getting to the diagnosis of aspergillosis: tests and their interpretation david w. denning...
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Getting to the diagnosis of aspergillosis: Tests and their
interpretation
David W. DenningWythenshawe Hospital
University of Manchester
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Spores inhaled
Aspergillus Life-cycle
www.aspergillus.man.ac.uk
Hyphal elongation and branching
Germination
Mass of hyphae (plateau phase)
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CLASSIFICATION OF ASPERGILLOSIS
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 (SAFS)• Allergic Aspergillus sinusitis (eosinophilic
fungal rhinosinusitis)
Persistencewithout disease- colonisation of the airways or nose/sinuses
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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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Early diagnosis of invasive aspergillosis is important
Treatment started <10d>11d
Mortality 40% 90%
Von Eiff et al, Respiration 1995;62:241-7.
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Modalities for early diagnosis of invasive aspergillosis
• CT scanning• Microscopy• Antigen (blood or respiratory fluid)• PCR (blood or respiratory fluid)
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Investigations for diagnosis of IPA
Abnormal/All %Chest X-ray 89/98 (91) Focal disease 58/98 (59) Cavitation 5/98 ( 5) Diffuse/multiple 26/98 (27)
Chest CT scan 23/23 (100) Focal disease 3/23 (13) Cavitation 4/23 (17) Diffuse/multiple 16/23 (70)
Bronchoalveolar lavage 36/61 (59)Transbronchial biopsy 4/6 (67)Open lung biopsy 4/8 (50)
Denning et al, J Infection 1998;37:173-80.
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Unequivocal ‘Halo sign’ surrounding a noduleUnequivocal ‘Halo sign’ surrounding a nodule
Herbrecht, Denning et al, NEJM 2002;347:408-15.
Small vessel angioinvasion
Halo
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Criteria for Halo Sign
gggg
ggggnn
n = nodular lesiongg = ground-glass halo
Identified early in angio-invasive aspergillosis
Differentiate from nodular lesions with unsharp
margination that lack a perimeter of ground-glass
“Perimeter of ground-glass opacity
surrounding a nodular lesion”
Greene et al, ECCMID 2003
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Criteria for Air Crescent Sign
ss
Usually appear late in angio-invasive aspergillosis after
recovery from neutropenia
S = sequestrumac = air crescent
acac
acac
Differentiate from non-specificthick- or thin-walled cavities
lacking sequestra
“Crescent of gas surmounting soft tissue sequestrum within a nodular or cavitary lesion”
Greene et al, ECCMID 2003
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Pulmonary nodules a useful feature if invasive pulmonary aspergillosis
CT features in 48 CTs of which 17 IPA
IPA OtherHalo 13/17 0/31Nodules 14/17 11/31Masses 6/17 2/31
Kami, Mycoses 2002;45:287-94.
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Pulmonary nodules a useful feature if invasive pulmonary aspergillosis
CT features in 235 CTs in patients with IPA
Macronodule (>1cm) 221 (94%)Halo 143 (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.
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Contribution of CT scans and antigen testing to rapid diagnosis of IA
Caillot et al, J Clin Oncol 2001;19:253
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Bronchoalveolar lavage for diagnosis
of invasive pulmonary aspergillosis% positive result in all those with definite or probable aspergillosis
Patients BAL BAL Either Referenceculture cytology or both
Acute leukaemia - - 50 Albeda, 1984Leukaemia 23 53 59 Kahn, 1986Leukaema 0 0 0 Saito, 1988 Leukaemia, BMT, 40 64 67 Levy, 1992 OncologyBMT focal 0 0 0 McWhinney, diffuse 100 0 100 1993
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Microscopy
Ruchel R, www.aspergillus.man.ac.uk/images
Fluorescent brighteners such as Calcufluor white,
Blankophor increase sensitivity and speed
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Sputum Cultures for Fungus
Horvath & Dummer, Am J Med 1996;100:171-8.
Bacteriological media inferior to fungal media –
32% higher yield on fungal media
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Aspergillus workload and significance
3 year survey in Spanish teaching hospital404 isolates from 260 patients1/1000 micro samples positive
31/260 (12%) had invasive disease
Point score system for IA developed:Invasive sample positive 1> 2 positive samples 2leukaemia 2neutropenia 5
corticosteroid Rx 2
Score of 1 or 2 = 10.3%, of 3 or 4 = 40%, of >5 = 70%
Bouza J Clin Microbiol 2005;43:2075.
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Prospective study of 197 bronchial washes in 176 patients (most leukaemia, most lung infiltrates on X-ray)
Results
PCR detection of Aspergillus (rRNA target)
31 6 0 5
2 102 0 30
+ve PCR
-ve PCR
Immunocom-promised pts IA not IA
‘normal’ pts IA not IA
Positive predictive value (PPV) - 83.8% in at risk patientsNegative predictive value (NPV) - 98.1% in at risk patients
Buchheidt Br J Haematol 2002;116:803-811.
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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.
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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
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• 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.
Aspergillus Antigen in BAL
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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.
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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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Simple aspergilloma
Patient RTDecember 2002
Cough (mild) &tired
Wythenshawe Hospital
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AspergillomaAspergilloma
Severo on www.aspergillus.man.ac.uk
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Chronic Cavitary Pulmonary Aspergillosis
Normal smoking 30 year woman
Patient JAJan 2001
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Chronic Cavitary Pulmonary Aspergillosis
Patient JAFeb 2002
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Chronic Cavitary Pulmonary Aspergillosis
Patient JAApril 2003
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Chronic Cavitary Pulmonary Aspergillosis
Patient JAJuly 2003
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Chronic cavitary pulmonary aspergillosis an example of radiographic failure
Patient SSApril 2004
www.aspergillus.man.ac.uk
Patient SSJuly 2004, despite receiving itraconazole for 3 months
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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
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Contribution of CT scans and antibody testing to rapid diagnosis
of IA
Caillot et al, J Clin Oncol 2001;19:253 (unpublished data)
Pre Oct ‘91 Post Oct ‘91 P value
Patients 22 19
Mean time from IPA sign to diagnosis
6.8 + 5 days
2.2 + 2.3 days
0.002
Pre-IPA Dx antibody tests positive
16 6 0.008
Post-IPA Dx antibody tests positive
16/19 14/19 NS
Antigen tests positive
8/14 7/19 NS
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Antibody diagnosis of invasive aspergillosis
Herbrecht et al, J Clin Microbiol 2002;20:1898-906
In house ELISA method
Definite IA20/31 (64.5)
Probable IA11/67 (16.4)
Possible IA14/55 (25.5)
All episodes 45/153 (29.4)
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www.aspergillus.man.ac.uk