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Diagnosis of pulmonary aspergillosis (ignoring allergy) David W. Denning Wythenshawe Hospital University of Manchester.

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Presentation on theme: "Diagnosis of pulmonary aspergillosis (ignoring allergy) David W. Denning Wythenshawe Hospital University of Manchester."— Presentation transcript:

1 Diagnosis of pulmonary aspergillosis (ignoring allergy) David W. Denning Wythenshawe Hospital University of Manchester

2 Conceptual framework Aspergilloma - CCPA - CNPA/subacute IPA - acute IPA Immune function Hyphal load in tissue Normal Massive Vascular invasion, necrosis, dissemination Granulomas, acute inflammation, central necrosis Chronic inflammation and fibrosis

3 Testing performance? Immune function Hyphal load in tissue Normal Massive Culture ++/- +/-+/- +/- Antigen Glucan+/-+? +?++ +/- Antibody ? - PCR (resp)+++? ++?++? ++ PCR (blood) -?-? -?+/- + Aspergilloma - CCPA - CNPA/subacute IPA - acute IPA

4 Testing performance? Pulmonary defect + innate immune defect corticosteroids neutrophil defect neutropenia multiple defects Immune function Hyphal load in tissue Normal Massive Culture ++/- +/-+/- +/- Antigen Glucan+/-+? +?++ +/- Antibody ? - PCR (resp)+++? ++?++? ++ PCR (blood) -?-? -?+/- +

5 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 Culture +ve in 56/67 (84%) Aspergillus antigen +ve 27/51 (53%) Meersemann et al, Am J Resp Med Crit Care 2004;170:621.

6 Testing performance? Pulmonary defect + innate immune defect corticosteroids neutrophil defect neutropenia multiple defects Immune function Hyphal load in tissue Normal Massive Culture(+)+/- +/-+/- +/- Antigen(-) Glucan(+/-)+? +?++ +/- Antibody(+++) ? - PCR (resp)(++)+? ++?++? ++ PCR (blood) -?-? -?+/- +

7 Organism/antigen/marker performance will vary by fungal load (in lung, but not necessarily blood) and possibly treatment

8 13/17 (76%) in acute leukaemia with CT abnormality 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 6 of 11 (55%) immunocompromised (8 of 11 +ve by PCR) 5/20 (25%) in suspected IFIs Becker, Br J Haem 2003;121:448; Sanguinetti, JCM 2003;41:3922; Musher, JCM 2004;42:5517. Aspergillus Antigen in BAL

9 Organism/antigen/marker performance will vary by fungal load (in lung, but not necessarily blood) and possibly treatment Antibody and imaging performance will be more independent of organism load to the same extent Antibody takes time to form (and tests are not standardised)

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

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

12 CT scan enlargement of IA on treatment despite good outcomes Caillot et al, J Clin Oncol 2001;19:253

13 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

14 Test sensitivity important: Microscopy methodology Culture versus PCR Histopathology versus culture

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

17 Test sensitivity important: Microscopy methodology Culture versus PCR Histopathology versus culture

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 PCR detection of Aspergillus (rRNA target) ve PCR -ve PCR Immunocom- promised pts IA not IA normal pts IA not IA Proven, probable and possible was 12, 13 and 5, of whom all proven and probable cases had abnormal chest CT scans, 11 had positive cultures from BAL (9) or sputum (2), 14 had positive cytology from BAL or sputum but were culture negative, 3 had positive galactomannan antigen tests and 3 had histological confirmation. 20 of the 31 patients died. Buchheidt Br J Haematol 2002;116:

20 Comparison of BAL antigen and real-time PCR Sanguinetti, Clin Microbiol. 2003;41: CultureAntigenPCR Proven/probable IA All haem malignancy 6/20 20/2018/20

21 Perlin, unpublished Real time PCR to distinguish Aspergillus species A. terreus resistant to amphotericin B Additional sensitivity will allow species detection and possibly resistance detection on culture negative clinical specimens

22 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 [All Tarrand, 2003] AlloBMT Roychowdhury, 2006

23 Test sensitivity important: Microscopy methodology Culture versus PCR Histopathology versus culture/antigen

24 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 Culture +ve in 56/67 (84%) Aspergillus antigen +ve 27/51 (53%) Autopsy +ve for hyphae in 27/41 (66%) Meersemann et al, Am J Resp Med Crit Care 2004;170:621.

25 Respiratory samples +ve for Aspergillus in ICU Vandewoude KH. Critical Care 2006;10:R31

26 Respiratory samples +ve for Aspergillus in ICU Vandewoude KH. Critical Care 2006;10:R31

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