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Problem
Antifungal expenditure is completely out of proportion with the scale of the problem Incidence of IFD in ICU (candida)
<0.6% Aspergillus infection in
haematological malignancy (0.5-12%) Aspergillus in SOT <5%
Harrison D et al Fungal Infection Risk Evaluation (FIRE) Study. Health Technol Assess 2013; 17(3).Pagano L et al. Haematologica 2006; 91: 1068-1075Pagano L et al. Clin Infect Dis 2007; 45: 1161-1170
Total UK antifungal expenditure c £112 million
Rising by 9% pa
Reasons Infection associated with significant
morbidity and mortality Signs and symptoms of systemic
infection are nonspecific Conventional diagnostic techniques are
suboptimal Delays in treatment associated with
poorer outcome
Fever Out of hoursAnxietyNo diagnosis
yes
yes
yes
yesno
no
no
no
no
no
yes
yes
yes
yesno
no
yes yes
yes
nono
no
no
no
no
yes
yes
yes
yes
no
Decision tree
Fever Out of hoursAnxietyNo diagnosis
yes
yes
yes
yesno
no
no
no
no
no
yes
yes
yes
yesno
no
yes yes
yes
nono
no
no
no
no
yes
yes
yes
yes
no
Decision tree
No therapy
Empirical therapy
include all patients likely to have invasive fungal infection and treat them with the safest and most effective drug
Aim of a directed strategy
exclude all patients unlikely to have invasive fungal disease and adopt a WAIT-and-SEE policy
Consensus criteria Aimed to provide definitions for proven,
probable and possible fungal infection that could facilitate clinical research
Designed for use in clinical trials Highly selective population Not representative of real life clinical practice Focus on specific radiological signs
Focus on defining DISEASE needs to shift towards INFECTION Needs a diagnostic approach
biomarkersDe Pauw et al CID
2008, 46
The biomarkers Antigen tests
Galactomannan (aspergillus) Beta D glucan (pan-fungal-ish) Lateral flow device
Molecular Aspergillus specific Panfungal Commercial (…….)
Galactomannan - in serum useful test in surveillance: high NPV Performance in
haematological malignancy better than in SOT neutropenic > corticosteroid treated group Adults >children
Influenced by pre-test probability (ie sensitivity increases with prevalence)
EORTC/MSG criteria heavily dependent on test being performed
Recommended by ECIL
Galactomannan – meta-analyses
30 studies > 7000 patients Prevalence 7.7% sensitivity78% (61% to 89%) specificity 81% (72% to 88%).
cut-off 0.5: 100 patients: 2 patients with IA, will be missed, 17 patients will be treated unnecessarily
cut-off 1.5 OD: 3 IA patients will be missed 5 patients will be treated unnecessarily
results were very heterogeneous. Insufficient data to look at clinical
utility
http://www.thecochranelibrary.com
PUO GM pos CT BAL
Pre test probabilityPre test probability
Maertens et al CID 2009
BAL
0.5 approved by FDA On the basis of clinical validity
PPV of GM BAL is 100% at an OD index cutoff of ≥3 only 76% at ≥ 0.5 (but NPV is high)
Beta D Glucan 4 different commercial tests
Heterogenous data : retrospective vs. prospective; Different cut offs “panfungal” – except cryptococcus and mucoracous
moulds Sensitivity, specificity variable but NPV high
High false-positives: up to 30% - bacteraemia, antibiotics, pre-/analytical contaminations
complex analytical procedures Analytical validity established Utility data limited Included in EORTC/MSG criteria
Beta D Glucan-meta-analysis
16 studies in 2979 patients Included case-controlled studies Included critical care, HM and
solid organ cancer patients Cut off 10-1000 pg/ml
Sensitivity 76.8% (67.1%–84.3%)
specificity 85.3% (79.6%–89.7%)
“area under ROC curve 0.89” “good diagnostic accuracy”
Karageorgopoulos et al Clin Infect Dis 2011;52(6):750
PCR The UK Fungal PCR consensus group
2004 technically validated candida PCR Made recommendations for aspergillus PCR
2006 European Aspergillus PCR Initiative set up 86 participants in 69 centres in 24 countries defined a standard for PCR for Aspergillus
Whole blood Serum plasma
optimal methodology to evaluate the performance and impact
QCMD availableWhite et al J Molec Diagn 2006; 8: 376White et al J Clin Micro 2010: 48 1231www.eapcri.eu/
NOTE: Weights are from random effects analysis
.
.
