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The spectrum of aspergillosis
David W. DenningUniversity Hospital of South
ManchesterThe University of Manchester
Myconostica Ltd
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CLASSIFICATION OF ASPERGILLOSIS
Persistence without disease -
colonisation
of
the airways or nose/sinuses
Airways/nasal exposure to airborne Aspergillus
Invasive aspergillosis• Acute (<1 month course)• Subacute/chronic necrotising
(1-3 months)
Chronic aspergillosis
(>3 months)• Chronic cavitary pulmonary• Aspergilloma of lung• Chronic fibrosing pulmonary• Chronic invasive sinusitis • Maxillary (sinus) aspergilloma
Allergic• Allergic bronchopulmonary (ABPA)• Extrinsic allergic (broncho)alveolitis
(EAA)
• Asthma with fungal sensitisation•
Allergic Aspergillus sinusitis (eosinophilic
fungal rhinosinusitis)
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Where in the hospital does invasive aspergillosis occur?
Cornillet
et al, Clin
Infect Dis
2006;43:577
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Risk factors for invasive aspergillosis
Major•
Neutropenia (+ monocytopenia)
•
Corticosteroid treatmentMinor•
CD4penia
•
Inherited immunodeficiency (ie
CGD)•
Lung or sinus damage/disease
•
Severe liver disease•
Exposure to high inocula
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Risk factors for invasive aspergillosis in ICU
Meersseman, Clin Infect Dis 2007;45:205
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Invasive aspergillosis in ICU
Vandewoude et al, Critical Care 2006;10:R31.
Aspergillus detected, no infection
N = 89Invasive aspergillosis
+ treatmentN = 73
Invasive aspergillosis no treatment
N = 12
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Radiology completely unhelpful in suspecting the diagnosis
Meersseman, Clin Infect Dis 2007;45:205
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www.aspergillus.org.uk
Airways aspergillosis -
spectrum
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CLASSIFICATION OF ASPERGILLOSIS
Persistence without disease -
colonisation
of
the airways or nose/sinuses
Airways/nasal exposure to airborne Aspergillus
Invasive aspergillosis• Acute (<1 month course)• Subacute/chronic necrotising
(1-3 months)
Chronic aspergillosis
(>3 months)• Chronic cavitary pulmonary• Aspergilloma of lung• Chronic fibrosing pulmonary• Chronic invasive sinusitis • Maxillary (sinus) aspergilloma
Allergic• Allergic bronchopulmonary (ABPA)• Extrinsic allergic (broncho)alveolitis
(EAA)
• Asthma with fungal sensitisation•
Allergic Aspergillus sinusitis (eosinophilic
fungal rhinosinusitis)
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Chronic pulmonary aspergillosis
www.aspergillus.org.uk
Chronic cavitary pulmonary
aspergillosis complicating ABPA
Chronic cavitary pulmonary aspergillosis with bilateral aspergillomas complicating
sarcoidosis
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‘Multicavity’
disease is the hallmark of chronic cavitary pulmonary aspergillosis (CCPA)
Wythenshawe Hospital
+ Aspergillus IgG antibodies (precipitins)
+ symptoms
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Underlying diseases in patients with CPA (%)
Smith, Eur
Resp
J 2010 In press
Smith 0thers
Classical tuberculosis 17
31-81Atypical tuberculosis 16
?
ABPA
14
12COPD/emphysema
33
42-56
Pneumothorax
17
12-17Lung cancer survivor 10
?
Pneumonia
22
9-12Sarcoidosis (stage II/III)
7
12-17
Thoracic surgery
14
8-11Rheumatoid arthritis
4
2
Asthma / SAFS
12
6-12Ankylosing
spondylitis
4
2-11
None
1
15
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Frequency of chronic pulmonary aspergillosis after TB
Anonymous. Tubercle 1970;51:227; Sonnenberg
et al, Lancet 2001;358:1687
25-33% of patients with TB are left with a cavity
~10% of all cases of pulmonary TB get CPA
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CLASSIFICATION OF ASPERGILLOSIS
Persistence without disease -
colonisation
of
the airways or nose/sinuses
Airways/nasal exposure to airborne Aspergillus
Invasive aspergillosis• Acute (<1 month course)• Subacute/chronic necrotising
(1-3 months)
Chronic aspergillosis
(>3 months)• Chronic cavitary pulmonary• Aspergilloma of lung• Chronic fibrosing pulmonary• Chronic invasive sinusitis • Maxillary (sinus) aspergilloma
Allergic• Allergic bronchopulmonary (ABPA)• Extrinsic allergic (broncho)alveolitis
(EAA)
• Asthma with fungal sensitisation•
Allergic Aspergillus sinusitis (eosinophilic
fungal rhinosinusitis)
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ABPA and severe asthma
www.emphysema-copd.co.uk
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Global ABPA cases per WHO region related to adult asthma (mean 2.1%)
Denning, Pleuvry
& Cole, Unpublished
BurdenEurope 466,891Americas
704,926
Eastern Medit.
