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Management of chronic and allergic aspergillosis

Management of chronic and allergic aspergillosis. David W. Denning Director, National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital] The University of Manchester. Antifungal treatments. Treatments available. Oral Itraconazole capsules ( 3+ formulations)

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Management of chronic and allergic aspergillosis

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  1. Management of chronic and allergic aspergillosis David W. Denning Director, National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital] The University of Manchester

  2. Antifungal treatments

  3. Treatments available Oral Itraconazole capsules ( 3+ formulations) Itraconazole solution Voriconazole capsules Voriconazole solution Posaconazole solution Intravenous AmBisome Voriconazole Micafungin Caspofungin Local Intracavitary AmB Immune therapy Gamma interferon (subcutaneous injections) Prednisolone or other steroids

  4. Treatment

  5. Allergic Bronchopulmonary Aspergillosis

  6. Open trial of itraconazole in ABPA - 1991 BeforeAfter Prednisone (mg/d) 43 24* Total IgE 2462 525* FEV1 1.48 1.79* FVC 2.3 2.9 *p=0.04 Only 1 patient failed – he had low itraconazole levels. Denning et al, Chest 1991; 35:1329

  7. Corticosteroid dependant ABPA with asthma Phase 1 - 200mg BID v placebo, 16 weeks Phase II - 200mg daily in all patients, 16 weeks Stevens et al, New Engl J Med 2000; 342:756

  8. Randomised trial of itraconazole in ABPA Stevens et al, New Engl J Med 2000; 342:756

  9. Overall 17/28 (61%) response rate Randomised trial of itraconazole in ABPA Corticosteroid dependant ABPA with asthma Phase 1 - 200mg BID v placebo, 16 weeks Phase II - 200mg daily in all patients, 16 weeks ItraPlacebo then Itra Phase 1 Overall response 13/28 (46%) 5/27 (19%) p = 0.04 Phase 2 No prior response 4/13 (31%) 8/20 (40%) NS (n=33) Number needed to treat = 3.58 Stevens et al, New Engl J Med 2000; 342:756

  10. Eosinophilic cationic protein Randomised trial of itraconazole in ABPA ABPA with asthma, n = 29 Phase 1 - 200mg BID v placebo, 16 weeks Primary outcome measure – Sputum eosinophil count P < 0.01 Reduced exacerbation rate No change in FEV1 or PEF Wark et al, J Clin All Immunol 2003; 111:952

  11. Retrospective comparison of antifungal treatment of SAFS with ABPA 22 patients with SAFS were compared with 11 with ABPA Pasquallotto et al, Resp Med 2009 In press

  12. Severe Asthma and Fungal Sensitisation (SAFS) www.emphysema-copd.co.uk

  13. Severe asthma Bel EH , Severe asthma. Breath magazine Dec 2006

  14. Antifungal treatment of severe asthma with fungal sensitisation (SAFS) • 11 patients with Trichophyton skin test allergy and moderate/severe asthma, • Rx with fluconazole or placebo for 5 months, then all received fluconazole. • Fluconazole v. placebo at 5 months • Bronchial hypersensitivity reduced (p = 0.012) • Steroid requirements reduced (p= 0.01) • Peak flow increased in 9/11 at 10 months Ward et al, J Allergy Clin Immunol 1999;104:541;

  15. Proof of concept RCT of antifungal Rx in SAFS • Inclusion criteria • Severe asthma [BTS 4 or 5] (ie high dose inhaled steroids, continuous oral steroids for >6 mo, or 4 courses of high dose oral/IV steroids in last 12 months, or 6 courses in last 24 mo. • + • Fungal sensitisation (RAST or skin test +ve) to Aspergillus, Cladosporium, Alternaria, Penicillium, Candida, Trichophyton and/or Botrytis • Exclusion criteria • Not ABPA (IgE <1000IU/mL) + -ve Aspergillus precipitins • Recurrent bacterial chest infections (6 weekly) • Prior azole therapy • Cardiac failure • LFTs >3x ULN Denning et al, Am J Resp Crit Care Med 2009; 179:11

  16. Proof of concept RCT of antifungal Rx in SAFS - endpoints • Primary endpoint • Improvement in score of Asthma Quality of Life Questionnaire (AQLQ) • Secondary endpoints • Improvement in weekly peak flow • FEV1 at 4, 8 and 12 months • Exacerbation rate (both total and steroid requiring) • Total IgE • Rhinitis score • Adrenal suppression indices Juniper et al, Thorax 1992;47:76.

  17. Proof of concept RCT of antifungal Rx in SAFS - study plan Study plan Randomised to itraconazole capsules (200mg BID) or placebo for 8 months (concealed by over-encapsulating) Assessments are regular intervals, including scores, respiratory function, blinded itraconazole levels, LFTs FU at 4 months post treatment 108 patients planned – 58 enrolled Denning et al, Am J Resp Crit Care Med 2009; 179:11

  18. Baseline demographics - asthma Denning et al, Am J Resp Crit Care Med 2009; 179:11

  19. Patients enrolled & randomised N = 58 Placebo N = 29 Active (itraconazole) N = 29 Withdrawal in <4 weeks Active N= 3 Placebo N=1 (p=0.60) MITT analysis set (placebo) N =28 MITT analysis set (active) N =26 P=0.014 AQLQ ∆ = 0.82 Withdrawal 4-32 weeks Active N= 8 Placebo N=5 (p=0.25) Per protocol analysis set (placebo) N=23 Per protocol analysis set (active) N= 18 P=0.002 AQLQ ∆ = 1.18 Proof of concept RCT of antifungal Rx in SAFS – key results Denning et al, Am J Resp Crit Care Med 2009; 179:11

