Clinical and radiological presentation and diagnosis

1
Clinical and radiological presentation and
diagnosis

• David W. Denning
• National Aspergillosis Centre
• University Hospital South Manchester
• Wythenshawe Hospital
• University of Manchester

2
The National Aspergillosis Centre

• 225-250 new patients with aspergillosis referred
  annually

3
CLASSIFICATION OF ASPERGILLOSIS

• Invasive aspergillosis
• Acute (lt1 month course)
• Subacute/chronic necrotising (1-3 months)

Airways/nasal exposure to airborne Aspergillus

• Chronic aspergillosis (gt3 months)
• Chronic cavitary pulmonary
• Aspergilloma of lung
• Chronic fibrosing pulmonary
• Chronic invasive sinusitis
• Maxillary (sinus) aspergilloma

• Persistence without disease - colonisation of the
  airways or nose/sinuses

• Allergic
• Allergic bronchopulmonary (ABPA)
• Extrinsic allergic (broncho)alveolitis (EAA)
• Asthma with fungal sensitisation
• Allergic Aspergillus sinusitis (eosinophilic
  fungal rhinosinusitis)

4
Interaction of Aspergillus with the hostA unique
microbial-host interaction
Subacute IA
Frequency of aspergillosis
Frequency of aspergillosis
Aspergilloma Chronic pulmonary
Immune dysfunction
Immune hyperactivity
.
After Casadevall Pirofski, Infect Immun
1999673703
5
Size of Aspergillus disease problem globally

1. 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).
2. Chronic pulmonary aspergillosis after TB 1.1M
   cases prevalence
3. Chronic pulmonary aspergillosis total - 3M
4. Asthma 197M in adults, of which 10-20 severe,
   UK and USA have very high prevalence rates

6
How common is ABPA in asthma?
10/1390 (0.72) 9/255 (3.5) 6/264
(2.3)
Donnelly, Irish J Med Sci 1991160288 Eaton,
Chest 200011866 Al-Mobeireek, Resp Med
200198341
7
Size of Aspergillus disease problem globally

1. 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).
2. Chronic pulmonary aspergillosis after TB 1.1M
   cases prevalence
3. Chronic pulmonary aspergillosis total - 3M
4. Asthma 197M in adults, of which 10-20 severe,
   UK and USA have very high prevalence rates
5. Allergic bronchopulmonary aspergillosis in asthma
   - 4M worldwide (2.1 of adults referred with
   asthma)
6. Severe asthma with fungal sensitisation - 6M
   worldwide (33 of 10 (severe only))

8
Interaction of Aspergillus with the hostA unique
microbial-host interaction
Human genetic influence on disease expression
Subacute invasive aspergillosis
Frequency of aspergillosis
Frequency of aspergillosis
Aspergilloma Chronic pulmonary aspergillosis
Immune dysfunction
Immune hyperactivity
.
After Casadevall Pirofski, Infect Immun
1999673703
9
Chronic Pulmonary Aspergillosis
10
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)

11
Underlying diseases
9 patients with chronic cavitary pulmonary
aspergillosis15 with chronic necrotising
pulmonary aspergillosis
Camuset et al, Chest 20071311435
12
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
13
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 37S265
14
Frequency of chronic pulmonary aspergillosis
after TB
10 of all cases of pulmonary TB get CPA
Anonymous. Tubercle 197051227
15
Acute tuberculosis
Cavities
Cavities
Before After treatment
Cavities
No cavities
Lee, Eur J Radiol 2008 67100
16
Chronic pulmonary aspergillosis
Infection of the lung by Aspergillus

