1. ApproachtoDifficultAsthma Prof. Bilun Gemicioglu

2. Also Known As • Severe asthma • Difficult to control asthma • Difficult to treath asthma • Refractory asthma • Steroid resistant asthma • Unstable asthma • Life threatening asthma

3. Agenda • Definition • Factors that could be preventing a normal response to asthma medication • Phenotypes • Risk Factors

4. Severe - Difficult Asthma • Definition • Factors that could be preventing a normal response to asthma medication • Phenotypes • Risk Factors

5. Definition - ERS Task Force • ‘failure to achieve asthma control when maximally recommended doses of inhaled therapy are prescribed for at least 6 - 12 months’ ERS Task Force: ERJ 1999;13:1198-6

6. Levels of asthma control GINA 2006

7. Maintain and fine lowestcontrolling step Controlled Consider stepping up togain control Partly controlled Uncontrolled Step up until controlled Exacerbation Treat as exacerbation Management approach based on control Level of control Treatment action Reduce Increase Reduce Treatment steps Increase GINA Workshop Report 2006

9. Definition - ATS ATS- JACI 2000;106:1033-1042

10. Severe - Difficult Asthma • Definition • Factors that could be preventing a normal response to asthma medication • Phenotypes • Risk Factors

11. Factors that could be preventing a normal response to asthma medication • Incorrect diagnosis • Continuing exposure to sensitising agents • Unrecognised aggravating comorbidities • Non-compliance with therapy

12. Incorrect Diagnosis -Alternative Diagnoses • COPD • Congestive heart failure • Central airway obstruction • Foreign body, tumour, sarcoidosis, tracheobronchomalacia • Cystic fibrosis • Recurrent pulmonary embolism • Obstructive bronchiolitis • Recurrent aspiration • Vocal cord disfunction • Allergic bronchopulmonary aspergillosis • Churg-Strauss syndrome Bel EH. Breathe 2006; 3:2; 129-139

13. Incorrect diagnosis : pseudo-tm

14. Incorrect diagnosis: tracheomalasia

15. Strategy for the diagnosis-1 • History of asthma development (age of onset, atopy, response to treatment, smoking) • Severity of disease (exacerbations, hospitalisations, ICU admissions) • Exogenous aggravating factors (allergens, occupationnal agents, drugs, foods..) • Endogenous aggrating factors (Rhinosinusitis, GER, OSA, influence of menstruation, psychiatric disease..) • Miscellaneous (adherence, advers effect, psychosocial circumstances) • Physical examination (specific points of attention) (Body mass index, Nasal polypes, cardiac failure, adverse effects of treatment)

16. Strategy for the diagnosis: Laboratory tests • Peripheral blood (ESR, blood count, tIgE, sIgE, T3, T4, TSH) • Lung function (spirometry, flow-volume, PEF variability, challenge tests, arterial blood gases) • Radiology (chest radiography, thorax CT or HRCT, sinus CT scans) • Additional tests for comorbidities and alternative diagnoses (nasal endoscopy, oesophageal pH or PPI, polysomnography, broncoscopy, D-dimer, ANCA, IgG againts aspergllus fumigatus….) Bel EH. Breathe 2006; 3:2; 129-139

17. Continuing exposure to sensitising agents • Allergen exposure at home • Allergen or occupationnal exposure at work • Drugs • Dietary factors - metabisulphite, salicylate, food allergens • Smoking Bel EH. Breathe 2006; 3:2; 129-139

18. Allergic Sensitization Patients with Severe Asthma Early-onset asthma Late-onset asthma 18% 30% 9% 56% 14% 73% Multiple allergies Single allergy Non-atopic Grootendorst DC et al., AJRCCM 2000

19. Allergic Sensitization Patients with Severe Asthma 100 80 60 Percentage of atopic patients 40 20 0 cat soy dog fish food milk birch fungi wheat peanut eggwhite alternaria cockroach mugworth aspergillus grass pollen house dust mite Grootendorst DC et al., AJRCCM 2000

20. Exposure to sensitizing drugs • ß-Blockers • Aspirin and NSAIDS • ACE inhibitors

21. Smokers (n=17) 0 0 Smoking and steroid responses in asthma Non-smokers (n=21) 30 ** Placebo 25 20 Fluticasone (1mg/day) 15 Change in morning PEF (%) 10 5 0 -5 Sputum Eos % change0 -1.8 * Chalmers GW et al: Thorax 2002