Overall (I-squared = 57.1%, p = 0.001)
Halliday 2006
Study
Ferns 2003
Scotter 2005
Williamson 2000
PCR=>2pos
ID
Kawazu 2004
Williamson 2000
Raad 2002
Buchheidt 2004
Buchheidt 2001
Stenghele 2006
El-Mahallawy 2006
Ferns 2003
Lass-Floerl 2004
Subtotal (I-squared = 52.9%, p = 0.030)
White 2006
Halliday 2006
Stenghele 2006
Subtotal (I-squared = 62.4%, p = 0.001)
Hebart 2000 JID
Hebart 2000 BJH
Buchheidt 2004
Jordanides 2005
Florent 2006
Kawazu 2004
PCR=>1pos
16.00 (8.60, 29.79)
81.00 (4.54, 1443.84)
0.75 (0.05, 11.31)
55.00 (2.44, 1238.39)
325.00 (12.25, 8623.71)
OR (95% CI)
7.61 (0.94, 61.24)
93.00 (4.58, 1889.51)
177.29 (8.35, 3765.07)
3.04 (0.84, 11.06)
47.88 (13.87, 165.35)
8.66 (1.02, 73.47)
33.75 (8.90, 128.02)
1.33 (0.09, 20.11)
1.43 (0.34, 6.08)
15.97 (6.83, 37.34)
211.50 (24.37, 1835.39)
24.51 (1.39, 430.66)
12.50 (2.58, 60.45)
16.41 (6.43, 41.88)
53.28 (2.87, 989.20)
139.92 (7.21, 2716.71)
6.86 (1.65, 28.50)
7.97 (1.52, 41.74)
15.17 (6.00, 38.34)
11.92 (3.13, 45.34)
100.00
3.08
%
3.32
2.77
2.57
Weight
4.48
2.90
2.84
6.51
6.66
4.37
6.40
3.32
6.07
44.60
4.32
3.10
5.73
55.40
3.02
2.96
6.14
5.51
7.54
6.39
16.00 (8.60, 29.79)
81.00 (4.54, 1443.84)
0.75 (0.05, 11.31)
55.00 (2.44, 1238.39)
325.00 (12.25, 8623.71)
OR (95% CI)
7.61 (0.94, 61.24)
93.00 (4.58, 1889.51)
177.29 (8.35, 3765.07)
3.04 (0.84, 11.06)
47.88 (13.87, 165.35)
8.66 (1.02, 73.47)
33.75 (8.90, 128.02)
1.33 (0.09, 20.11)
1.43 (0.34, 6.08)
15.97 (6.83, 37.34)
211.50 (24.37, 1835.39)
24.51 (1.39, 430.66)
12.50 (2.58, 60.45)
16.41 (6.43, 41.88)
53.28 (2.87, 989.20)
139.92 (7.21, 2716.71)
6.86 (1.65, 28.50)
7.97 (1.52, 41.74)
15.17 (6.00, 38.34)
11.92 (3.13, 45.34)
100.00
3.08
%
3.32
2.77
2.57
Weight
4.48
2.90
2.84
6.51
6.66
4.37
6.40
3.32
6.07
44.60
4.32
3.10
5.73
55.40
3.02
2.96
6.14
5.51
7.54
6.39
1.0001 1 10000
Mengoli et al Lancet Infectious Diseases. 2009; 9: 89-96
PCR
Single negative PCR to exclude disease
2 consecutive PCRs to diagnose IA
Sensitivity 88% Specificity 75% DOR22
“Directed/pre-emptive” therapy
References Country Clinical HRCT GMMicro-
biologicalPCR
Non-comparative studies
Maertens 2005 Belgium X X X
Girmenia 2010 Italy X (X) X
Aguilar-Guisado 2010 Spain X X X
Barnes 2009 UK X X X X
Dignan 2009 UK X
Randomised, comparative studies
Cordonnier 2009 France X X (X)
Hebart 2009 Germany X
Observational studies
Pagano 2012 Italy X (X)
Galactomannan EIA
Open study 136 episodes of
neutropenia Patients receiving flucon
prophylaxis daily EIA GM + early CT
scanning in neutropenic febrile episodes
Antifungal given if 2 consecutive EIA GM results +ve (index ≥ 0.5)
and confirmed by BAL or CT Maertens et al. Clin Infect Dis 2005; 41: 1242
Maertens et al 35% of episodes met criteria for empirical
antifungal but only7.7% treated on basis of pre-emptive therapy
Duration of fever not affected 22 cases of IFD only one missed 3 breakthrough infections
2 candidaemias 1 mucorales
No excess mortality or fungal related death No impact on overall antifungal usage
despite deceased empirical use
Cordonnieret al CID 2009 48:1043
293 patients randomised empirical or pre-emptive therapy empirical arm received antifungals if they had
persistent/recurrent fever after 4 days pre-emptive patients given antifungal only if they
showed clinical and radiological signs of pneumonia/sinusitis positive GM index ≥ 1.5 Aspergillus colonization Septic shock CNS signs/periorbital inflammation Diarrhoea/mucositis ≥ grade 3 fever > 14 days
Cordonnieret al
Survival was not significantly “Non inferiority” demonstrated pre-emptive patients had more IFI
9.1% vs 2.7% pre-emptive patients received
significantly less antifungals no significant cost savings were
achieved Used ampho B deoxycholate first -line
Empirical vs. pre-emptive antifungal therapy
Empirical
Pre-emptive
IFI in Pre-emptive
IFI in Empirical
Cordonnier et al, Clin Infect Dis, 2009; 48: 1042-1051
Pagano et al Haematologica 2011; 96:1363
Observational: Empiric versus “pre-emptive” Data collection 397 HM patients
190 empiric ; 207”pre-emptive” More IFD in pre-emptive arm Increased mortality and antifungal use in
“pre-emptive arm” Fever driven, no screening, diagnostic work
up not standardized some GM usage, no PCR Pre-emptive group largely diagnosed on basis of
HRCT
PCR randomised
study of a PCR directed versus an empirical antifungal
more than 400 SCT patients
Safe Improved
survival at 30 days (not 100)
No reduction in antifungal drug use.
