Transcript No Slide Title

Clinical and radiological presentation
and diagnosis
David W. Denning
National Aspergillosis Centre
University Hospital South Manchester
[Wythenshawe Hospital]
University of Manchester
The National Aspergillosis Centre
225-250 new patients with aspergillosis referred annually
CLASSIFICATION OF ASPERGILLOSIS
Airways/nasal
exposure to
airborne
Aspergillus
Persistence
without disease
- colonisation of
the airways or
nose/sinuses
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)
Interaction of Aspergillus with the host
Acute IA
Subacute IA
ABPA
Severe asthma with
fungal sensitisation
Allergic sinusitis
Aspergilloma
Chronic pulmonary
Immune dysfunction
Immune hyperactivity
.
Frequency of aspergillosis
Frequency of aspergillosis
A unique microbial-host interaction
Size of Aspergillus disease problem
globally
1.
2.
3.
4.
Over 200,000 patients develop IA annually. Key groups
include ~10% of acute leukaemia (30,000) and stem cell
and other transplants (7,500) and 1.3% of COPD patients
admitted to hospital (60,000 IA cases).
Chronic pulmonary aspergillosis after TB – 1.1M cases
prevalence
Chronic pulmonary aspergillosis total - ~3M
Asthma 197M in adults, of which ~10-20% severe, UK
and USA have very high prevalence rates
How common is ABPA in asthma?
10/1390 (0.72%)
9/255 (3.5%)
6/264 (2.3%)
Donnelly, Irish J Med Sci 1991;160:288; Eaton, Chest 2000;118:66; Al-Mobeireek, Resp Med 2001;98:341
Size of Aspergillus disease problem
globally
1.
2.
3.
4.
5.
6.
Over 200,000 patients develop IA annually. Key groups
include ~10% of acute leukaemia (30,000) and stem cell
and other transplants (7,500) and 1.3% of COPD patients
admitted to hospital (60,000 IA cases).
Chronic pulmonary aspergillosis after TB – 1.1M cases
prevalence
Chronic pulmonary aspergillosis total - ~3M
Asthma 197M in adults, of which ~10-20% severe, UK
and USA have very high prevalence rates
Allergic bronchopulmonary aspergillosis in asthma - ~4M
worldwide (2.1% of adults referred with asthma)
Severe asthma with fungal sensitisation - ~6M worldwide
(33% of 10% (severe only))
Interaction of Aspergillus with the host
Acute invasive
aspergillosis
Subacute invasive
aspergillosis
Human genetic
influence on disease
expression
ABPA
Severe asthma with
fungal sensitisation
Allergic sinusitis
Aspergilloma
Chronic pulmonary
aspergillosis
Immune dysfunction
Frequency of aspergillosis
Frequency of aspergillosis
A unique microbial-host interaction
Immune hyperactivity
.
After Casadevall
& Pirofski, Infect Immun 1999;67:3703
Chronic Pulmonary Aspergillosis
Common symptoms
Common symptoms
• Cough, usually productive
• Shortness of breath
• Weight loss
• Tiredness
• Coughing up blood
• Chest ache / discomfort
Occasionally
• Fever
• Severe chest pain from rib fracture
• Additional chest infections
• Angina and heart attacks (chronic inflammation)
Underlying diseases
9 patients with chronic cavitary pulmonary aspergillosis
15 with chronic necrotising pulmonary aspergillosis
Camuset et al, Chest 2007:131:1435
Underlying diseases - CPA
• Classical tuberculosis *
• Atypical tuberculosis *
• Allergic bronchopulmonary aspergillosis *
• Lung cancer survivor *
• Pneumothorax *
• COPD/emphysema *
• Sarcoidosis (stage II/III) *
• Rheumatoid arthritis
• Thoracic surgery
• Asthma
• Chest radiotherapy
• None
* Common
Smith, ISHAM 2009
Chronic pulmonary aspergillosis –
pre-existing disease
Prior pulmonary disease esp:
Atypical mycobacteria pulmonary infection
Sarcoidosis
Tuberculosis
Recurrent pneumothorax
Prior pulmonary surgery
ABPA
Denning DW et al, Clin Infect Dis 2003; 37:S265
Frequency of chronic pulmonary aspergillosis after TB
~10% of all cases of pulmonary TB get CPA
