Clinical and radiological presentation and diagnosis David W. Denning National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital]

Clinical and radiological presentation and diagnosis

David W. DenningNational 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

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)

Interaction of Aspergillus with the host

A unique microbial-host interaction

Immune dysfunction

Frequency

of a

sperg

illosis

Immune hyperactivity

Frequency

of

asp

erg

illosi

s

Acute IA

Subacute IA

AspergillomaChronic pulmonary

ABPASevere asthma with fungal sensitisation

Allergic sinusitis

. After Casadevall & Pirofski, Infect Immun 1999;67:3703

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 - ~3M4. 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. 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 - ~3M4. Asthma 197M in adults, of which ~10-20% severe,

UK and USA have very high prevalence rates5. 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))

Interaction of Aspergillus with the host

A unique microbial-host interaction

Immune dysfunction

Frequency

of a

sperg

illosis

Immune hyperactivity

Frequency

of

asp

erg

illosi

s

Acute invasiveaspergillosis

Subacute invasiveaspergillosis

AspergillomaChronic pulmonaryaspergillosis

ABPASevere asthma with fungal sensitisationAllergic sinusitis

. After Casadevall & Pirofski, Infect Immun 1999;67:3703

Human genetic influence on disease

expression

Chronic Pulmonary Aspergillosis

Common symptomsCommon 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

Camuset et al, Chest 2007:131:1435

9 patients with chronic cavitary pulmonary aspergillosis15 with chronic necrotising pulmonary aspergillosis

Underlying diseases - CPA

Smith, ISHAM 2009

• 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

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

Anonymous. Tubercle 1970;51:227

~10% of all cases of pulmonary TB get CPA

Acute tuberculosis

Lee, Eur J Radiol 2008; 67:100;

Before After treatment

Cavities

Cavities

Cavities

No cavities

Chronic pulmonary aspergillosis

Single fungal ball or aspergillomain a pre-existing

cavity

Infection of the lung by Aspergillus

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 aspergillomaHistology of an aspergilloma

Severo on www.aspergillus.man.ac.uk

Aspergillus fumigatus

Aspergilloma due to Aspergilloma due to A. nigerA. niger and oxalosis and oxalosis

Oxalate crystals in wall of the aspergilloma


Renal oxalosis

Early Aspergillus infection of a pulmonary Early Aspergillus infection of a pulmonary cavity – ‘pre-aspergilloma’cavity – ‘pre-aspergilloma’

Aspergillus growth on the surface of a pulmonary cavity


Orderly hyphal growth on the inside of the cavity

‘Multicavity’ disease is the

hallmark of chronic cavitary pulmonary

aspergillosis (CCPA)


Aspergilloma #3 – spatially ordered isolates from multiple cavities

Bowyer et al, unpublished

Aspergillus precipitins (Aspergillus antibody (IgG) ) in blood

Severo on www.aspergillus.org.uk

Patient 1blood

Patient 2blood

Patient 3blood

Patient 4blood

Patient 5blood

Patient 6blood

Aspergillus extract

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

Single fungal ball or aspergillomain a pre-existing

cavity

Infection of the lung by Aspergillus

Chronic cavitary

pulmonary aspergillosis+/- fungal

ball

Chronic cavitary pulmonary aspergillosis – CT reconstruction


Chronic cavitary pulmonary aspergillosis (CCPA) – sputum production


Aspergillus cultures positive in CCPA in 10-40% of cases only

‘Multicavity’ disease is the hallmark of chronic cavitary pulmonary aspergillosis

(CCPA)


Chronic cavitary pulmonary aspergillosis (CCPA) – haemoptysis


Chronic Cavitary Pulmonary Aspergillosis

Normal 30 year female smoker

Patient JAJan 2001

Chronic Cavitary Pulmonary Aspergillosis

Patient JAApril 2003

Multifocal cavities with aspergillomas – unrecognised phenotype


18F-FDG PET positive pulmonary nodules in aspergillosis – a differential diagnosis of lung

cancer

Baxter, Thorax 2011

10 patients

Presentations like lung cancer

1 subacute IPA1 ABPA1 aspergilloma7 CPA

Aspergillus IgG 28 ->200 mg/L

All positive on histology

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)

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

Patient SY, Aspergillus Website

Inhaled steroids

Proposed new criteria for ABPA

1. Serum IgE >1000 IU/mL2. Asthma OR CF 3. 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 ABPAPatient AL

www.aspergillus.org.uk

May 2010 January 2011 June 2011

Exacerbation of ABPAPatient AL


September 2011

Mucoid impaction due to ABPA


Mucoid impaction due to ABPA


Sputum in ABPA


ABPA – bronchoscopy views showing mucous plugging


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

Green et al, J Allergy Clin Immunol 2005;115:1043

Airborne fungal fragments

Fungal fragment

Diffusing allergen leeching out of fungus in contact with liquid

Bowyer et al, BMC Genomics 2006;7:251

Genomic analysis of allergens

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

0.0

2.5

5.0

7.5

10.0

12.5

15.0

17.5

20.0M

ea

n s

en

siti

zati

on

sc

ore

(m

m)

(Mea

n a

nd

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

Colonisation in ‘normal’ lungs

Lass-Florl et al, Br J Haematol 1999;104:745

22 of 30 (73%) grew a fungus in both lung

samples taken

10/30 (33%) grew >1 species

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).

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 ABPA

Asthma in ICU 29/57 (51%) 22/57 (39%)

Outpatient asthma 90/755 (39%) 155/755 (21%)

P value 0.010.001

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)

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)

Comparison of ABPA and SAFS serology

ABPA results normal range date 1 date 2

SAFS results

Patient1

2

O’Driscoll, unpublished

Skin prick testing – example of SAFS result

Cladosporium +ve

Fungal sensitisation in severe asthma – skin prick test or RAST for

diagnosis?N= 121 patients screened

O’Driscoll et al, Clin Exp Allergy. In press

SPT + RAST both positive

100%

50%

4310 13

34

SPT positiveRAST negative

SPT negativeRAST positive

SPT negativeRAST negative

}>23%

discordant results

Fungal sensitisation in severe asthma – number sensitised to one or more

fungi

O’Driscoll et al, Clin Exp Allergy. In press

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 Aspergillus 8 to Candida 3 to Trichophyton 3 to Penicillium 1 to Alternaria 1 to Cladosporium

Distinguishing different forms of aspergillosisDisease 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)

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 mentagrophyt

e

33.3% (2/6) 100% (3/3) 65.2% (30/46) 25.0% (9/36) 23.1% (3/13)

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)

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 mentagrophyt

e

33.3% (2/6) 100% (3/3) 65.2% (30/46) 25.0% (9/36) 23.1% (3/13)

Distinguishing different forms of aspergillosis

Conceptual framework for CPA and Conceptual framework for CPA and IAIA


Aspergilloma - CCPA - CNPA/subacute IPA - acute IPA

Imm

une

func

tion

Hyphal load in tissue

Normal

Massive

Vascular invasion, necrosis,

disseminationGranulomas, acute

inflammation, central necrosis

Chronic inflammation and fibrosis

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

Arendrup, Scand J Infect Dis 2006:38:945

6th Jan 24th Feb

Obstructing bronchial aspergillosis

Patient ML Pre-bronchscopy

Denning et al, New Engl J Med 1991;324: 654

Patient ML After bronchoscopy

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

Documents

Clinical and radiological presentation and diagnosis David W. Denning National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital]