1. Workshop: «Difficult-to-treat»-asthma in children Urs Frey, MD PhD University Children’s Hospital Basel, Switzerland

2. Seite 2 Eur Respir J. 2014 Feb;43(2):343-73

3. Special aspects in childhood asthma Lung development, side effects of treatment on development Age dependent phenotypes → focus on schoolage Differences in drug response, phenotyp-specific treatment Different differential diagnosis Different degrees of co-operation, therapy adherence, understanding of disease Less published evidence Seite 3

4. Content Definition (difficult asthma vs. severe therapy resistant asthma) Phenotypes and endotypes Related biomarkers of severe asthma Related diagnostics Stability of phenotypes and monitoring of severe asthma Therapy of childhood severe asthma Summary, clinical diagnostic algorithm Seite 4

5. Definition: Severe asthma (>6 yrs) Despite Medicationdespite high doses ICS+ LABA + LTRA + low dose Theophylline (or failed trials of these add-on therapies, or >50% OCS) for the previous year Poor symptom control or –Uncontrolled: ACQ consistently >1.5, ACT<19 (not well controlled by NAEPP/GINA) –Controlled: that worsens on tapering these high doses Frequent severe exacerbations or –2 or more bursts of systemic CS (>3days) in the previous years Serious exacerbations or –One PICU visit or mechanical ventilation in the last year –At least one hospitalisation Airflow limitation –FEV1 < 80% after SABA withhold (in the face of FEV1/FVC) Seite 5 ICS (  g)age 6-12 age>12 Beclomethason 800 dp1200 Budenoside 8001200 Ciclosonide 320 640 Flunisolide12502000 Mometasone 500 880 Triamcinolone12002000

6. Definition: Severe asthma (>6 yrs) Despite Medicationdespite high doses ICS+ LABA + LTRA + low dose Theophylline (or failed trials of these add-on therapies, or >50% OCS) for the previous year Poor symptom control or –Uncontrolled: ACQ consistently >1.5, ACT<19 (not well controlled by NAEPP/GINA) –Controlled: that worsens on tapering these high doses Frequent severe exacerbations or –2 or more bursts of systemic CS (>3days) in the previous years Serious exacerbations or –One PICU visit or mechanical ventilation in the last year –At least one hospitalisation Airflow limitation –FEV1 < 80% after SABA withhold (in the face of FEV1/FVC) Seite 6

7. Diagnostics of problematic severe asthma Seite 7 Entry label: problematic severe asthma Consider other diagnosis VCD, GoeR, CF, PCD, CLD, Malformations, others Assess co-morbidities Obesity, rhino-sinusitis, OSAS, GER, dysfunctional breathing, food allergy Difficult asthmaTherapy resistant severe asthma define phenotype based on: therapy adherence, environmental triggers (allergens, ETS, pollutants), psycho-social factors Bush, Frey& Teague Eur Resp Monograph 2011: 51; 59-81 Dysfunctional breathing Vocal cord dysfunction Bronchiolitis, CLD Reflux, Microaspiration Cystic fibrosis Immune deficiencies Primary ciliary dyskinesia Airway Malformation/ Compression Tumors Congenital heat disease Interstitial lung disease Obesity Psychosocial factors Dysfunctional breathing Smoking Hormonal factors GOe-Reflux Drugs: NSAID

8. Phenotypes of severe childhood asthma (>6 yrs) Cluster analysis based on clinical characteristics and lung function (SARP) AdultsChildren Mild early onset atopic asthmaEarly onset atopic asthma (Lufu=n) Moderate early onset atopic asthma Early onset atopic asthma (Lufu=reduced) Severe early onset atopic asthma Obese (female) late onset (red. FEV 1)Early onset asthma (Lufu=markedly reduced) Late onset, less atopic, less reversible Late onset asthma (Lufu=n) obstruction Seite 8 Fitzpatrick et al. SARP JACI 2011: 127; 362-89. N=161