Anonymous. Tubercle 1970;51:227
Acute tuberculosis
Cavities
Before
Cavities
Cavities
After treatment
No cavities
Lee, Eur J Radiol 2008; 67:100;
Chronic pulmonary aspergillosis
Infection of the lung by Aspergillus
Single fungal
ball or
aspergilloma
in a preexisting cavity
Simple (single) aspergilloma
Patient RK
Haempotysis,
nil else
Positive
Aspergillus
antibodies in
blood
Lobectomy
Wythenshawe Hospital
Aspergillomas from 2 patients
Wythenshawe Hospital; Severo on www.aspergillus.org.uk
Histology of an aspergilloma
Severo on www.aspergillus.man.ac.uk
Aspergillus fumigatus
Aspergilloma due to A. niger and oxalosis
Renal oxalosis
Oxalate crystals in wall of the aspergilloma
Severo on www.aspergillus.man.ac.uk
Early Aspergillus infection of a pulmonary
cavity – ‘pre-aspergilloma’
Orderly hyphal growth on
the inside of the cavity
Aspergillus growth on
the surface of a
pulmonary cavity
Severo on www.aspergillus.man.ac.uk
‘Multicavity’ disease
is the hallmark of
chronic cavitary
pulmonary
aspergillosis (CCPA)
Wythenshawe Hospital
Aspergilloma #3 –
spatially ordered
isolates from multiple
cavities
Bowyer et al, unpublished
Aspergillus precipitins (Aspergillus
antibody (IgG) ) in blood
Patient 2
blood
Patient 3
blood
Patient 1
blood
Aspergillus
extract
Patient 4
blood
Patient 6
blood
Patient 5
blood
Severo on www.aspergillus.org.uk
Aspergillus IgG serology
Baxter, AAA 2010;Abstr 51
Chronic pulmonary aspergillosis serology
All 18 patients had positive Aspergillus precipitins
(1+-4+)
All 18 patients had elevated inflammatory
markers, CRP, PV and / or ESR
May have elevated total IgE and Aspergillus
specific IgE (RAST)
Only 40% have a positive sputum culture
Denning DW et al, Clin Infect Dis 2003; 37:S265
Chronic pulmonary aspergillosis
Infection of the lung by Aspergillus
Single fungal
ball or
aspergilloma
in a preexisting cavity
Chronic
cavitary
pulmonary
aspergillosis
+/- fungal ball
Chronic cavitary pulmonary aspergillosis –
CT reconstruction
Wythenshawe Hospital
Chronic cavitary pulmonary aspergillosis (CCPA) –
sputum production
Aspergillus cultures positive in
CCPA in 10-40% of cases only
Wythenshawe Hospital
‘Multicavity’ disease is the hallmark of chronic
cavitary pulmonary aspergillosis (CCPA)
Wythenshawe Hospital
Chronic cavitary pulmonary aspergillosis (CCPA) –
haemoptysis
Wythenshawe Hospital
Chronic Cavitary Pulmonary Aspergillosis
Normal 30 year female smoker
Patient JA
Jan 2001
Chronic Cavitary Pulmonary Aspergillosis
Patient JA
April 2003
Multifocal cavities with aspergillomas –
unrecognised phenotype
Wythenshawe Hospital
18F-FDG PET positive pulmonary nodules in
aspergillosis – a differential diagnosis of lung
cancer
10 patients
Presentations like
lung cancer
1 subacute IPA
1 ABPA
1 aspergilloma
7 CPA
Aspergillus IgG
28 ->200 mg/L
All positive on
histology
Baxter, Thorax 2011
CLASSIFICATION OF ASPERGILLOSIS
Airways/nasal
exposure to
airborne
Aspergillus
Persistence
without disease
- colonisation of
the airways or
nose/sinuses
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)
Allergic Bronchopulmonary
Aspergillosis
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
Asthma – variable airflow obstruction
Inhaled steroids
Patient SY, Aspergillus Website
Proposed new criteria for ABPA
1.
2.
3.
Serum IgE >1000 IU/mL
Asthma OR CF
Airway obstruction (ie CT scan/bronchoscopy) by
or production of mucus plugs containing hyphae
Which fungus?
1. Fungal sensitisation (IgE or SPT) and/or fungus
detected in respiratory secretions
Knutsen et al, AAAAI Task Force on Fungus and Asthma
ABPA - March – doing well
FEV1 = 3.00
Aspergillus IgE = 31
IgE = 1900.
No treatment
September – episode of pneumonia
FEV1 = 1.6.
IgE = 3000
Aspergillus IgE = 52.5.
