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

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Presentation on theme: "Management of chronic and allergic aspergillosis David W. Denning Director, National Aspergillosis Centre University Hospital South Manchester [Wythenshawe."— Presentation transcript:

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) 43 24* Total IgE 2462 525* FEV1 1.48 1.79* FVC 2.3 2.9 *p=0.04 Denning et al, Chest 1991; 35:1329 Only 1 patient failed – he had low itraconazole levels.

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

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

9 Itra Placebo 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) Stevens et al, New Engl J Med 2000; 342:756 Corticosteroid dependant ABPA with asthma Phase 1 - 200mg BID v placebo, 16 weeks Phase II - 200mg daily in all patients, 16 weeks Number needed to treat = 3.58 Overall 17/28 (61%) response rate

10 Randomised trial of itraconazole in ABPA Wark et al, J Clin All Immunol 2003; 111:952 ABPA with asthma, n = 29 Phase 1 - 200mg 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

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

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

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

14 Antifungal treatment of severe asthma with fungal sensitisation (SAFS) Ward et al, J Allergy Clin Immunol 1999;104:541; 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

15 Proof of concept RCT of antifungal Rx in SAFS Denning et al, Am J Resp Crit Care Med 2009; 179:11 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

16 Proof of concept RCT of antifungal Rx in SAFS - endpoints Juniper et al, Thorax 1992;47:76. 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

17 Proof of concept RCT of antifungal Rx in SAFS - study plan Denning et al, Am J Resp Crit Care Med 2009; 179:11 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

18 Denning et al, Am J Resp Crit Care Med 2009; 179:11 Baseline demographics - asthma Mean (range) or % (no.) Active (n=29) Placebo (n=29) Gender (Male)48% (14) Age49.2 (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 10 9 )/L24% (7)43% (12) No. of hospitalisations last 12 months (>1) 39%17%

19 Proof of concept RCT of antifungal Rx in SAFS – key results Denning et al, Am J Resp Crit Care Med 2009; 179:11 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

20 Proof of concept RCT of antifungal Rx in SAFS – outcomes at 32 weeks MITT Denning et al, Am J Resp Crit Care Med 2009; 179:11 Mean (95% CI) or % (n)P-value ActivePlacebo 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) NS 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) NS Number needed to treat = 3.22

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

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

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 P= 0.013

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

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 DiseaseAntifungal, duration Benefit?Author, year ABPANatamycin inh, 52 wks NoCurrie, 1990 ABPAItraconazole, 32 wks YesStevens, 2000 ABPAItraconazole, 16 wks YesWark, 2003 Trichophyton asthmaFluconazole, 20 wksYesWard, 1999 SAFSItraconazole, 32 wks YesDenning, 2009

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. TreatmentNo of coursesStable or improved (%) Treatment failure / progression Toxicity Itraconazole primary therapy 1712 (71)53 Voriconazole17 9/11 (82)212 Amphotericin B IV 119 (82)27 Gamma IFN with itraconazole 3303 Itraconazole maintenance after AmB IV 6600

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

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

34 Effect of voriconazole on CPA Jain & Denning J Infect 2006; 52:e133-7 16 patients, all failing or intolerant of itraconazole 5 patients were able to take >3 months Rx Symptom response Cough3/11 (27%) sputum6/11 (55%) chest pain4/10 (40%) breathlessness4/11 (36%) well being6/11 (55%) weight4/10 (40%)

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 Camuset et al, Chest 2007:131:1435 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)

38 Time to initial response with posaconazole therapy 6 months 12 months Mean 95% confidence interval 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 Al-shair et al, AAA 2012 poster Clinical Less tired Better appetite Weight gain Less coughing Less productive Less coughing of blood Generally feeling better

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 Kohno et al. J Infect Dis 2010;61:410 Micafungin 150-300mg/d versus voriconazole 12 8mg/Kg/d 107 patients with CPA 2-4 weeks treatment

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

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

47 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

48 Dry microspheres, made up in saline and radiocontrast material

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

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

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

52 Upper right bronchial artery embolisation PrePost

53 Bronchial artery embolisation (2) PrePost

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

55 Bronchial artery embolisation (3) PrePost

56 Intercostal artery embolisation PrePost

57 Intercostal artery embolisation (2) PrePost

58 Thyrocervical axis artery embolisation PrePost

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

63

64 Bronchial Embolisation avoiding the anterior spinal artery

65 Chronic cavitary pulmonary aspergillosis an example of radiographic failure Patient SS April 2004 www.aspergillus.man.ac.uk 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 www.aspergillus.org.uk

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

69 Patient RW September 1992 Chronic cavitary pulmonary aspergillosis www.aspergillus.man.ac.uk 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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