• Single fungal ball or aspergilloma
• in a pre-existing cavity

17
Simple (single) aspergilloma
Patient RK Haempotysis, nil else Positive
Aspergillus antibodies in blood Lobectomy
Wythenshawe Hospital
18
Aspergillomas from 2 patients
Wythenshawe Hospital Severo on
www.aspergillus.org.uk
19
Histology of an aspergilloma
Severo on www.aspergillus.man.ac.uk
20
Aspergillus fumigatus
21
Aspergilloma due to A. niger and oxalosis
Renal oxalosis
Oxalate crystals in wall of the aspergilloma
Severo on www.aspergillus.man.ac.uk
22
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
23
Multicavity disease is the hallmark of chronic
cavitary pulmonary aspergillosis (CCPA)
Wythenshawe Hospital
24
Aspergilloma 3 spatially ordered isolates from
multiple cavities
Bowyer et al, unpublished
25
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
26
Aspergillus IgG serology
Baxter, AAA 2010Abstr 51
27
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 37S265
28
Chronic pulmonary aspergillosis
Infection of the lung by Aspergillus

• Single fungal ball or aspergilloma
• in a pre-existing cavity

Chronic cavitary pulmonary aspergillosis /-
fungal ball
29
Chronic cavitary pulmonary aspergillosis CT
reconstruction
Wythenshawe Hospital
30
Chronic cavitary pulmonary aspergillosis (CCPA)
sputum production
Aspergillus cultures positive in CCPA in 10-40
of cases only
Wythenshawe Hospital
31
Multicavity disease is the hallmark of chronic
cavitary pulmonary aspergillosis (CCPA)
Wythenshawe Hospital
32
Chronic cavitary pulmonary aspergillosis (CCPA)
haemoptysis
Wythenshawe Hospital
33
Chronic Cavitary Pulmonary Aspergillosis Normal
30 year female smoker
Patient JA Jan 2001
34
Chronic Cavitary Pulmonary Aspergillosis
Patient JA April 2003
35
Multifocal cavities with aspergillomas
unrecognised phenotype
Wythenshawe Hospital
36
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 -gt200 mg/L All positive
on histology
Baxter, Thorax 2011
37
CLASSIFICATION OF ASPERGILLOSIS

• Invasive aspergillosis
• Acute (lt1 month course)
• Subacute/chronic necrotising (1-3 months)

Airways/nasal exposure to airborne Aspergillus

• Chronic aspergillosis (gt3 months)
• Chronic cavitary pulmonary
• Aspergilloma of lung
• Chronic fibrosing pulmonary
• Chronic invasive sinusitis
• Maxillary (sinus) aspergilloma

• Persistence without disease - colonisation of the
  airways or nose/sinuses

• Allergic
• Allergic bronchopulmonary (ABPA)
• Extrinsic allergic (broncho)alveolitis (EAA)
• Asthma with fungal sensitisation
• Allergic Aspergillus sinusitis (eosinophilic
  fungal rhinosinusitis)

38
Allergic Bronchopulmonary Aspergillosis
39
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

40
Asthma variable airflow obstruction
Inhaled steroids
Patient SY, Aspergillus Website
41
Proposed new criteria for ABPA

• Serum IgE gt1000 IU/mL
• Asthma OR CF
• Airway obstruction (ie CT scan/bronchoscopy) by
  or production of mucus plugs containing hyphae
• Which fungus?
• Fungal sensitisation (IgE or SPT) and/or fungus
  detected in respiratory secretions

Knutsen et al, AAAAI Task Force on Fungus and
Asthma
42
ABPA - March doing well
FEV1 3.00 Aspergillus IgE 31 IgE 1900.
No treatment
43
September episode of pneumonia
FEV1 1.6. IgE 3000 Aspergillus IgE 52.5.
Exacerbation of ABPA
44
Exacerbation of ABPAPatient AL
May 2010
www.aspergillus.org.uk
45
Exacerbation of ABPAPatient AL
September 2011
www.aspergillus.org.uk
46
Mucoid impaction due to ABPA
www.aspergillus.org.uk
47
Mucoid impaction due to ABPA
www.aspergillus.org.uk
48
Sputum in ABPA
www.aspergillus.org.uk
49
ABPA bronchoscopy views showing mucous plugging
www.aspergillus.org.uk
50
A. fumigatus in BAL and in bronchial tissue in
ABPA
51
Severe Asthma and Fungal Sensitisation
www.emphysema-copd.co.uk
52

• 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
53
Airborne fungal fragments
Fungal fragment
Diffusing allergen leeching out of fungus in
contact with liquid
Green et al, J Allergy Clin Immunol 20051151043
54
Genomic analysis of allergens
Bowyer et al, BMC Genomics 20067251
55
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 2002325411
56
20.0
17.5
 