9. Endotypes of severe childhood asthma Inflammatory patterns -Eosinophilia /neutrophilia/mixed cellularity changing over time -Evidence of TH 1 versus TH 2 pattern controversal = ǂ = Eosinophilia -High FeNO -Role of Vit D deficiency? -Role of specific cytokines and chemokines: IL6, GRO, RANTES,IL12,IF ,IL10, IL33 -Reduced I interferon-  and type III interferon-  induction by rhinoviruses -Impaired alveolar macrophage phagocytosis Seite 9 ERS/ATS Diagnostics FeNO (DD: CF, PCD) IgE, IgG,M,A Blood eosinophils Skin Prick BAL, induced sputum not generally recommended

10. Endotypes of severe childhood asthma Structural features and remodelling Seite 10 Epithelial damage Increased areas of mucus glands Higher number of fibroblasts and collagen deposition Reticular basement membrane thickening in difficult asthma (Eos) Evidence of angiogenesis Particularly severe asthma with persistent obstructive pattern shows increased smooth muscle Airway smooth muscle content related to Vit D levels Payne DN et al. AJRCCM 2003; 167: 78-82 Benayoun et al. AJRCCM 2003; 167: 1360-68 Barbato A et al. AJRCCM 2006; 174: 975-81 ERS/ATS diagnostics Chest X Ray HR-CT not generally recommended Biopsy not generally recommended Alternative diagnosis? Saglani et al. AJRCCM 2005; 171; 722-27 Tillie-Leblond Allergy 2008; 63: 553-41 Gupta et al. AJRCCM 2011:184:1342-49

11. Endotypes of severe childhood asthma Functional abnormalities - Variable versus persistent airway obstruction - Missing response to bronchodilators (FEV 1 < -1.96 Z-s) - Missing response to corticosteroids - No clear relation to BHR - Reduced fluctuations in lung function Seite 11 ERS/ATS Diagnostics Lung function Bronchodilator response Steroid response BHR not generally recommended PEF/FEV1 monitoring

12. Testing steroid response in children with difficult asthma (DA) Seite 12 89 severe asthmatic children (mean age 11.6 SD 2.8 yrs) 40 mg/day OCS for 14 days or 80 mg triamcinolone i.m. Assess clinical and functional improvement Symptoms FEV1 BDR FeNO Full response: 11% all parameters Partial response: 80%1-3 parameters No response: 9%none Bossley CJ et al. Eur Resp J 2009; 34: 1052-59.

13. Diagnostics of problematic severe asthma Seite 13 Bush, Frey& Teague Eur Resp Monograph 2011: 51; 59-81 Difficult asthma Regular asthma treatment: optimise concomitant factors Therapy resistant severe asthma Specify mechanism: Airway Inflammation (discordance, pattern, distribution) Steroid responsiveness Lung mechanics, BR (Persistent flow limitation) (Phenotype specific) treatment Diagnostic tests: Bronchoscopy, BAL, Biopsy, induced Sputum, FENO, IgE, SkinPrick Steroid trial Lung function, BDR PEF/FEV1 monitoring

14. Monitoring adherence, a key factor of the therapy of problematic severe asthma Important role of nurse led home visits Improvement of adherence, parental coping Medication changed, inhaler technique changed Alterations of home environment (obvious allergic triggers) Psychosocial counseling Smoking cessation Seite 14 Bracken et al. Arch Dis Child 2009: 94: 780-84. Sales et al. J. Ped. Psychol 2008; 33: 208-19. ERS/ATS All recommended

15. Stability of Phenotype: Monitoring of severe asthma in children Seite 15 Sears MR et al. N Engl J Med 2003;349:1414-22 Persistence of symptoms Tracking of lung function over time Changing Inflammatory pattern Fleming et al. Thorax 2012: 67; 675-81. Fleming et al. AJRCCM 2013: 188: 401-402.

16. Monitoring severe asthma in children Seite 16 Bush, Frey& Teague Eur Resp Monograph 2011: 51; 59-81 Difficult asthma Regular asthma treatment: optimise concomitant factors Therapy resistant severe asthma (Phenotype specific) treatment Monitoring : Control, exacerbation risk, functional development, guide therapy Controlled severe asthma Adapt treatment NO RESPONSE RESPONSE

