FRACP Teaching ASTHMA and COPD Update 2007

1. FRACP Teaching ASTHMA and COPD Update 2007

2. With respect to prevalence of asthma worldwide, all are correct except one A.People emigrating from countries of low prevalence to countries of high prevalence maintain the same prevalence of asthma exhibited in their country of origin. B.Prevalence of asthma has increased by as much as 50% in some countries over 20 years. C.Has been mainly based on questionnaires which have a high sensitivity but low specificity for diagnosis of clinical asthma. D.The gold standard is a standardised questionnaire in association with a test of BHR.

3. Prevalence of Asthma • There are five fold differences in prevalence of asthma between countries such as China, Australia and NZ • The prevalence of asthma has almost doubled over 20 years in Australia and NZ • The prevalence of asthma is likely to be due to environmental exposure to allergens • The lack of specificity in definitions of asthma make comparisons and longitudinal trends difficult to interpret

4. Non Invasive measurements of Airway Inflammation in asthma • These include tests of airway hyperresponsiveness, induced sputum examination and exhaled nitric oxide. (True/False) • ENO is the most sensitive measure of airway inflammation. • Sputum eosinophilia is a predictor of steroid responsiveness • Regular use of AHR and sputum examination to adjust steroid dose in asthma for optimum control, reduces asthma exacerbations and improves lung function in the long term. • Regular use of ENO to adjust steroid dose in asthma for optimum control, reduces asthma exacerbations and improves lung function in the long term.

5. Measures of AI in asthma • Symptoms + spirometry + ANOTHER MEASURE • GUIDELINE BASED CONTROL • AIRWAY HYPERRESPONSIVENESS • EXHALED NITRIC OXIDE • INDUCED SPUTUM EXAMINATION • Guideline based control • Aiming to achieve optimum asthma control based on strict adherence by patient and doctor to best practice guidelines (national/international) • Better asthma outcomes: significantly improved quality of life, fewer symptoms and exacerbations, less time off work, lower economic costs . Bateman Eur Respir J 2002;Gibson et al Cochrane Database Syst Rev 2000; Boulet et al Chest 2002

6. Predicts steroid responsive disease A rise in counts measured longitudinally predicts subsequent loss of asthma control Management protocols aimed at titrating steroid therapy to maintain normal counts lead to superior asthma control Pavord 1999Pizzichini 1999Brightling 2000Green 2002 Jatakanon 2000Deykin 2004 Green 2002 Jayaram 2005Chlumsky 2006 ‘Inflammometry’ • The use of information gathered from measures of airway inflammation to guide assessment and treatment. • Success with induced sputum eosinophil counts.(Gold standard)

7. Sputum induction and examination • Sputum induction • B2 agonist • 2 methods • success rate • safety • children • low FEV1

8. Sputum examination

9. Sputum: causes of increase in cell type • Eosinophilic: uncontrolled asthma • non compliance with medications • occupational asthma • Steroid responsive COPD • Neutrophilic: cigarette smoking • infections - bacterial, viral • steroid resistant asthma

10. Does normalising the sputum eosinophil count in asthma lead to fewer symptoms and exacerbations, improve lung function and reduce costs? • Green et al Lancet 2002 • Single centre study over 12 months. • 74 subjects attending a specialist hospital centre with moderate asthma managed by British Thoracic Society Guidelines alone, vs addition of sputum examination with normalisation of induced sputum eosinophil count ( < 3%). • Reduced frequency of severe exacerbations in sputum group : Mean( SEM) 0.9(0.2) vs 3.0(0.7)p=0.013 ; hospitalisations: 1 vs 6 p=0.047. • Trend to reduce direct costs • ENO measurements reduced by 48% in sputum strategy cf clinical strategy.