Nested PCR to guide antifungal therapy 42 patients with
cancer, neutropenia
AmB required in only 2 patients
Hebart et al. Blood 2004;104: 59A.
Lin et al. Clin Infect Dis. 2001;33:1621-1627
In Cardiff 549 high-risk haematology patients entering
neutropenic pathway 2005-2010 audited and followed up for a minumum of 12
months Twice weekly antigen and PCR testing (or GvHD) Itraconazole prophylaxis or AmBisome 7mg/kg/weekly Empiric antifungals not used unless
Clinical/mycological evidence of disease Itraconazole levels were subtherapeutic or unmeasured
First 125 patients analysed for safety and proof of concept
Data collected on compliance, incidence of IFD and efficacy of prophylaxis
Barnes et al Journal of Clinical Pathology 2009
Incidence of IFD (2005-2011) Invasive aspergillosis 9.6%
6 histologically proven (2 postmortem) 4 pulmonary (2 with dissemination) 2 invasive sinusitis
47 probable (23 possible IA)
Invasive Candidal infection 2% 12 proven
4 C. albicans, 3C. glabrata, 2C. tropicalis, 1C. parapsilosis, 1C. guilliermondii, 1 mixedC. albicans + C. glabrata
1 probable 2 non-aspergillus moulds
1 Mucoraceous mould, 1 Scedosporium prolificans Incidence of proven/probable IFD 12.3%
IA disease status of subjects
By EORTC/MSG diagnostic criteriaProven – 6Probable – 47Possible – 23NEF – 473
• 248 of NEF showed some signs suggestive of IA
• EIA positive n=36• PCR positive n=136• EIA and PCR positive n=75
• Aspergillus isolated n=5
Diagnostic accuracy Explore analytical validity. Clinical
validity, clinical utility Sensitivity specificity PPV, NPV, LR, DORs
Use ROC analysis to explore different thresholds for defining “cases”
EORTC/MSG EORTC – GM EIA EORTC + PCR Dual biomarker positivity Multiple positives versus single
Population AssayPositivity
ThresholdSensitivity (%) Specificity (%) PPV (%) NPV (%) LR+ LR- DOR
Provena, probableb vs No IFDc EIA
Single 96.2 (87.3-99.0) 76.7 (72.7-80.3) 31.7 (25.0-39.2) 99.5 (98.0-99.9) 4.14 0.05 84.15
Multiple 62.3 (48.8-74.1) 91.8 (88.9-93.9) 45.8 (34.8-57.3) 95.6 (93.3-97.1) 7.55 0.41 18.36
Provena, probableb, possibled
vs No IFDc EIA
Single 67.1 (55.9-76.6) 76.7 (72.7-80.3) 31.7 (25.0-39.2) 93.6 (93.7-97.6) 2.89 0.43 6.73
Multiple 43.4 (32.9-54.6) 91.8 (88.9-93.9) 45.8 (34.8-57.3) 91.0 (88.1-93.2) 5.27 0.62 8.54
Provena, probable
incorporating PCRe vs No IFDc
EIASingle 72.9 (61.5-81.9) 76.7 (72.7-80.3) 31.7 (25.0-39.2) 95.0 (92.4-96.8) 3.13 0.35 8.86
Multiple 47.1 (35.9-58.7) 91.8 (88.9-93.9) 45.8 (34.8-57.3) 92.1 (89.4-94.3) 5.72 0.58 9.93
