adjunct (in moderate to severe exacerbations) to short acting B-agonists; not as effective. • Not useful for EIA or allergy induced asthma

32. Long Term Control: Inhaled Corticosteroids • Low to high dose, local Corticosteroids: most importantandeffective for long term control in persistent asthma. • Reduce chronic and acute inflammation; mild persistent asthma and worse. • Inhaled preparations for prevention; dose titrated to symptom relief; may take weeks for optimal efficacy; adrenal suppression unlikely.

33. Inhaled Corticosteroids • Several agents- varying potency (Fluticasone, Beclomethazone, Flunisolide et. al.). • Usually 2x or 3x daily dosing • Follow by H2O or mouth wash gargle to avoid local yeast (Candida) infection.

34. Long Term Control: Long Acting -agonists • Used for long term (8-12 hrs) bronchodilation and EIA; not for acute episodes. • Especially beneficial for night time symptoms. • Salmeterol (Serevent): 50mcg 2x/d. Formoterol is new with similar effects.

35. Salmeterol Safety Concerns • Two large clinical trials salmeterol s asthma exacerbations and asthma related deaths (small number of patients, but statistically significant). • Black-box warning on labeling since 2005 • Little change in prescribing since. • Message: Use with caution. Confine use only to patients already on inhaled corticosteroids with ongoing symptoms.

36. Leukotriene Modifiers • Leukotriene modifiers: Inhibit synthesis (Zileuton/Zyflow) or action (Zafirlukast/Accolade) of leukotrienes; inhibit inflammatory mediators; decreases need for rescue inhaler. Modest efficacy for patients with mild persistent asthma. • Alternative to low dose inhaled steroids in treatment of mild persistent asthma.

37. Mediator Inhibitors • Chromolyn, Nedocromil- mild improvement in airway function in mild persistent or EIA. Inhibit mast cell release of mediators of inflammation; inhibit asthmatic response to allergens. • Alternative to IC for some patients with mild persistent asthma and allergies. Limited usefullness. • Excellent safety profile

38. Systemic Corticosteroids • Systemic steroids are used in Rx of moderate to severeasthmaexacerbations; marked anti-inflammatory properties speed (6+ hours) the resolution of airway obstruction and reduce rate of relapse; oral or IV dosing. • Long term use may be required in some patients with severe persistent asthma.

39. Systemic Corticosteroids • Prednisone et. al. (40-60 mgs/daily for out-patient care); higher doses required if severity requires hospitalization. • Safe when used for short term treatment (see below) of moderate to severe exacerbations. • May occasionally be needed (short term course) in some patients with mild asthma during severe exacerbations.

40. Systemic Corticosteroids • Dangers: Supraphysiologic dosing over time leads to long term risks: Adrenal suppression, HTN, osteoporosis, glucose intolerance/DM, easy bruisability, weight gain, etc. • Goal: Pulse dosing followed by taper and D/C, overlapping with  dosing of inhaled agents whichhave minimal systemic side effects. • Tapering dose (days to weeks) allows return of adrenal-pituitary axis.

41. Interest Only • Phosphodiesterase inhibitors- aminophylline, theophylline- less effective and potentially toxic; adjunctive Rx for mod to severe persistent asthma. • Toxicity- Low therapeutic/toxic ratio- GI (nausea, abd. pain), CNS stimulation (anxiety, HA,tremors, seizures)and Cardiac (arrhythmias, tachycardia). • Must monitor serum theophylline levels to maintain therapeutic range (10-20 ug/ml).

42. Still Other……IO • Oral -agonists- terbutaline, albuterol tablets- usually add little to inhaled agents; may be useful as an adjunct; terbutaline causes tremors. • Immunosuppresive agents: Methotrexate, cyclosporine, trolandomycin- for patients unresponsive to other drugs or where steroids contraindicated.

43. Combination Meds • Advair Diskus: Combination inhaler with Fluticasone in varying strengths combined with a fixed dose (50mcg) of Salmeterol, one inhalation b.i.d, decreases number of inhalers and inhalations. • Combivent: Albuterol + ipratropium

44. Case 1: Many Years Later • He remains asymptomatic and has reduced meds over time. Rare coughing episodes rapidly respond to albuterol inhaler. • Meds: • Fluticasone MDI 220mcg 2x/d • Abuterol MDI (90mcg/puff)- 2-3 puffs prn • Notes breathing is best when teaching PA students at UNE!

45. Long Term Control: Daily meds Either low dose inhaled steroid or Cromolyn/Nedocromil Alternative: Leukotriene modifier If needed increase dose of IC’s Quick Relief: Short acting B2 agonist Frequent or increasing use of B2 agonist suggests need for additional therapy. Mild Persistent Asthma Current, Chapter 9

46. Long Term Control: Daily meds Low, medium or high dose inhaled streroid If needed, add long acting bronchodilator-B2 agonist (esp for night time Sx) Alt: SR theophylline Quick Relief: Short acting inhaled B2 agonist Frequent or increasing use of B2 suggests need for additional therapy Moderate Persistent Asthma Current, Chapter 9

47. Long Term Control: Daily meds High dose inhaled corticosteroid Long acting bronchodilator-B2 agonist Alt: SR theophylline Oral steroid therapy often needed for long periods. Quick Relief: Short acting B2 agonist Frequent or increasing use of B2 suggests need for additional therapy Severe Persistent Asthma Current, Chapter 9

48. Mild Asthma Exacerbations • Stepped care incremental therapy • Most are treated at home with quick response to ’d dose/frequency of short acting “rescue” ß-agonist. • These drugs may be needed every 3-6 hours for a short course. • Inhaled corticosteroids may need to be added (*MIA) or dose ’d (x2) if already taken (*PA); full effect will take weeks. *PA- persistent asthma *MIA- mild intermittent asthma

49. Mild Asthma Exacerbations • If already taking an inhaled corticosteroid, the dose is doubled during an acute exacerbation until PEFR return to normal. • If unresponsive, an oral systemic corticosteroid may be needed for a short course, then tapered, returning to inhaled corticosteroids.

50. Moderate/Severe Attacks • Some patients (caution) managed as out patient- require very close monitoring via phone. • Most patients warrant hospitalization. • Supplemental O2 as needed to maintain SaO2>90%. • Continuous O2 saturation monitoring via oximetry if hospitalized.