11. Advantageous in a practical setting. Predicts steroid responsive disease in steroid naïve cases.Smith et al 2005 Moderate association with eosinophilic airway inflammation in cross sectional studies.Berry et al 2005 r2= 0.26Smith et al 2004 r2= 0.45 Mixed evidence for predicting loss of asthma control in longitudinal studies. Exhaled NO as an Inflammometer Vs Harkins et al 2004Jones et al 2001 Deykin et al 2004Leuppi et al 2001

12. Exhaled nitric oxide • Produced by airway epithelial cells and inflammatory cells • marker of AI • diffuses into airway lumen • Increased in asthma> bronchiectasis/infections, • Reduced in CF, PCD • upregulation of inducible NO synthase by proinflammatory cytokines • Reduced by corticosteroids, smoking, alcohol

13. Factors thought to influence exhaled NO NO NO (Genetic factors) Viral infectionsAtopy and AHR SmokingCorticosteroids Acute lung allograft rejection? BronchiectasisFemale sex hormonesSLELiver cirrhosis Pulmonary hypertensionImmunodeficiencyPrimary Ciliary DyskinesiaCystic Fibrosis Factors that effect exhaled NO independent of sputum eosinophils will result in discordance between the 2 variables.

14. Exhaled nitric oxide • Measured by rapid linear-response chemiluminescence • standardised measurement • 50 ml/sec flow rate • reproducible,discriminates between subjects with and without asthma • normal values: mean (SD) 12 (11) ppb • 10th percentile: 6 ppb • 90th percentile: 23 ppb Bates et al J Allergy Clin Immunol 2003

15. ENO and loss of asthma control • Assessed usefulness of ENO for predicting an exacerbation of asthma prospectively. PPV Jones Am J Respir Crit Care Med 2001

16. ENO to guide asthma management • Taylor et al NEJM 2005 352: 2163-2173 • Single blind, placebo controlled trial • 94 subjects with asthma on ICS ( 46 ENO group, and 48 in control group) had ICS dose adjusted stepwise based on ENO measurements or standard guidelines. • Once optimal dose determined ( phase 1) subjects followed for 12 months ( P2) • Primary Outcome: frequency of asthma exacerbations • Secondary outcome: mean daily dose of ICS • Cut off for ENO 15 ppb at 250 ml/sec flow rate

17. Control group FENO group Intensive Asthma Study 2006 Eos=3% 300 0.67* 0.38* O* 0.09* * Exacerbations/patient/yr 100 E (ppb) 30 NO FENO=26 ppb F 10 3 0.1 10 100 3 30 0.3 1 Differential sputum eosinophil count (%)

18. AHR: Indirect challenge tests (T/F) • Include hypertonic saline, mannitol, adenosine monophosphate and Eucapnic Voluntary hyperpnea with dry air. • Are more specific for asthma than histamine or methacholine challenge • Are more sensitive for asthma than histamine or methacholine challenge • Are the tests of choice to exclude asthma in divers and police force. • Are more sensitive to inhaled steroid dose than direct challenges (methacholine /histamine)

19. Airway hyperresponsiveness • “Abnormal increase in airflow limitation following exposure to a nonallergic stimulus” • Characteristic in asthma • sensitive not specific • Direct: histamine, methacholine smooth muscle • Indirect : exercise, nonisotonic aerosols, drugs • release endogenous mediators smooth muscle Joos et al ERS Task Force.Eur Respir J 2003

21. All of the following are correct regarding allergy testing in asthma except one A.Of benefit to document specific allergens suggested by the clinical history. B.Is useful to reinforce the need for environmental control. C.Is useful in identifying occupational allergens. D.Is useful as a screening test for ABPA. E.A positive test invariably has clinical relevance.

22. Allergy Testing in Asthma To document specific allergens suggested by the clinical history To confirm and reinforce the need for environmental control To identify occupational allergens Note: A positive test may not have clinical relevance. A negative test usually rules out clinical sensitivity to that aeroallergen.

23. All of the following have been known to cause asthma symptoms except one A.B-Blockers including B-Blocker eye drops B.Aspirin C.Metabisulphites D.NSAIDs E.Calcium Channel Blockers

24. Appendix 1: Medications Known to Cause Asthma Symptoms Note: this list is an indication only. • Beta-blockersAll may lead to bronchoconstriction • Cholinergic agents • Cholinesterase inhibitors • Beta-blockers applied as eye-drops may also cause problems • Aspirin and NSAIDs - usually characterised by flushing and rhinorrhoea. May produce a life threatening asthma attack • Carbemazepine • Some parenteral drugs (such as penicillin, iron dextran complex, hydrocortisone, ipratropium bromide, aminophylline, N-acetyl cysteine) • Tartrazine (yellow food dye) • Preservatives (such as bisulphates, metabisulphates and benzalkonium chloride) • Echinacea (frequently recommended for colds, fl u and respiratory infections, but triggers asthma in some people) • Royal Jelly (has caused fatal exacerbations in some people). Source: Asthma Management Handbook 2002 [3].

