diagnosis of pulmonary aspergillosis (ignoring allergy) david w. denning wythenshawe hospital...
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Diagnosis of pulmonary aspergillosis(ignoring allergy)
David W. DenningWythenshawe Hospital
University of Manchester
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Conceptual framework
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
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Testing performance?Im
mu
ne
fu
nc
tio
n
Hy
ph
al lo
ad
in tis
su
e
NormalMassive
Culture + +/- +/- +/- +/-Antigen - - - + ++Glucan +/- +? +? ++ +/-Antibody +++ +++ ++ +? -PCR (resp) ++ +? ++? ++? ++PCR (blood) -? -? -? +/- +
Aspergilloma - CCPA - CNPA/subacute IPA - acute IPA
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Testing performance?
Pulmonary defect + innate immune defect
corticosteroidsneutrophil defect
neutropeniamultiple defects
Imm
un
e f
un
cti
on
Hy
ph
al lo
ad
in tis
su
e
NormalMassive
Culture + +/- +/- +/- +/-Antigen - - - + ++Glucan +/- +? +? ++ +/-Antibody +++ +++ ++ +? -PCR (resp) ++ +? ++? ++? ++PCR (blood) -? -? -? +/- +
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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 Culture +ve in 56/67 (84%)Aspergillus antigen +ve 27/51 (53%)
Meersemann et al, Am J Resp Med Crit Care 2004;170:621.
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Testing performance?
Pulmonary defect + innate immune defect
corticosteroidsneutrophil defect
neutropeniamultiple defects
Imm
un
e f
un
cti
on
Hy
ph
al lo
ad
in tis
su
e
NormalMassive
Culture (+) +/- +/- +/- +/-Antigen (-) - - + ++Glucan (+/-) +? +? ++ +/-Antibody (+++) +++ ++ +? -PCR (resp) (++) +? ++? ++? ++PCR (blood) -? -? -? +/- +
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Organism/antigen/marker performance will vary by fungal load (in lung, but not necessarily blood) and possibly treatment
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• 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
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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)
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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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Unequivocal ‘Halo sign’ surrounding a nodule
Herbrecht, Denning et al, NEJM 2002;347:408-15.
Small vessel angioinvasion
Halo
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CT scan enlargement of IA on treatment despite good outcomes
Caillot et al, J Clin Oncol 2001;19:253
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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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Test sensitivity important:
Microscopy methodology
Culture versus PCR
Histopathology versus culture
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Test sensitivity important:
Microscopy methodology
Culture versus PCR
Histopathology versus culture
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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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Test sensitivity important:
Microscopy methodology
Culture versus PCR
Histopathology versus culture
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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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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
• 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;116:803-811.
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Comparison of BAL antigen and real-time PCR
Sanguinetti, Clin Microbiol. 2003;41:3922-5.
Culture Antigen PCRProven/probable IAAll haem malignancy 6/20 20/20 18/20
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Perlin , unpublished
Real time PCR to distinguish Aspergillus
speciesA. terreus resistant to
amphotericin B
Additional sensitivity will allow species detection and possibly resistance detection on culture negative clinical specimens
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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[All 41 83 100 Tarrand, 2003]AlloBMT 17 0 17 Roychowdhury, 2006
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Test sensitivity important:
Microscopy methodology
Culture versus PCR
Histopathology versus culture/antigen
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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 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.
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Respiratory samples +ve for
Aspergillus in ICU
Vandewoude KH. Critical Care 2006;10:R31
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Respiratory samples +ve for
Aspergillus in ICU
Vandewoude KH. Critical Care 2006;10:R31
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www.aspergillus.man.ac.uk