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

10 Randomised trial of itraconazole in ABPA
ABPA with asthma, n = 29 Phase mg BID v placebo, 16 weeks Primary outcome measure – Sputum eosinophil count Eosinophilic cationic protein 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)

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
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
Mean (range) or % (no.) Active (n=29) Placebo Gender (Male) 48% (14) Age 49.2 (18,79) 51.7 (19,76) Severity of asthma (BTS) (>4) 3% (1) 11% (3) Baseline total serum IgE (IU/L) 212 (24,820) 245 (36,990) Baseline eosinophilia (>0.4x 109)/L 24% (7) 43% (12) No. of hospitalisations last 12 months (>1) 39% 17% Denning et al, Am J Resp Crit Care Med 2009; 179:11

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

20 Number needed to treat = 3.22
Proof of concept RCT of antifungal Rx in SAFS – outcomes at 32 weeks MITT Mean (95% CI) or % (n) P-value Active Placebo Change in AQLQ score +0.85 (0.28, 1.41) -0.01 (-0.43, 0.42) 0.014 Improvement in AQLQ score of >0.75 54% (14) 18% (5) 0.013 Percentage change in total IgE (IU/L) -27% (-14%, -38%) +12% (-5%, +31%) 0.001 Change in FEV1 (L/min) -0.22 (-0.56, 0.11) -0.02 (-0.16, 0.11) NS Change in FEV1 (% predicted) -3.66 (-9.39, 2.08) 0.13 (-3.67, 3.93) Change in average PEFR (am) 20.8 (3.5, 38.1) -5.5 (-21.6, 10.7) 0.028 Change in average PEFR (pm) 16.8 (1.5, 35.2) 8.9 (-33.9, 51.8) 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
Denning et al, Am J Resp Crit Care Med 2009; 179:11

22 RCT of anti-IgE (omalizumab) v. placebo, moderate and severe asthma
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
Denning et al, Am J Resp Crit Care Med 2009; 179:11

24 Relationship of itraconazole drug level to response
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
Disease Antifungal, duration Benefit? Author, year ABPA Natamycin inh, 52 wks No Currie, 1990 Itraconazole, 32 wks Yes Stevens, 2000 Itraconazole, 16 wks Wark, 2003 “Trichophyton” asthma Fluconazole, 20 wks Ward, 1999 SAFS Denning, 2009

29 Chronic Pulmonary Aspergillosis

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

31 Treatment failure / progression
Treatment of chronic cavitary pulmonary aspergillosis Treatment No of courses Stable or improved (%) Treatment failure / progression Toxicity Itraconazole primary therapy 17 12 (71) 5 3 Voriconazole 9/11 (82) 2 12 Amphotericin B IV 11 9 (82) 7 Gamma IFN with itraconazole Itraconazole maintenance after AmB IV 6 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 itraconazole 5 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 aspergillosis 15 with chronic necrotising pulmonary aspergillosis 13/24 (54%) primary therapy with voriconazole 3 intolerant of voriconazole Median duration of Rx 6.4 mos (4-36) Camuset et al, Chest 2007:131:1435

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

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 mg/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 43

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 45

46 Technique 1 Must lie flat Femoral access Flush aortogram or pre-op CT
optimise respiratory function oxygen NIPPI Consider anaesthetic support Femoral access Flush aortogram or pre-op CT 4F systems Microcatheters 46

47 Technique 2 Embolic agents Embolise bronchial arteries
PVA/ microspheres Avoid liquids Avoid coils Embolise bronchial arteries Look for accessory feeders if recurrent Consider closure device May need multiple procedures 47

48 Dry microspheres, made up in saline and radiocontrast material
48

49 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

50 Patient PA April 2010 Jan 2010 Nov 2010 Posaconazole Rx Nov 2009
Stopped posaconazole Nov 2008 50

51 Patient PA Nov 2010 Aug 2011 Dec 2011 Stopped posaconazole No therapy
51

52 Upper right bronchial artery embolisation
Pre Post

53 Bronchial artery embolisation (2)
Pre Post

54 Angiographic signs of bronchial bleeding
Direct (rare) Extravasation of contrast Thrombosis of branch vessels Indirect Hypertrophy of parent vessel Neovascularisation Aneurysm formation Systemic to pulmonary shunting 54

55 Bronchial artery embolisation (3)
Pre Post

56 Intercostal artery embolisation
Pre Post

57 Intercostal artery embolisation (2)
Pre Post

58 Thyrocervical axis artery embolisation
Pre Post

59 Internal mammary artery embolisation
Pre Note the large coil inferiorly in the internal mammary artery which prevents embolisation of the coeliac axis inadvertently Post

60 Lateral thoracic artery embolisation
Pre Note the smaller catheter inside the larger one Post

61 Subclavian artery embolisation
Pre Note the second catheter within the lumen of the R subclavian artery Post

62 Bronchial Embolisation - Complications
Minor - common fever pleuritic chest pain dysphagia Major - rare bronchial infarction bronchial stenosis Broncho oesophageal fistula paraplegia Chemotoxic embolic TIA/stroke 62

63 63

64 Bronchial Embolisation avoiding the anterior spinal artery
64

65 Chronic cavitary pulmonary aspergillosis an example of radiographic failure
Patient SS April 2004 Patient SS July 2004, despite receiving itraconazole for 3 months

66 Stopping treatment after good response in CPA?

67 Chronic cavitary pulmonary aspergillosis
Patient RW June 2002 Stable, asymptomatic, normal inflammatory markers, just detectable Aspergillus precipitins Itraconazole stopped after 5 years

68 Chronic cavitary pulmonary aspergillosis - relapse
Patient RW January 2003 Marked change, with new cough, weight loss, ↑CRP/ESR and ↑Aspergillus precipitins Itraconazole restarted

69 Chronic cavitary pulmonary aspergillosis
Patient RW September 1992 Patient RW June 2003

70 CPA treatment - principles
Important defects in innate immunity so long term (i.e. life-long) antifungal treatment, if possible Some patients appear not to progress, but should to be kept under observation, as progression may be subclinical Minimise other causes of lung infection with immunisation and antibiotics Itraconazole, voriconazole and posaconazole all effective, but adverse events Amphotericin B useful for oral azole therapy and failure Gamma IFN helpful in some cases Monitor for azole resistance


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