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Getting to the diagnosis of aspergillosis: Tests and their interpretation. David W. Denning Wythenshawe Hospital University of Manchester. Aspergillus Life-cycle. Germination. Spores inhaled. Hyphal elongation and branching. Mass of hyphae (plateau phase). www.aspergillus.man.ac.uk.

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Getting to the diagnosis of aspergillosis tests and their interpretation l.jpg

Getting to the diagnosis of aspergillosis: Tests and their interpretation

David W. Denning

Wythenshawe Hospital

University of Manchester


Aspergillus life cycle l.jpg

Aspergillus Life-cycle

Germination

Spores inhaled

Hyphal elongation and branching

Mass of hyphae (plateau phase)

www.aspergillus.man.ac.uk


Classification of aspergillosis l.jpg

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

Persistence

without disease

  • colonisation of

    the airways or nose/sinuses

Allergic

  • Allergic bronchopulmonary (ABPA)

  • Extrinsic allergic (broncho)alveolitis (EAA)

  • Asthma with fungal sensitisation (SAFS)

  • Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

CLASSIFICATION OF ASPERGILLOSIS

Airways/nasal exposure to airborne Aspergillus


Classification of aspergillosis4 l.jpg

CLASSIFICATION OF ASPERGILLOSIS

Invasive aspergillosis

  • Acute (<1 month course)

  • Subacute/chronic necrotising (1-3 months)

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

Airways/nasal exposure to airborne Aspergillus

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)


Early diagnosis of invasive aspergillosis is important l.jpg

Early diagnosis of invasive aspergillosis is important

Treatment started <10d>11d

Mortality 40% 90%

Von Eiff et al, Respiration 1995;62:241-7.


Modalities for early diagnosis of invasive aspergillosis l.jpg

Modalities for early diagnosis of invasive aspergillosis

  • CT scanning

  • Microscopy

  • Antigen (blood or respiratory fluid)

  • PCR (blood or respiratory fluid)


Investigations for diagnosis of ipa l.jpg

Investigations for diagnosis of IPA

Abnormal/All %

Chest X-ray89/98 (91)

Focal disease 58/98 (59)

Cavitation 5/98 ( 5)

Diffuse/multiple26/98 (27)

Chest CT scan23/23(100)

Focal disease 3/23 (13)

Cavitation 4/23 (17)

Diffuse/multiple 16/23 (70)

Bronchoalveolar lavage36/61 (59)

Transbronchial biopsy 4/6 (67)

Open lung biopsy 4/8 (50)

Denning et al, J Infection 1998;37:173-80.


Slide8 l.jpg

Unequivocal ‘Halo sign’ surrounding a nodule

Halo

Small vessel angioinvasion

Herbrecht, Denning et al, NEJM 2002;347:408-15.


Criteria for halo sign l.jpg

gg

gg

Criteria for Halo Sign

“Perimeter of ground-glass opacity surrounding a nodular lesion”

Identified early in angio-invasive aspergillosis

n

Differentiate from nodular lesions with unsharp margination that lack a perimeter of ground-glass

gg= ground-glass halo

n= nodular lesion

Greene et al, ECCMID 2003


Criteria for air crescent sign l.jpg

Differentiate from non-specificthick- or thin-walled cavities lacking sequestra

ac

ac

Criteria for Air Crescent Sign

“Crescent of gas surmounting

soft tissue sequestrum within

a nodular or cavitary lesion”

Usually appear late in angio-invasive aspergillosis after recovery from neutropenia

s

ac=air crescent

S=sequestrum

Greene et al, ECCMID 2003


Pulmonary nodules a useful feature if invasive pulmonary aspergillosis l.jpg

Pulmonary nodules a useful feature if invasive pulmonary aspergillosis

CT features in 48 CTs of which 17 IPA

IPAOther

Halo13/17 0/31

Nodules 14/1711/31

Masses 6/17 2/31

Kami, Mycoses 2002;45:287-94.


Pulmonary nodules a useful feature if invasive pulmonary aspergillosis12 l.jpg

Pulmonary nodules a useful feature if invasive pulmonary aspergillosis

CT features in 235 CTs in patients with IPA

Macronodule (>1cm)221 (94%)

Halo143 (60%)

Consolidation 71 (30%)

Macro-nodule, infarct shaped 63 (27%)

Cavitary lesion 48 (20%)

Air bronchograms 37 (16%)

Clusters of small nodules (<1cm) 25 (11%)

Pleural effusion 25 (11%)

Air crescent sign 24 (10%)

Non-specific ground glass 21 (9%)

Greene submitted, from Herbrecht N Engl J Med 2002:347:408.


Contribution of ct scans and antigen testing to rapid diagnosis of ia l.jpg

Contribution of CT scans and antigen testing to rapid diagnosis of IA

Caillot et al, J Clin Oncol 2001;19:253


Bronchoalveolar lavage for diagnosis of invasive pulmonary aspergillosis l.jpg

Bronchoalveolar lavage for diagnosis of invasive pulmonary aspergillosis

PatientsBALBALEitherReference

culturecytologyor both

Acute leukaemia--50Albeda, 1984

Leukaemia235359Kahn, 1986

Leukaema000Saito, 1988 Leukaemia, BMT, 406467Levy, 1992

Oncology

BMT focal000McWhinney,

diffuse10001001993

% positive result in all those with

definite or probable aspergillosis


Microscopy l.jpg

Fluorescent brighteners such as Calcufluor white, Blankophor increase sensitivity and speed

Microscopy

Ruchel R, www.aspergillus.man.ac.uk/images


Sputum cultures for fungus l.jpg

Sputum Cultures for Fungus

Bacteriological media inferior to fungal media – 32% higher yield on fungal media

Horvath & Dummer, Am J Med 1996;100:171-8.