Exacerbation of ABPA
Exacerbation of ABPA
Patient AL
May 2010
January 2011
June 2011
www.aspergillus.org.uk
Exacerbation of ABPA
Patient AL
September 2011
www.aspergillus.org.uk
Mucoid impaction due to ABPA
www.aspergillus.org.uk
Mucoid impaction due to ABPA
www.aspergillus.org.uk
Sputum in ABPA
www.aspergillus.org.uk
ABPA – bronchoscopy views
showing mucous plugging
www.aspergillus.org.uk
A. fumigatus in BAL and in bronchial
tissue in ABPA
Severe Asthma and Fungal Sensitisation
www.emphysema-copd.co.uk
Fungal exposure in asthmatics is related to:
• Life-threatening asthmatic attacks (ie thunderstorm
asthma)
• Severe asthma and hospital admission
• Increased wheezing and symptoms
• Loss of medication control
• Allergic bronchopulmonary mycosis
• Eosinophilic fungal rhinosinusitis
O'Hollaren, N Engl J Med 1991; 324: 359; and many others
Airborne fungal fragments
Fungal fragment
Diffusing
allergen
leeching out of
fungus in
contact with
liquid
Green et al, J Allergy Clin Immunol 2005;115:1043
Genomic
analysis of
allergens
Bowyer et al, BMC Genomics 2006;7:251
Severe asthma and mould
senstivity – Alternaria
and Cladosporium
Mild asthma – 564 (50%)
Moderate asthma – 333 (29%)
Severe asthma – 235 (21%)
Zureik et al, Br Med J 2002;325:411
Multiple
Admissions
Mean sensitization score (mm)
(Mean and 95% CI)
20.0
17.5
15.0
No
Hospital
Admission
12.5
Multiple
Admissions
10.0
7.5
Single
Admission
P= <0.0001
5.0
2.5
0.0
No
Hospital
Admission
Single
Admission
Mould allergens
Non-Mould allergens
O’Driscoll et al, BMC Pulmonary Medicine 2005;5:4
Colonisation in ‘normal’ lungs
22 of 30 (73%) grew a fungus
in both lung samples taken
10/30 (33%) grew >1 species
Lass-Florl et al, Br J Haematol 1999;104:745
Asthma and Aspergillus
79 adult asthmatics and 14 controls
Patients sensitised to A. fumigatus compared with nonsensitised 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).
Fairs et al, Am J Respir Crit Care Med 2010; July 16
Severe asthma and aspergillosis in ICU
57 of 357 (16%) admitted ICU with acute asthma
Compared with 755 outpatients with asthma
Aspergillus skin prick test used to screen for aspergillus
hypersensitivity, if positive IgE etc for ABPA checked
Aspergillus positive
Asthma in ICU
Outpatient asthma
P value
ABPA
29/57 (51%)
22/57 (39%)
90/755 (39%)
155/755 (21%)
0.01
0.001
Agarwal et al, Mycoses 2009 Jan 24th
Severe asthma with invasive
aspergillosis
Felton et al Chest 2010;137:724
Severe asthma with fungal sensitisation
(SAFS)
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)
Denning et al, Eur Resp J 2006; 27;27:615
Comparison of ABPA and SAFS serology
ABPA results
Patient
1
SAFS results
2
normal range
date 1 date 2
Skin prick testing – example of SAFS result
Cladosporium +ve
O’Driscoll, unpublished
Fungal sensitisation in severe asthma –
skin prick test or RAST for diagnosis?