187,963Africa
294,058
Western Pacific
881,860SE Asia
614,353
TOTALS
3,150,062
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ABPA –
Diagnostic clues
•
Asthma/CF not well controlled•
History of ‘pneumonia’
•
History of coughing up plugs, or paroxysms of coughing that clear when chest clears
•
Central bronchiectasis on CT scan, or mucoid impaction•
Eosinophilia
Rare cases in non-asthmatics, non-CF patients
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ABPA –
bronchoscopy views showing mucous plugging
www.aspergillus.org.uk
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Mucoid
impaction due to ABPA
www.aspergillus.org.uk
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Mucoid
impaction due to ABPA
www.aspergillus.org.uk
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Sputum in ABPA
www.aspergillus.org.uk
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Charcot Leyden crystals
www.aspergillus.org.uk
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Central bronchiectasis as a complication of ABPA
www.aspergillus.org.uk
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CF and Aspergillus colonisation or infection
Amin, Chest 2010;137:171
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0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0M
ean
sens
itiza
tion
scor
e (m
m)
(Mea
n an
d 95
% C
I)
Non-Mould allergens
NoHospitalAdmission
SingleAdmission
MultipleAdmissions
O’Driscoll et al, BMC Pulmonary Medicine 2005;5:4
Mould allergens
NoHospitalAdmission
SingleAdmission
MultipleAdmissions
P= <0.0001
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Severe asthma and fungal sensitisation (SAFS)
Denning et al, Eur
Resp
J 2006; 27;27:615
Criteria for diagnosis•
Severe asthma (BTS step 4 or 5)
AND•
RAST (IgE) positive for any fungus
OR•
Skin prick test positive for any fungus
AND•
Exclude ABPA (ie
total IgE <1,000 iu/mL)
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Comparison of ABPA and SAFS serology
ABPA results
normal range date 1 date 2
SAFS results
Patient1
2
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Fungal sensitisation in severe asthma – skin prick test or RAST for diagnosis?
N= 121 patients screened
O’Driscoll
et al, Clin
Exp Allergy 2009;39:1677
SPT + RAST both positive
100%
50%
4310 13 34
SPT positiveRAST negative
SPT negativeRAST positive
SPT negativeRAST negative
>23% discordant
results
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Fungal sensitisation in severe asthma – skin prick test or RAST
O’Driscoll
et al, Clin
Exp Allergy 2009;39:1677
Aspergillus Candida Penicillium Cladosporium Alternaria Botrytis
100%
50%
68 54 44 36 34 28
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Fungal sensitisation in severe asthma – number sensitised to one or more fungi
O’Driscoll
et al, Clin
Exp Allergy. 2009;39:1677
1 2 3 4 5 6 7
N = 40
N = 20
29 11 11 123
77
Sensitisation to one or more fungi
13 sensitised to only Aspergillus8 to Candida3 to Trichophyton3 to Penicillium1 to Alternaria1 to Cladosporium
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Asthma and Aspergillus
Fairs et al, Am J Respir
Crit
Care Med 2010; July 16
79 adult asthmatics and 14 controls
Patients sensitised to A. fumigatus compared with non- sensitised asthmatics had:
lower lung function (% pred. FEV1 68% vs
88% p < 0.05), more bronchiectasis
(68% versus 35% p < 0.05) and more
sputum neutrophils
(80.9% vs
49.5% p < 0.01).
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RandomisedRandomised
studies of studies of antifungalsantifungals and ABPA and/or asthmaand 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
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Interaction of Aspergillus with the host A unique microbial-host interaction
Immune dysfunction
Frequency of aspergillosis
Immune hyperactivity
Freq
uenc
y of
asp
ergi
llosi
s
Acute IA
Subacute IA
AspergillomaChronic cavitaryChronic fibrosing
ABPASevere asthma with fungal sensitisationAllergic sinusitis
.After Casadevall
& Pirofski, Infect Immun
1999;67:3703
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www.aspergillus.org.uk