Management of chronic and allergic aspergillosis

David W. DenningDirector, National Aspergillosis CentreUniversity Hospital South Manchester

[Wythenshawe Hospital]The University of Manchester

Antifungal treatments

Treatments availableOralItraconazole capsules ( 3+ formulations)Itraconazole solutionVoriconazole capsulesVoriconazole solutionPosaconazole solution

IntravenousAmBisomeVoriconazoleMicafunginCaspofungin

LocalIntracavitary AmB

Immune therapyGamma interferon (subcutaneous injections)Prednisolone or other steroids

Treatment

Allergic Bronchopulmonary Aspergillosis

Open trial of itraconazole in ABPA - 1991

Before AfterPrednisone (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.

Stevens et al, New Engl J Med 2000; 342:756

Corticosteroid dependant ABPA with asthmaPhase 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

Randomised trial of itraconazole in ABPA

Randomised trial of itraconazole in ABPA

Itra Placebo then ItraPhase 1Overall response 13/28 (46%) 5/27 (19%) p = 0.04Phase 2No 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 asthmaPhase 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

Randomised trial of itraconazole in ABPA

Wark et al, J Clin All Immunol 2003; 111:952

ABPA with asthma, n = 29Phase 1 - 200mg BID v placebo, 16 weeks

Primary outcome measure – Sputum eosinophil count

Eo

sin

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P < 0.01

Reduced exacerbation rateNo change in FEV1 or PEF

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

Severe Asthma and Fungal Sensitisation (SAFS)

www.emphysema-copd.co.uk

Bel EH , Severe asthma. Breath magazine Dec 2006

Severe asthma

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

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

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

Proof of concept RCT of antifungal Rx in SAFS - study plan

Denning et al, Am J Resp Crit Care Med 2009; 179:11

Study planRandomised 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

Baseline demographics - asthma

  Mean (range) or % (no.)

Active(n=29)

Placebo(n=29)

Gender (Male) 48% (14) 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%

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=0.014AQLQ ∆ = 0.82

P=0.002AQLQ ∆ = 1.18

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

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)

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

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

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

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

Relationship of itraconazole drug level to response

Denning et al, Am J Resp Crit Care Med 2009; 179:11

P= 0.22

302520151050

mean itraconazole

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AQLQ change vs itraconazole level

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]

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

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

Randomised studies of antifungals and ABPA and/or

asthmaDisease Antifungal,

durationBenefit? Author, year

ABPA Natamycin inh, 52 wks

No Currie, 1990

ABPA Itraconazole, 32 wks

Yes Stevens, 2000

ABPA Itraconazole, 16 wks

Yes Wark, 2003

“Trichophyton” asthma Fluconazole, 20 wks

Yes Ward, 1999

SAFS Itraconazole, 32 wks

Yes Denning, 2009

Chronic Pulmonary Aspergillosis

Antifungal therapy

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

Treatment of chronic cavitary pulmonary aspergillosis

Denning DW et al, Clin Infect Dis 2003; 37:S265; Jain & Denning. J Infect 2006;52:e133-7.

Treatment No of courses Stable or improved (%)

Treatment failure /

progression

Toxicity

Itraconazole primary therapy

17 12 (71) 5 3

Voriconazole 17 9/11 (82) 2 12

Amphotericin B IV

11 9 (82) 2 7

Gamma IFN with itraconazole

3 3 0 3

Itraconazole maintenance after AmB IV

6 6 0 0

Felton, Clin Infect Dis 2010; 51:1383.

Nivoix et al, Clin Infect Dis 2008;47:1176

Impact of voriconazole in real life

weeks

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 RxSymptom 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%)

Parameters of response in CPA (with voriconazole)

Jain & Denning J Infect 2006; 52:e133-7

CPA and voriconazole Rx

Sambatakou et al, Am J Med 2006:119:527.e17-24

CPA and voriconazole Rx

Camuset et al, Chest 2007:131:1435

9 patients with chronic cavitary pulmonary aspergillosis15 with chronic necrotising pulmonary aspergillosis

13/24 (54%) primary therapy with voriconazole3 intolerant of voriconazoleMedian duration of Rx 6.4 mos (4-36)

Time to initial response with posaconazole therapy

6 months 12 months

Mean

95% confidence interval

Felton et al. Clin Infect Dis 2010. In press.

Judging response to treatmentClinicalLess tiredBetter appetiteWeight gainLess coughingLess productiveLess coughing of bloodGenerally feeling better

Judging response to treatment

Al-shair et al, AAA 2012 poster

ClinicalLess tiredBetter appetiteWeight gainLess coughingLess productiveLess coughing of bloodGenerally feeling better

Judging response to treatmentClinicalLess tiredBetter appetiteWeight gainLess coughingLess productiveLess coughing of bloodGenerally feeling better

TestsPlasma viscosity and C reactive protein (CRP) fallingAspergillus precipitins falling (slow)Total IgE fallingChest Xray shows no new cavities, and eventually thin walled

cavities

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/d107 patients with CPA 2-4 weeks treatment

Chronic cavitary pulmonary aspergillosis (CCPA) – coughing up blood (haemoptysis)

Wythenshawe Hospital

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

Technique 1

• Must lie flat– optimise respiratory function– oxygen– NIPPI– Consider anaesthetic support

• Femoral access• Flush aortogram or pre-op CT• 4F systems• Microcatheters

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

Dry microspheres, made up in saline and radiocontrast material

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

Patient PA

Nov 2008

Nov 2009

Jan 2010Posaconazole Rx

April 2010Posaconazole

Rx

Nov 2010Stopped posaconazole

Patient PA

Nov 2010Stopped posaconazole

Aug 2011No therapy

Dec 2011No therapy

Upper right bronchial artery embolisation

Pre Post

Bronchial artery embolisation (2)

Pre Post

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

Bronchial artery embolisation (3)

Pre Post

Intercostal artery embolisation

Pre Post

Intercostal artery embolisation (2)

Pre Post

Thyrocervical axis artery embolisation

Pre Post

Internal mammary artery embolisation

PreNote the large coil inferiorly in the internal mammary artery which prevents embolisation of the coeliac axis inadvertently

Post

Lateral thoracic artery embolisation

PreNote the smaller catheter inside the larger one

Post

Subclavian artery embolisation

PreNote the second catheter within the lumen of the R subclavian artery

Post

Bronchial Embolisation - Complications

• Minor - common– fever– pleuritic chest pain– dysphagia

• Major - rare– bronchial infarction– bronchial stenosis– Broncho oesophageal fistula– paraplegia

• Chemotoxic• embolic

– TIA/stroke

Bronchial Embolisation avoiding the anterior spinal artery

Chronic cavitary pulmonary aspergillosis Chronic cavitary pulmonary aspergillosis an example of radiographic failurean example of radiographic failure

Patient SSApril 2004

www.aspergillus.man.ac.uk

Patient SSJuly 2004, despite receiving itraconazole for 3 months

Stopping treatment after good response in CPA?

Chronic cavitary pulmonary aspergillosis

Patient RWJune 2002

Stable, asymptomatic, normal inflammatory markers, just detectable Aspergillus precipitins

Itraconazole stopped after 5 years

www.aspergillus.org.uk

Chronic cavitary pulmonary aspergillosis - relapse

Patient RWJanuary 2003

Marked change, with new cough, weight loss, ↑CRP/ESR and ↑Aspergillus precipitins

Itraconazole restarted

www.aspergillus.org.uk

Patient RWSeptember 1992

Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis

www.aspergillus.man.ac.uk

Patient RWJune 2003

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