N= 121 patients screened
100%
>23%
discordant
results
}
50%
43
SPT + RAST
both positive
10
13
SPT positive
SPT negative
RAST negative RAST positive
34
SPT negative
RAST negative
O’Driscoll et al, Clin Exp Allergy. In press
Fungal sensitisation in severe asthma –
number sensitised to one or more fungi
N = 40
13 sensitised to only Aspergillus
8 to Candida
3 to Trichophyton
3 to Penicillium
1 to Alternaria
1 to Cladosporium
N = 20
29
1
11
2
11
12
7
3
4
5
3
6
7
7
Sensitisation to one or more fungi
O’Driscoll et al, Clin Exp Allergy. In press
Distinguishing different forms of aspergillosis
Disease group
CCPA
ABPA + CCPA
ABPA
SAFS
SAFS
n
116
16
98
52
52
Median serum
IgE level (IQR)
99.8 (26.4-350)
(n=107)
2739
(1100-7500)
(n=16)
2300
(1100-4550)
(n=97)
370
(140-750)
(n=52)
93.6% (103/110)
81.3% (13/16)
65.4% (53/81)
35.9% (14/39)
25% (29/116)
25.0% (4/16)
23.5% (23/98)
21.2% (11/52)
Aspergillus
specific IgG
Positive fungal
culture
Positive
specific IgE
Positive SPT
Mixed mould
N/T
N/T
88.9% (8/9)
90.9% (20/30)
100% (2/2)
A. fumigatus
37.7% (40/106)
93.8% (15/16)
96.9% (94/97)
78.8% (41/52)
90.9% (20/30)
Alternaria
alternata
10.0% (1/10)
100% (10/10)
77.5% (55/71)
32.5% (13/40)
47.4% (9/19)
C. albicans
33.3% (3/9)
90.0% (9/10)
81.4% (57/70)
37.5% (15/25)
52.6% (10/19)
Cladosporium
herbarum
20.0% (2/10)
80.0% (8/10)
70.4% (50/71)
24.4% (10/41)
35.5% (6/17)
Penicillium
chrysogenum
27.3% (3/11)
100% (10/10)
85.3% (58/68)
30.0% (12/40)
43.8% (7/16)
Trichophyton
mentagrophyte
33.3% (2/6)
100% (3/3)
65.2% (30/46)
25.0% (9/36)
23.1% (3/13)
Distinguishing different forms of aspergillosis
Disease group
CCPA
ABPA + CCPA
ABPA
SAFS
SAFS
n
116
16
98
52
52
Median serum
IgE level (IQR)
99.8 (26.4-350)
(n=107)
2739
(1100-7500)
(n=16)
2300
(1100-4550)
(n=97)
370
(140-750)
(n=52)
93.6% (103/110)
81.3% (13/16)
65.4% (53/81)
35.9% (14/39)
25% (29/116)
25.0% (4/16)
23.5% (23/98)
21.2% (11/52)
Aspergillus
specific IgG
Positive fungal
culture
Positive
specific IgE
Positive SPT
Mixed mould
N/T
N/T
88.9% (8/9)
90.9% (20/30)
100% (2/2)
A. fumigatus
37.7% (40/106)
93.8% (15/16)
96.9% (94/97)
78.8% (41/52)
90.9% (20/30)
Alternaria
alternata
10.0% (1/10)
100% (10/10)
77.5% (55/71)
32.5% (13/40)
47.4% (9/19)
C. albicans
33.3% (3/9)
90.0% (9/10)
81.4% (57/70)
37.5% (15/25)
52.6% (10/19)
Cladosporium
herbarum
20.0% (2/10)
80.0% (8/10)
70.4% (50/71)
24.4% (10/41)
35.5% (6/17)
Penicillium
chrysogenum
27.3% (3/11)
100% (10/10)
85.3% (58/68)
30.0% (12/40)
43.8% (7/16)
Trichophyton
mentagrophyte
33.3% (2/6)
100% (3/3)
65.2% (30/46)
25.0% (9/36)
23.1% (3/13)
Conceptual framework for CPA and IA
Normal
Chronic
inflammation
and fibrosis
Granulomas, acute
inflammation,
central necrosis
Vascular
invasion,
necrosis,
dissemination
Hyphal load in tissue
Immune function
Massive
Aspergilloma - CCPA - CNPA/subacute IPA - acute IPA
www.aspergillus.org.uk
Alternative Aspergillus diagnoses
•
•
•
•
•
Aspergillus bronchitis
Obstructing bronchial aspergillosis
Invasive Aspergillus tracheobronchitis
Community acquired Aspergillus pneumonia
Sub-acute invasive pulmonary aspergillosis
(often called chronic necrotising pulmonary
aspergillosis or CNPA)
• Extrinsic allergic (bronchiol)alveolitis (EAA)
• Aspergillus empyema
6th Jan
24th Feb
Arendrup, Scand J Infect Dis 2006:38:945
Obstructing bronchial aspergillosis
Patient ML
Pre-bronchscopy
Patient ML
After bronchoscopy
Denning et al, New Engl J Med 1991;324: 654
Subacute invasive pulmonary aspergillosis in
AIDS
Patient HB
Day +14, CD4 cells 84/uL
Biopsy positive for Aspergillus
Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628
Conclusions
• CPA = 3 months of pulmonary cavitation or nodule +/aspergilloma, with symptoms + Aspergillus IgG or
precipitins positive
• CPA patients almost all have an underlying diagnosis
• ABPA = asthma (any severity) or cystic fibrosis + total
IgE >1,000 + SPT or Aspergillus IgE positive.
• SAFS = severe asthma + fungal SPT or IgE positive +
total IgE <1,000
• Some patients have overlap syndromes and more than 1
Aspergillus diagnosis