22. 0 NS -0.2 -0.4 Δ Asthma control score -0.6 NS p<0.001 -0.8 Asthma control -1 Smoking and response to oral steroids Prednisolone 40mg daily x 2 weeks Non-smokers (26) Ex-smokers (10) Current smokers (14) FEV1 300 p<0.01 200 Δ FEV1 (ml) NS 100 NS 0 Chaudhuri R et al: AJRCCM 2003

23. Unrecognised aggravating comorbidities • Chronic rhinosinusitis • Recurrent respiratory tract infections • Gastro-oesophageal reflux • Obstructive sleep apnea • Psychological dysfunctioning • Obesity • Systemic diseases (thyrotoxicosis…) Bel EH. Breathe 2006; 3:2; 129-139

24. 100 p=0.10 p=0.03 p=0.03 p=0.04 p=0.01 75 50 Prevlanece (%) 25 0 sleep apnoea psycho- pathology sinus disease gastric reflux recurrent infections Co-morbid factors in asthmatic patients with frequent exacerbations ten Brinke A etal., ERJ 2005;26:812-8.

25. Co-morbid factors in asthmatic patients with frequent exacerbations ten Brinke A et al., ERJ 2005;26:812-8.

26. Co-morbid factorsin severe asthma * Women Mild 90 80 Severe * 70 60 % Total 50 * 40 * * 30 20 10 0 Premenstrual Exercise Sinusitis Stress Rhinitis Aspirin ENFUMOSA Study: ERJ 2003,22:470-477

27. Reccurent infectionsin severe asthma Pasternack et al. J Allergy Clin Immunol 2005; 116: 1123-8

28. Reccurent infectionsin severe asthma Pasternack et al. J Allergy Clin Immunol 2005; 116: 1123-8

29. PCR - NS B/L Clari Reccurent infectionsin severe asthma PCR for Mycoplasma pneumoniae and Chlamydia pneumoniae PCR + p<0.05 3 FEV1 (litres) 2.5 2 B/L Clari Clarithromycin 500mg b.d. Kraft M et al: Chest 2002

30. Non- compliance with therapy • Psychological problembs • Missed appointments • Complexity of treatement • Lack of insight into illness • Inhalation technique Bel EH. Breathe 2006; 3:2; 129-139

31. İnhaler cihaza uyumsuzluk • Kullanımında hata % 14 - 74 • Kullanmak istememe % 31 Wilson A. Aerosol delivery system. In: Weiss EB, Stein M.(eds). Bronchial Asthma.1993:749-755 Osman LM et al. Thorax 1993, 48: 827-830

32. Severe - Difficult Asthma • Definition • Factors that could be preventing a normal response to asthma medication • Phenotypes • Risk Factors

33. Difficult asthma phenotypes • Unstable asthma (Brittle, Nocturnal, Premenstrual) • Poor response to treatment (Steroid-dependentasthma, Steroid-resistant asthma) • “Fixed” asthma

34. Type II:sudden attack from normally well controlledasthma Brittle asthma • Type I: wide variability in PEFdespite maximum therapy Ayres J, Miles J, Barnes PJ: Thorax 1998

35. Nocturnal Asthma • Nocturnal hyperreactivity with an increase 8-10 fold • High PEF variability Teraschima T: Chest 2002, Barnes PJ. ERJ 1998

36. Premenstrual asthma • Worsening of asthma ~7days premenstrually • Recovers with menstruation 0 1 2 3 4wk PEF Beynon H et al: Lancet 1988

37. Steroid dependent Systemic side effects Resistant Oral steroids Spectrum of steroid responsiveness Mild Moderate Severe Asthma control 100 400 1600 Inhaled steroids (µg)

38. Poor response to corticosteroids • Poor adherence • Wrong diagnosis • Dose too low • Increased metabolism • (e.g. carbamazepine, rifampicin) • Relative resistance / Complete resistance

39. Peak flow CORTICOSTEROID-RESISTANT 0 1 2 weeks Corticosteroid-resistant asthma Prednisolone 30-40 mg om Peak flow CORTICOSTEROID-SENSITIVE 0 1 2 weeks

