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Management of chronic and allergic aspergillosis

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... 27:319-28 Patient PA Nov 2008 Nov 2009 Jan 2010 Posaconazole Rx April 2010 Posaconazole Rx Nov 2010 Stopped posaconazole Patient PA Nov 2010 Stopped ... – PowerPoint PPT presentation

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Title: Management of chronic and allergic aspergillosis


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 Micafu
ngin 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 p0.04
Only 1 patient failed he had low itraconazole
levels.
Denning et al, Chest 1991 351329
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 342756
8
Randomised trial of itraconazole in ABPA
Stevens et al, New Engl J Med 2000 342756
9
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
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 (n33)
Number needed to treat 3.58
Stevens et al, New Engl J Med 2000 342756
10
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 lt 0.01
Reduced exacerbation rate No change in FEV1 or PEF
Wark et al, J Clin All Immunol 2003 111952
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 1999104541
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 gt6 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 lt1000IU/mL) -ve Aspergillus
    precipitins
  • Recurrent bacterial chest infections (6 weekly)
  • Prior azole therapy
  • Cardiac failure
  • LFTs gt3x ULN

Denning et al, Am J Resp Crit Care Med 2009
17911
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 19924776.
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
17911
18
Baseline demographics - asthma
  Mean (range) or (no.) Mean (range) or (no.)
  Active (n29) Placebo (n29)
Gender (Male) 48 (14) 48 (14)
Age 49.2 (18,79) 51.7 (19,76)
Severity of asthma (BTS) (gt4) 3 (1) 11 (3)
Baseline total serum IgE (IU/L) 212 (24,820) 245 (36,990)
Baseline eosinophilia (gt0.4x 109)/L 24 (7) 43 (12)
No. of hospitalisations last 12 months (gt1) 39 17
Denning et al, Am J Resp Crit Care Med 2009
17911
19
Proof of concept RCT of antifungal Rx in SAFS
key results
Denning et al, Am J Resp Crit Care Med 2009
17911
20
Proof of concept RCT of antifungal Rx in SAFS
outcomes at 32 weeks MITT
Mean (95 CI) or (n) Mean (95 CI) or (n) P-value
Active Placebo P-value
Change in AQLQ score 0.85 (0.28, 1.41) -0.01 (-0.43, 0.42) 0.014
Improvement in AQLQ score of gt0.75 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
Denning et al, Am J Resp Crit Care Med 2009
17911
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
17911
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 2002201088
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
17911
24
Relationship of itraconazole drug level to
response
P 0.22
Denning et al, Am J Resp Crit Care Med 2009
17911
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
17911
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
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
29
Chronic Pulmonary Aspergillosis
30
Antifungal therapy
IDSA guidelines. Walsh et al. Clin Infect Dis
200846327
31
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 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
Denning DW et al, Clin Infect Dis 2003 37S265
Jain Denning. J Infect 200652e133-7.
32
Felton, Clin Infect Dis 2010 511383.
33
Impact of voriconazole in real life
weeks
Nivoix et al, Clin Infect Dis 2008471176
34
Effect of voriconazole on CPA
16 patients, all failing or intolerant of
itraconazole5 patients were able to take gt3
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 52e133-7
35
Parameters of response in CPA (with voriconazole)
Jain Denning J Infect 2006 52e133-7
36
CPA and voriconazole Rx
Sambatakou et al, Am J Med 2006119527.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 20071311435
38
Time to initial response with posaconazole therapy
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 201061410
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
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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 gt90 patients
  • 30-50 rebleed rate at 3 years
  • Mean rebleed free interval 9 months
  • Serisli et al Int Angio 200827319-28

50
Patient PA
  • Nov 2008

51
Patient PA
  • Dec 2011
  • No therapy

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

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

63
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64
Bronchial Embolisation avoiding the anterior
spinal artery
65
Chronic cavitary pulmonary aspergillosis an
example of radiographic failure
Patient SS April 2004
Patient SS July 2004, despite receiving
itraconazole for 3 months
www.aspergillus.man.ac.uk
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
Chronic cavitary pulmonary aspergillosis
Patient RW June 2003
Patient RW September 1992
www.aspergillus.man.ac.uk
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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