17. Monitoring severe asthma in children Guidance of therapy – FEV1 or PEF unknown (improves adherence?) – BHR unknown – Sputum Eosinophils not stable – FeNO only trend benefit (mainly data from non severe asthma) Seite 17 Flemming et al. Thorax 2012 67: 675-81. Flemming et al AJRCCM 2013; 188: 400-2. ERS/ATS (treatment guidance) Symptoms, QoL, Lufu FeNO not recommended Induced sputum not recommended Zacharasiewicz et al. AJRCCM 2005; 177:1077-82 Pinijenburg et al. AJRCCM 2005: 172:831-36 De Jongste et al. AJURCCM 2009 15:179(2): 93-7 Szefler. et al Lancet. 2008 ;372(9643):1065-72 Monitoring of functional loss over time  Lung function

18. Severe asthma therapy beyond Guidelines Does the child need ‘beyond guidelines therapy’ at all? Environmental tobacco exposure reduction and allergy avoidance Standard therapy at unusual doses? Beyond guideline therapies: – Evidence for Omalizumab (anti-Ig-E) – Other therapies low evidence – Phenotype specific Seite 18

19. Phenotype specific treatment in children Severe allergic asthma –High eosinophils, high IgE Eosinophilic asthma –High IgE, recurrent exacerbations Neutrophilic asthma (rare, consider DD) –Chronic airflow obstruction – Bacterial infections Chronic airflow obstruction –Remodelling of airway walls Recurrent exacerbations –Sputum Eos, reduced ICS response Corticosteroid insensitivity – Sputum neutrophils high – Reduced ICS response Seite 19 ERS/ATS (some) Anti Ig-E (Omalizumab) ERS/ATS (very low) Anti-LTB4 Macrolides ERS/ATS (low) Anti Ig-E (Omalizumab) ERS/ATS (very low) Theophilline Macrolides

20. Summary Algorithm Severe asthma in children Seite 20 Childhood severe asthma more unstable phenotype Different from adults Effect on development Close monitoring and repetitive re-evaluation Important role of leading doctors and nurses team Bush, Frey& Teague Eur Resp Monograph, 2011:51; 59-81

21. Reserve slides Seite 21

22. Seite 22 DA STRA Sharples J et al. Eur Respir J. 2012; 40: 264-7 Difficult asthmaSTRA

23. Diagnostics: assess lung function ERS 2013 - Severe asthma in children - Frey Seite 23 Difficult asthmatics showed:  Higher FEV 1 % predicted  Less bronchodilator reversibility  Lower FENO DA: Difficult asthma STRA: Severe therapy resistant asthma CAVE: children with severe asthma can have normal lung function Bracken et al. Arch Dis Child 2009; 94: 780-4 Slide with permission from Prof A. Bush

24. Severe asthma therapy beyond guidelines: Anti-IgE: Omalizumab After all efforts to reduce burden of allergen exposure Good short term safety Consider local and systemic allergic reactions Thrombocytopenia Effect on symptoms and QoL, little effect on Lufu Dosing according to Ig-E levels and weight, 2-4 weekly max 16 wks Mainly relevant for school age Further studies are needed for aspects of long term safety Seite 24 NEJM 2011; 364: 1005-15 Chest 2011; 139: 28-35 ERS/ATS recommended Allergy 2005; 60: 309-16 Clin Pediatr 2009; 48: 859-65 JACI 2009; 124: 1210-6

25. Severe asthma therapy beyond guidelines: Antifungals (Itraconazole) in SAFS Seite 25 Recommendation in adults (very low evidence) Only in ABPA with recurrent exacerbations Do not use if no ABPA, but just sensitisation No evidence in children: (isolated case reports) Current recommendations adapted from adult criteria but no IgE Criteria ERS/ATS (very low) Antifungals only used in special situations In specialised centres Side effects Hepatotoxicity

26. Others: no to low evidence in children Macrolide antibiotics – little published evidence – Good safety profile – Known immun-modulatory properties –‘Neutrophilic’ asthma? – DD: Atypical infections? Immunosuppressives –Methotrexate – small open trials –Cyclosporin – one case series –Azathioprine – no published evidence Immunoglobulin infusions –No trial data Subcutaneous terbutaline infusion –No systematic evidence Seite 26

27. Severe asthma therapy beyond guidelines: Macrolides and LTRAs as ICS sparing agents Seite 27 Time to inadequate asthma control after sequential budenoside reduction Strunk et al. JACI 2008; 122: 1138-44. Large confidence intervals (N= 55 randomised school children with moderate to severe asthma)