25. Question A young woman with a history of nasal polyposis presents with severe asthma one hour after ingestion of salicylates. Which of these treatments is more likely to be effective in her long term management than would usually be expected? • A.Ventolin • B.Flixotide • C.Salmeterol and Flixotide in combination • Montelukast • (Anti–leukotriene antagonist) • E.Salmeterol

26. Asthma All of the following statements around efficacy and safety of short (SABA) and long acting beta-agonist (LABA) medications in the management of asthma are correct except for one. A.Overall there is an increase in bronchial hyper-responsiveness both during and following use of inh B-Agonists (whether SABA or LABA). B.Asthma control is less good when SABAs are taken regularly 4 times a day. C.There is good evidence that when SABAs are withdrawn or reduced to prn use that asthma control improves. D.There is an increase in both early and late phase responses to allergens after treatment with regular salbumatol. E.LABAs are more effective than QID SABAs in controlling asthma.

27. Which of the following statements is correct with respect to LABAs A.They have been found to be safe whether administered concurrently with inhaled steroids or not. B.They have been found to have an anti-inflammatory effect in vitro which has been reproduced in clinical trials C.Tachyphylaxis of broncho-protection to exercise induced asthma has been shown with regular LABAs. D.When LABAs are combined with inhaled steroids in the same inhaler they are found to be more effective than when administered in the same dose through separate inhalers. E.Salmeterol has a quicker onset of action than formoterol.

28. With respect to LABAs all are correct except for one A.When added to 400 - 800mcg beclamethasone LABAs are found to be more efficacous than doubling the dose of beclamethasone. B.Adding LABAs to 800mcg beclamethasone is more cost effective than doubling the dose of beclamethasone. C.When combined with inhaled steroids varying the dose and frequency of administration of LABAs is more effective than staying on a fixed and regular dose. D.Systemic availability and efficacy is dependent on the deposition characteristics of the inhaler in which they are administered. E.LABAs are equipotent to oral theophylline wrt broncho-dilation but are preferred because they have less side effects.

29. All of the following are correct wrt acute asthma therapies except for one A.Intravenous aminophylline contributes nothing to usually employed doses of inhaled B-Agonists. B.Ipratropium contributes a small improvement in FEV1 when combined with salbutamol compared with salbutamol alone. C.IV or nebulised Magnesium offers useful broncho-dilation in the management of acute asthma. D.Ipratropium use in the ED does not reduce the need for admission. E.Spirometry is a more robust measure of assessing severity of asthma than is PEF measurement. F.B-Agonists delivered by spacing devices are equivalent in efficacy to wet nebulisation.

30. With respect to monitoring asthma control, all of the following are correct except one A.An elevated expired nitric oxide level suggests sub-optimal control of inflammation within the airways and need for more inhaled steroid. B.An increase in eosinophils (>3%) within induced sputum samples infers sub-optimal control and need for more inhaled steroid. C.A 15% reduction in PEF remains the most sensitive measure of sub-optimal control and supports its use in Action Plans. D.FEF 25 - 75%, takes the longest of all clinical measures to improve and is least likely to return to normal in patients treated with high dose inhaled steroids. E.An increase in BHR is the strongest argument for increasing anti-inflammatory therapy.

31. Question 4 With respect to COPD and asthma: A.The two disorders can never co-exist. B.The chronic airway inflammation in asthma is predominantly eosinophilic and driven by CD8+ lymphocytes. C.The chronic airway inflammation in COPD is mainly neutrophilic and characterised by presence of increased numbers of macrophages and CD8+T lymphocytes. D.Nebulised anticholinergics have a proven place in acute management of both asthma and COPD. E.In patients with fixed airways obstruction due to chronic asthma, or smoking related airways disease, once FEV1 falls below 30% predicted, mortality rates are remarkably similar.

