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Getting to the diagnosis of aspergillosis: Tests and their interpretation David W. Denning Wythenshawe Hospital University of Manchester.

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Presentation on theme: "Getting to the diagnosis of aspergillosis: Tests and their interpretation David W. Denning Wythenshawe Hospital University of Manchester."— Presentation transcript:

1 Getting to the diagnosis of aspergillosis: Tests and their interpretation David W. Denning Wythenshawe Hospital University of Manchester

2 Spores inhaled Aspergillus Life-cycle Hyphal elongation and branching Germination Mass of hyphae (plateau phase)

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

4 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)

5 Early diagnosis of invasive aspergillosis is important Treatment started 11d Mortality 40% 90% Von Eiff et al, Respiration 1995;62:241-7.

6 Modalities for early diagnosis of invasive aspergillosis CT scanning Microscopy Antigen (blood or respiratory fluid) PCR (blood or respiratory fluid)

7 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:

8 Unequivocal Halo sign surrounding a nodule Herbrecht, Denning et al, NEJM 2002;347: Small vessel angioinvasion Halo

9 Criteria for Halo Sign ggggn n = nodular lesion gg = 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

10 Criteria for Air Crescent Sign s Usually appear late in angio-invasive aspergillosis after recovery from neutropenia S = sequestrum ac = air crescent acac Differentiate from non-specific thick- or thin-walled cavities lacking sequestra Crescent of gas surmounting soft tissue sequestrum within a nodular or cavitary lesion Greene et al, ECCMID 2003

11 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:

12 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.

13 Contribution of CT scans and antigen testing to rapid diagnosis of IA Caillot et al, J Clin Oncol 2001;19:253

14 Bronchoalveolar lavage for diagnosis of invasive pulmonary aspergillosis % positive result in all those with definite or probable aspergillosis PatientsBALBALEitherReference culturecytologyor both Acute leukaemia--50Albeda, 1984 Leukaemia235359Kahn, 1986 Leukaema000Saito, 1988 Leukaemia, BMT, Levy, 1992 Oncology BMT focal000McWhinney, diffuse

15 Microscopy Ruchel R, Fluorescent brighteners such as Calcufluor white, Blankophor increase sensitivity and speed

16 Sputum Cultures for Fungus Horvath & Dummer, Am J Med 1996;100: Bacteriological media inferior to fungal media – 32% higher yield on fungal media

17 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.

18 Prospective study of 197 bronchial washes in 176 patients (most leukaemia, most lung infiltrates on X-ray) Results PCR detection of Aspergillus (rRNA target) ve PCR -ve PCR Immunocom- promised pts IA not IA normal pts IA not IA Positive predictive value (PPV) % in at risk patients Negative predictive value (NPV) % in at risk patients Buchheidt Br J Haematol 2002;116:

19 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.

20 Aspergillus Antigen Test Diagnosis or surveillance? Only blood, or BAL, CSF etc Best OD cut-off 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: ; and others

21 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

22 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.

23 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)

24 Simple aspergilloma Patient RT December 2002 Cough (mild) & tired Wythenshawe Hospital

25 Aspergilloma Severo on

26 Chronic Cavitary Pulmonary Aspergillosis Normal smoking 30 year woman Patient JA Jan 2001

27 Chronic Cavitary Pulmonary Aspergillosis Patient JA Feb 2002

28 Chronic Cavitary Pulmonary Aspergillosis Patient JA April 2003

29 Chronic Cavitary Pulmonary Aspergillosis Patient JA July 2003

30 Chronic cavitary pulmonary aspergillosis an example of radiographic failure Patient SS April Patient SS July 2004, despite receiving itraconazole for 3 months

31 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

32 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 91Post Oct 91P value Patients2219 Mean time from IPA sign to diagnosis days days0.002 Pre-IPA Dx antibody tests positive Post-IPA Dx antibody tests positive 16/1914/19NS Antigen tests positive8/147/19NS

33 Antibody diagnosis of invasive aspergillosis Herbrecht et al, J Clin Microbiol 2002;20: In house ELISA method Definite IA 20/31 (64.5) Probable IA 11/67 (16.4) Possible IA 14/55 (25.5) All episodes45/153 (29.4)

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