15.0
12.5
Mean sensitization score (mm)
(Mean and 95 CI)
10.0
7.5
5.0
2.5
0.0
ODriscoll et al, BMC Pulmonary Medicine 200554
57
Colonisation in normal lungs
22 of 30 (73) grew a fungus in both lung samples
taken 10/30 (33) grew gt1 species
Lass-Florl et al, Br J Haematol 1999104745
58
Asthma and Aspergillus
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 lt 0.05),
more bronchiectasis (68 versus 35 p lt 0.05)
and more sputum neutrophils (80.9 vs 49.5 p lt
0.01).
Fairs et al, Am J Respir Crit Care Med 2010 July
16
59
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 As
pergillus positive ABPA Asthma in
ICU 29/57 (51) 22/57
(39) Outpatient asthma 90/755 (39)
155/755 (21) P value 0.01
0.001
Agarwal et al, Mycoses 2009 Jan 24th
60
Severe asthma with invasive aspergillosis
Felton et al Chest 2010137724
61
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 lt1,000 iu/mL)

Denning et al, Eur Resp J 2006 2727615
62
Comparison of ABPA and SAFS serology
ABPA results normal range date 1 date 2
Patient 1 2
SAFS results
63
Skin prick testing example of SAFS result
Cladosporium ve
ODriscoll, unpublished
64
Fungal sensitisation in severe asthma skin
prick test or RAST for diagnosis? N 121 patients
screened
100
50
43
34
13
10
SPT RAST both positive
SPT negative RAST negative
SPT positive RAST negative
SPT negative RAST positive
ODriscoll et al, Clin Exp Allergy. In press
65
Fungal sensitisation in severe asthma number
sensitised to one or more fungi
N 40
N 20
11
29
12
11
7
7
3
1 2 3 4 5 6 7
Sensitisation to one or more fungi
ODriscoll et al, Clin Exp Allergy. In press
66
Distinguishing different forms of aspergillosis
Disease group Disease group Disease group Disease group
CCPA ABPA CCPA ABPA SAFS SAFS
n 116 16 98 52 52
Median serum IgE level (IQR) 99.8 (26.4-350) (n107) 2739 (1100-7500) (n16) 2300 (1100-4550) (n97) 370 (140-750) (n52)
Aspergillus specific IgG 93.6 (103/110) 81.3 (13/16) 65.4 (53/81) 35.9 (14/39)
Positive fungal culture 25 (29/116) 25.0 (4/16) 23.5 (23/98) 21.2 (11/52)
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)
67
Distinguishing different forms of aspergillosis
Disease group Disease group Disease group Disease group
CCPA ABPA CCPA ABPA SAFS SAFS
n 116 16 98 52 52
Median serum IgE level (IQR) 99.8 (26.4-350) (n107) 2739 (1100-7500) (n16) 2300 (1100-4550) (n97) 370 (140-750) (n52)
Aspergillus specific IgG 93.6 (103/110) 81.3 (13/16) 65.4 (53/81) 35.9 (14/39)
Positive fungal culture 25 (29/116) 25.0 (4/16) 23.5 (23/98) 21.2 (11/52)
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)
68
Conceptual framework for CPA and IA
Chronic inflammation and fibrosis
Vascular invasion, necrosis, dissemination
Granulomas, acute inflammation, central necrosis
Aspergilloma - CCPA - CNPA/subacute IPA - acute
IPA
www.aspergillus.org.uk
69
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

70
6th Jan
24th Feb
Arendrup, Scand J Infect Dis 200638945
71
Obstructing bronchial aspergillosis
Patient ML Pre-bronchscopy
Patient ML After bronchoscopy
Denning et al, New Engl J Med 1991324 654
72
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
200524628
73
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 gt1,000 SPT or Aspergillus IgE
  positive.
• SAFS severe asthma fungal SPT or IgE positive
  total IgE lt1,000
• Some patients have overlap syndromes and more
  than 1 Aspergillus diagnosis