Aspergillus workload and significance l.jpg

Aspergillus workload and significance

3 year survey in Spanish teaching hospital

404 isolates from 260 patients

1/1000 micro samples positive

31/260 (12%) had invasive disease

Point score system for IA developed:

Invasive sample positive 1

> 2 positive samples 2

leukaemia2

neutropenia5

corticosteroid Rx2

Score of 1 or 2 = 10.3%, of 3 or 4 = 40%, of >5 = 70%

Bouza J Clin Microbiol 2005;43:2075.


Slide18 l.jpg

PCR detection of Aspergillus (rRNA target)

Prospective study of 197 bronchial washes in 176 patients (most leukaemia, most lung infiltrates on X-ray)

Results

Immunocom-promised pts

IA not IA

‘normal’ pts

IA not IA

+ve PCR

-ve PCR

Positive predictive value (PPV) - 83.8% in at risk patients

Negative predictive value (NPV) - 98.1% in at risk patients

Buchheidt Br J Haematol 2002;116:803-811.


Bsmm proposed standards of care l.jpg

BSMM proposed standards of care

  • All bronchoscopy fluids from patients suspected of infection should be examined microscopically for hyphae and cultured on specialised media.

  • All clinical isolates of Aspergillus should be identified to species level

Denning, Barnes and Kibbler. Lancet Infect Dis 2003;3:230.


Slide20 l.jpg

  • Aspergillus Antigen Test

  • Diagnosis or surveillance?

  • Only blood, or BAL, CSF etc

  • Best OD cut-off - 0.7

  • False positives in kids / antibiotics

  • False negative with antifungal

  • prophylaxis

  • Not as useful for non-hematology

  • Not useful if pre-existing antibody

Herbrecht et al, J Clin Microbiol 2002;20:1898-906; and others


Slide21 l.jpg

Aspergillus Antigen in BAL

  • 13/17 (76%) in acute leukaemia with CT abnormality

  • 5/20 (25%) in suspected IFIs

  • 17/17 (100%) in neutropenic patients before antifungal Rx, 0% after 3d antifungal therapy

  • 20/20 (100%) in haem-onc pts with IPA

  • 37/49 (76%) in HSCT & haem-onc with IPA

Becker, Br J Haem 2003;121:448; Sanguinetti, JCM 2003;41:3922; Musher, JCM 2004;42:5517.


Invasive aspergillosis in icu l.jpg

Invasive aspergillosis in ICU

127 of 1850 (6.9%) consecutive medical ICU admissions with IA or colonisation (micro/histol).

89/127 (70%) did not have haematological malignancy

67/89 proven/probable IA, 33 of 67 (50%) COPD

In 67 IA patients without haem malignancy:

Culture +ve in 56/67 (84%)

Aspergillus antigen +ve 27/51 (53%)

Autopsy +ve for hyphae in 27/41 (66%)

Predicted mortality = 48%, actual 91%

Meersemann et al, Am J Resp Med Crit Care 2004;170:621.


Classification of aspergillosis23 l.jpg

CLASSIFICATION OF ASPERGILLOSIS

Invasive aspergillosis

  • Acute (<1 month course)

  • Subacute/chronic necrotising (1-3 months)

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

Airways/nasal exposure to airborne Aspergillus

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)


Slide24 l.jpg

Simple aspergilloma

Patient RT

December 2002

Cough (mild) &

tired

Wythenshawe Hospital


Slide25 l.jpg

Aspergilloma

Severo on www.aspergillus.man.ac.uk


Slide26 l.jpg

Chronic Cavitary Pulmonary Aspergillosis

Normal smoking 30 year woman

Patient JA

Jan 2001


Slide27 l.jpg

Chronic Cavitary Pulmonary Aspergillosis

Patient JA

Feb 2002


Slide28 l.jpg

Chronic Cavitary Pulmonary Aspergillosis

Patient JA

April 2003


Slide29 l.jpg

Chronic Cavitary Pulmonary Aspergillosis

Patient JA

July 2003


Slide30 l.jpg

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


Chronic pulmonary aspergillosis serology l.jpg

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

14 of 18 (78%) had elevated total IgE (>20), 13 >200 and 7 >400

9 of 14 (67%) had Aspergillus specific IgE (RAST)

Denning DW et al, Clin Infect Dis 2003; 37:S265


Contribution of ct scans and antibody testing to rapid diagnosis of ia l.jpg

Contribution of CT scans and antibody testing to rapid diagnosis of IA

Caillot et al, J Clin Oncol 2001;19:253 (unpublished data)


Antibody diagnosis of invasive aspergillosis l.jpg

Antibody diagnosis of invasive aspergillosis

In house ELISA method

Definite IA20/31 (64.5)

Probable IA11/67 (16.4)

Possible IA14/55 (25.5)

All episodes45/153 (29.4)

Herbrecht et al, J Clin Microbiol 2002;20:1898-906


Slide34 l.jpg

www.aspergillus.man.ac.uk


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