  20. Proof of concept RCT of antifungal Rx in SAFS – outcomes at 32 weeks MITT Number needed to treat = 3.22 Denning et al, Am J Resp Crit Care Med 2009; 179:11

  21. Proof of concept RCT of antifungal Rx in SAFS – AQLQ change P= 0.014 Denning et al, Am J Resp Crit Care Med 2009; 179:11

  22. RCT of anti-IgE (omalizumab) v. placebo, moderate and severe asthma omalizumab Improvement in AQLQ ∆ = ~0.4 placebo Buhl et al Eur Resp J 2002;20:1088

  23. Proof of concept RCT of antifungal Rx in SAFS – improvement in rhinitis P= 0.013 Denning et al, Am J Resp Crit Care Med 2009; 179:11

  24. Relationship of itraconazole drug level to response P= 0.22 Denning et al, Am J Resp Crit Care Med 2009; 179:11

  25. Itraconazole inhaled steroid interaction • Itraconazole reduces the metabolism of inhaled steroids • Documented for beclomethasone, fluticasone • Ciclosenide probably not • No interaction with prednisolone, dexamethasone, hydrocortisone • Reduces metabolism of methylprednisolone • [Voriconazole reduces prednisolone metabolism, but probably no interaction with inhaled steroid]

  26. Itraconazole inhaled steroid interaction in 50% of patients, with complete suppression of cortisol AQLQ improvements identical in those with this interaction and those without Denning et al, Am J Resp Crit Care Med 2009; 179:11

  27. Management of inhaled steroids in patients on itraconazole • Start itraconazole without changing steroid doses • At one month, attempt steroid reduction, first prednisolone, then inhaled steroids + check random cortisol • Reduce inhaled steroid by 50% initially for ~1 month. • At month 2, if asthma well (possibly better) controlled, attempt a second inhaled steroid reduction. If low cortisol, do short synacthen test (timing in day not important – increment the key result) • If adrenals functional, and asthma well controlled, consider switch to ciclosonide • If poor adrenal reserve, assess total steroid needs, and ensure patient can be supported with oral steroids if unwell

  28. Randomised studies of antifungals and ABPA and/or asthma

  29. Chronic Pulmonary Aspergillosis

  30. Antifungal therapy IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

  31. Treatment of chronic cavitary pulmonary aspergillosis Denning DW et al, Clin Infect Dis 2003; 37:S265; Jain & Denning. J Infect 2006;52:e133-7.

  32. Felton, Clin Infect Dis 2010; 51:1383.

  33. Impact of voriconazole in real life weeks Nivoix et al, Clin Infect Dis 2008;47:1176

  34. Effect of voriconazole on CPA 16 patients, all failing or intolerant of itraconazole5 patients were able to take >3 months Rx Symptom response Cough 3/11 (27%) sputum 6/11 (55%)  chest pain 4/10 (40%)  breathlessness 4/11 (36%)  well being 6/11 (55%)  weight 4/10 (40%) Jain & Denning J Infect 2006; 52:e133-7

  35. Parameters of response in CPA (with voriconazole) Jain & Denning J Infect 2006; 52:e133-7

  36. CPA and voriconazole Rx Sambatakou et al, Am J Med 2006:119:527.e17-24

  37. CPA and voriconazole Rx 9 patients with chronic cavitary pulmonary aspergillosis15 with chronic necrotising pulmonary aspergillosis13/24 (54%) primary therapy with voriconazole3 intolerant of voriconazoleMedian duration of Rx 6.4 mos (4-36) Camuset et al, Chest 2007:131:1435

  38. Time to initial response with posaconazole therapy Mean 95% confidence interval 6 months 12 months Felton et al. Clin Infect Dis 2010. In press.

  39. Judging response to treatment Clinical Less tired Better appetite Weight gain Less coughing Less productive Less coughing of blood Generally feeling better

  40. Judging response to treatment Clinical Less tired Better appetite Weight gain Less coughing Less productive Less coughing of blood Generally feeling better Al-shair et al, AAA 2012 poster

  41. Judging response to treatment Clinical Less tired Better appetite Weight gain Less coughing Less productive Less coughing of blood Generally feeling better Tests Plasma viscosity and C reactive protein (CRP) falling Aspergillus precipitins falling (slow) Total IgE falling Chest Xray shows no new cavities, and eventually thin walled cavities

  42. Randomised controlled open comparison of micafungin and voriconazole for chronic pulmonary aspergillosis Micafungin 150-300mg/d versus voriconazole 12 ➞ 8mg/Kg/d 107 patients with CPA 2-4 weeks treatment Kohno et al. J Infect Dis 2010;61:410

  43. Chronic cavitary pulmonary aspergillosis (CCPA) – coughing up blood (haemoptysis) Wythenshawe Hospital

  44. CPA and haemoptysis • Minor haemoptysis common • Manageable with tranexamic acid orally • Bronchial embolisation a good option, if vessel can be embolised & patient can lie flat for 2-3 hours

  45. Technique 1 Must lie flat optimise respiratory function oxygen NIPPI Consider anaesthetic support Femoral access Flush aortogram or pre-op CT 4F systems Microcatheters

  46. Technique 2 Embolic agents PVA/ microspheres Avoid liquids Avoid coils Embolise bronchial arteries Look for accessory feeders if recurrent Consider closure device May need multiple procedures

  47. Dry microspheres, made up in saline and radiocontrast material

  48. Results of bronchial artery embolisation 50% patients have multiple blood supply Control of haemorrhage in >90% patients 30-50% rebleed rate at 3 years Mean rebleed free interval 9 months Serisli et al Int Angio 2008;27:319-28

  49. Patient PA Nov 2008 April 2010 Posaconazole Rx Jan 2010 Posaconazole Rx Nov 2010 Stopped posaconazole Nov 2009

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