32. Asthma and COPD COPD Noxious Agent Asthma Sensitising Agent Airway Inflammation CD4+ Lymphocytes Eosinophils LTD4, IL-4, IL-5 Airway Inflammation CD8+T Lymphocytes Macrophages, Neutrophils LTB4, IL-8, INF- Completely AirflowCompletely ReversibleLimitationIrreversible

33. COPD - Definition With respect to airflow limitation in COPD A.Anti-inflammatory therapy if used appropriately will reduce rate of development of airflow limitation in persistent smokers. B.Airflow limitation is caused by a mixture of small airways disease (obstructive bronchiolitis) and parenchymal destruction. C.Rate of decline of lung function always returns to that of the normal population after smoking cessation. D.Airflow limitation is best assessed utilising regular Peak Flow monitoring. E.Severity of airflow limitation is best assessed by HRCT Scan.

34. Mechanisms Underlying Airflow Limitation in COPD Inflammation Small Airways Disease Parenchymal Destruction Airflow Limitation

35. With respect to smoking related COPD all are correct except one A.As a rule patients need to develop an FEV1 of around 25-30% predicted before they develop symptoms of breathlessness. B.Patients with a chronic productive cough are more likely to have reduction in FEV1. C.Between 15-25% of patients who smoke will lose lung function at a rate faster than that of the normal population. D.Patients with COPD are at increased risk of developing lung cancer, CVA, and IHD than patients who smoke but who do not have COPD. E.Once patient stops, their rate of loss of lung function usually returns to that of the normal population.

37. Tiotropium [Spiriva] is a new broncho-dilator. Which of the following is incorrect A.It is an anticholinergic with longer half life than Ipratropium. B.It has a unique selectivity for M3receptors. C.Peak effects are seen after 1-2 hours. D.Only needed once per day. E.Not as effective as regular SABAs or LABAs in treatment of COPD.

38. Tiotropium (Spirivia) • Long acting version of ipratropium • Unique selectivity for M3 receptors • Suitable for single daily dosing • 12h + improvement in spirometry • Peak effects seen after 1-2h • Residual benefit at 24h

39. Tiotropium vs Salmeterol 623 patients (S 213, T209, P201) treated for 6 months Donnohue et al. Chest 2002: 122: 47-55

40. Tiotropium vs Salmeterol 623 patients (S 213, T209, P201) treated for 6 months Donnohue et al. Chest 2002: 122: 47-55

41. In relationship to steroids in COPD which is correct? A.20% of COPD patients will exhibit a short term (> 15% improvement in FEV1) benefit from short course of prednisone for 14-21 days. B.After introduction in COPD, inhaled steroids exert most of their effects on lung function only after at least 6 months treatment. C.Inhaled steroids have no effect on frequency of exacerbations of bronchitis. D.Use of inhaled steroids over a 1 year period does not influence measures of quality of life. E.Independent of the effect of steroids patients with COPD are not at increased risk of osteoporosis.

42. Evaluation of ICS in COPD Reversible vs irreversible structural change Short term vs long term benefits Cost benefit Which outcome measures?

44. EUROSCOP STUDY SUMMARY PulmicortPlacebo 0 - 6 mths+ 17mls+ 1ml 6 mths - 3 years- 157mls- 181mls

45. § Fluticasone propionate 500 mcg b.I.d. Placebo Adjusted placebo Adjusted fluticasone propionate 1.53 1.48 1.43 FEV1 (L) 1.38 1.33 1.28 0 Pre V1 V2 V2 BL BL 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Treatment phase Pretrial steroid withdrawal 2-week oral steroid course ISOLDE Study Postbronchodilator FEV1 Over 3 Years Adapted from Burge et al. BMJ. 2000;320:1297-1303.

46. Question: In utilising oxygen therapy in COPD all are correct except one A.Needs to be used for > 16 hours per day to show a survival effect. B.Has no effect on survival if patients continue to smoke. C.Is shown to be effective in patients with corpulmonale and with PaO2< 8 kPa. D.Is beneficial wrt prolongation of life, reduced admissions and improved quality of life if administered overnight to patients with resting PaO2 of > 8 kPa but who desaturate to < 90% for more than 2 hours overnight. E.Portable oxygen has been shown to improve quality of life but not survival in COPD.

47. Types of Oxygen Therapy Long Term Oxygen Therapy (LTOT) > 15 days; +/- portable (Grade A 24 hrs, C normoxic) Short Term Oxygen Therapy (STOT) post discharge (unstable); 6-8/52 (Grade C) Short Burst Oxygen Therapy (SBOT) relief of SOB, palliative care (Grade B) Ambulatory Oxygen Therapy portable; (Grade B immediate, Grade A QoL)