Transcript No Slide Title

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)
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
Treatment
Allergic Bronchopulmonary
Aspergillosis
Open trial of itraconazole in ABPA - 1991
Prednisone (mg/d)
Total IgE
FEV1
FVC
Before
43
2462
1.48
2.3
After
24*
525*
1.79*
2.9
*p=0.04
Only 1 patient failed – he had low itraconazole levels.
Denning et al, Chest 1991; 35:1329
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
Randomised trial of itraconazole in ABPA
Stevens et al, New Engl J Med 2000; 342:756
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 17/28 (61%) response rate
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
Randomised trial of itraconazole in ABPA
P < 0.01
Eosinophilic cationic protein
ABPA with asthma, n = 29
Phase 1 - 200mg BID v placebo, 16 weeks
Primary outcome measure – Sputum eosinophil count
Reduced exacerbation rate
No change in FEV1 or PEF
Wark et al, J Clin All Immunol 2003; 111:952
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
Severe Asthma and Fungal
Sensitisation (SAFS)
www.emphysema-copd.co.uk
Severe asthma
Bel EH , Severe asthma. Breath magazine Dec 2006
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;
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
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.
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
Baseline demographics - asthma
Mean (range) or % (no.)
Active
(n=29)
Placebo
(n=29)
48% (14)
48% (14)
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)
24% (7)
43% (12)
39%
17%
Gender (Male)
Age
Baseline eosinophilia (>0.4x 109)/L
No. of hospitalisations last 12
months (>1)
Denning et al, Am J Resp Crit Care Med 2009; 179:11
Proof of concept RCT of antifungal Rx in
SAFS – key results
Patients enrolled & randomised N = 58
Placebo N = 29
Active (itraconazole) N = 29
Withdrawal in <4 weeks
Active N= 3
MITT analysis set (active) N =26
Placebo N=1 (p=0.60)
MITT analysis set (placebo) N =28
P=0.014
AQLQ ∆ = 0.82
Withdrawal 4-32 weeks
Active N= 8
Per protocol analysis set (active)
N= 18
Placebo N=5 (p=0.25)
Per protocol analysis set (placebo)
N=23
P=0.002
AQLQ ∆ = 1.18
Denning et al, Am J Resp Crit Care Med 2009; 179:11
Proof of concept RCT of antifungal Rx in
SAFS – outcomes at 32 weeks MITT
Mean (95% CI) or % (n)
P-value
Active
Placebo
+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
0.13
3.22
(-3.67, 3.93)
NS
Change in AQLQ score
Change in FEV1 (% predicted)
Number
-3.66
needed
to2.08)
treat
(-9.39,
=
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
Denning et al, Am J Resp Crit Care Med 2009; 179:11
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
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
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
Relationship of itraconazole drug level to
response
AQLQ change vs itraconazole level
AQLQ change (week 32 lvcf - week 1)
4
3
2
P= 0.22
1
0
-1
-2
0
5
10
15
20
25
30
mean itraconazole
Denning et al, Am J Resp Crit Care Med 2009; 179:11
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 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
Fluconazole, 20 wks
Yes
Ward, 1999
Itraconazole, 32
wks
Yes
Denning, 2009
“Trichophyton” asthma
SAFS
Chronic Pulmonary Aspergillosis
Antifungal therapy
IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327
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; 37:S265; Jain & Denning. J Infect 2006;52:e133-7.
Felton, Clin Infect Dis 2010; 51:1383.
Impact of voriconazole in real life
weeks
Nivoix et al, Clin Infect Dis 2008;47:1176
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
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
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
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 treatment
Clinical
Less tired
Better appetite
Weight gain
Less coughing
Less productive
Less coughing of blood
Generally feeling better
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
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
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
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
April
2010
Jan
2010
Nov
2010
Nov 2009
Rx
Posaconazole
RxPosaconazole
Stopped
posaconazole
Nov 2008
Patient PA
Nov 2010
Aug 2011
Stopped posaconazole
No therapy
Dec 2011
No 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
Pre
Post
Note the large coil inferiorly in the internal mammary artery which
prevents embolisation of the coeliac axis inadvertently
Lateral thoracic artery embolisation
Pre
Post
Note the smaller catheter inside the larger one
Subclavian artery embolisation
Pre
Note 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 an
example of radiographic failure
Patient SS
April 2004
Patient SS
July 2004, despite receiving
itraconazole for 3 months
www.aspergillus.man.ac.uk
Stopping treatment after good
response in CPA?
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
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
Chronic cavitary pulmonary aspergillosis
Patient RW
September 1992
Patient RW
June 2003
www.aspergillus.man.ac.uk
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