40. Fixed asthma Pepe C et al, J Allergy Clin Immunology 2005;116:544-9)

41. Fixed Asthma Pepe C et al, J Allergy Clin Immunology 2005;116:544-9)

43. Fixed Asthma (r = −0.58, P < .05). Pepe C et al, J Allergy Clin Immunology 2005;116:544-9)

44. Severe - Difficult Asthma • Definition • Factors that could be preventing a normal response to asthma medication • Phenotypes • Risk Factors

45. ENFUMOSA Study: Risk factors • Female predominance • Reduced influence of atopy on asthma phenotypes • Exposure to aspirin as a risk factor • Association with increased body mass index, especially in women • A proportion of fixed airflow obstruction with increased residual volumes to total lung capacity ratio, suggesting the presence of structural changes Eur Res J 22:470-477 (2003)

46. Severe Asthma is associated with Increased Health Care Utilization p-value 0.02 0.78 0.01 0.02 0.04 0.71 0.62 0.03 Health care utilization parameters GP visits:  4 last yr Chest physician visits:  4 last yr Emergency visits:  2 last yr Exacerbations:  2 last yr * Hospital admissions:  2 last yr Maintenance oral corticosteoids Ever ICU admission Ever mechanical ventilation Cases (n=21) Non-cases (n=77) n 15 17 15 12/13 4 8 3 3 % 71.4 81.0 71.4 92.3 19.0 38.1 14.3 14.3 n 23 60 24 29/51 4 26 8 2 % 29.9 77.9 31.2 56.9 5.2 33.8 10.4 2.6 PARAPLUstudy, AJRCCM 2001;163:1093-1096

47. Associated Factors of Airflow Obstruction in Patients with Severe Asthma Adjusted OR* 7.7 3.9 3.3 1.9 1.7 1.7 1.5 1.4 1.3 0.8 (95% CI) (2.4 – 25.1) (1.2 – 13.0) (1.2 – 9.0) (0.8 – 4.8) (0.8 – 3.6) (0.8 – 3.7) (0.6 – 3.6) (0.5 – 4.0) (0.6 – 2.9) (0.4 – 1.9) Sputum eosinophils  2% PC20 histamine  1.0 mg/ml Adult-onset of asthma Exhaled NO  10 ppb Reversibility FEV1  9% Total IgE > 100 IE/ml Blood eosinophil count > 450.106/l Sputum neutrophils  64% Ex-smoker Atopic *OR adjusted for age, gender, and asthma duration PARAPLU-study, LUMC Leiden: AJRCCM 164:744-748 (2001)

48. Risk factors: FEV1 decline and Chlam P. «« 150 1 100 (ml/yr) Estimated loss in FEV 50 0 Cp- Cp+ Cp+ Cp+ Cp- Cp- Cp+ Cp- ______ ______ ______ ______ atopic non-atopic non-atopic atopic ______________ ______________ adult-onset childhood-onset PARAPLU-study, LUMC Leiden: JACI 2001;107:449-454

49. Risk Profile of Patients with Frequent Asthma Exacerbations Adjusted OR 10.8 6.9 4.9 3.7 3.4 2.8 1.9 0.7 0.6 0.6 0.5 0.4 0.2 (95% CI) 1.1 – 108.4 1.9 – 24.7 1.4 – 17.8 1.2 – 11.9 1.2 – 10.4 0.5 – 15.8 0.2 – 19.6 0.2 – 2.1 0.1 – 2.9 0.1 – 3.5 0.2 – 1.3 0.1 – 1.7 0.1 – 1.9 Psychological dysfunctioning Recurrent respiratory tract infections Gastro-oesophageal reflux Severe chronic sinus disease Obstructive sleep apnoea Hormonal influences Hyperthyroidism Occupational sensitisers Poor inhaler technique Food allergens Ongoing allergen exposure Relative immune deficiency Drugs PARAPLU-study, LUMC Leiden: JACI 2001;107:449-454

50. Severe - Difficult Asthma • Definition (!!) • Factors that could be preventing a normal response to asthma medication (many factors) • Phenotypes (Yes - Distinct Clinical Presentations) • Risk Factors (Multiple)