Provena, probableb vs No IFDc PCR
Single 92.5 (82.1-97.0) 55.6 (51.1-60.0) 18.9 (14.6-24.1) 98.5 (96.2-99.4) 2.08 0.14 15.34
Multiple 73.6 (60.4-83.6) 79.9 (76.1-83.3) 29.1 (22.1-37.3) 96.4 (94.1-97.9) 3.66 0.33 11.08
Provena, probableb, possibled
vs No IFDc PCRSingle 86.8 (77.5-92.7) 55.6 (51.1-60.0) 23.9 (19.3-29.3) 96.3 (93.4-98.0) 1.96 0.24 8.27
Multiple 65.8 (54.6-75.5) 79.9 (76.1-83.3) 34.5 (27.2-42.5) 93.6 (90.7-95.6) 3.28 0.43 7.65
Provena, probable
incorporating PCRe vs No IFDc
PCRSingle 94.3 (86.2-97.8) 55.6 (51.1-60.0) 23.9 (19.3-29.3) 98.5 (96.2-99.4) 2.12 0.10 20.66
Multiple 71.4 (60.0-80.7) 79.9 (76.1-83.3) 34.5 (27.2-42.5) 95.0 (92.4-96.7) 3.56 0.36 9.95
Provena, probableb vs No IFDc
PCR or ELISA
Single 98.1 (93.4-100) 47.8 (42.0-53.5) 17.4 (11.9-22.9) 99.6 (98.5-100) 1.88 0.04 47.6
Multiple 79.2 (65.3-93.2) 76.7 (71.9-81.6) 27.6 (0.19-36.7) 97.1(94.9-99.2) 3.41 0.27 12.6
Provena, probableb, possibled
vs No IFDc
PCR or ELISA
Single 90.8 (82.5-99.1) 47.8 (42.0-53.5) 21.8 (16.0-27.6) 97.0 (94.2-99.8) 1.74 0.19 9.0
Multiple 69.7 (56.6-82.9) 76.7 (71.9-81.6) 32.5 (23.341.7) 94.0 (91.0-97.1) 3.00 0.39 7.6
Provena, probable
incorporating PCRe vs No IFDc
PCR or ELISA
Single 98.6 (92.3-100) 47.8 (42.0-53.5) 21.8 (0.17-0.28) 99.6 (96.1-100) 1.89 0.03 63.13
Multiple 90.0 (80.8-95.1) 76.7 (71.9-81.6) 36.4 (27.6-46.2) 98.1 (95.5-99.3) 3.87 0.13 29.7
Provena, probableb vs No IFDc
Both PCR and
ELISA
Single 90.6 (79.8-95.9) 84.4 (80.8-87.4) 39.3 (31.1-48.2) 98.8 (97.1-99.5) 5.79 0.11 51.76
Multiple (1 assay) 71.7 (56.2-87.2) 87.7 (84.0-91.5) 39.6 (27.1-52.1) 96.5 (94.3-98.7) 5.85 0.32 18.13
Multiple (both assays) 56.6 (43.3-69.1) 94.9 (92.6-96.6) 55.6 (42.4-68.0) 95.1 (92.8-96.7) 11.16 0.46 24.40
Provena, probableb, possibled
vs No IFDc
Both PCR and
ELISA
Single 63.2 (51.9-73.1) 84.4 (80.8-87.4) 39.3 (31.1-48.2) 93.4 (90.7-95.4) 4.04 0.44 9.24
Multiple (1 assay) 50.0 (35.7-91.5) 87.7 (84.0-91.5) 39.6 (27.1-52.1) 91.6 (88.4-94.90 4.08 0.57 7.16
Multiple (both assays) 39.5 (29.3-50.7) 94.9 (92.6-96.6) 55.6 (42.4-68.0) 90.7 (87.8-93.0) 7.78 0.64 12.20
Provena, probable
incorporating PCRe vs No IFDc
Both PCR and
ELISA
Single 68.6 (57.0-78.2) 84.4 (80.8-87.4) 39.3 (31.1-48.2) 94.8 (92.2-96.5) 4.38 0.37 11.76
Multiple (1 assay) 54.3 (39.4-69.2) 87.7 (84.0-91.5) 39.6 (27.1-52.1) 92.8 (89.8-95.9) 4.43 0.52 8.5
Multiple (both assays) 42.9 (31.9-54.5) 94.9 (92.6-96.6) 55.6 (42.4-68.0) 91.8 (89.1-93.9) 8.45 0.60 14.03
Statistical parameters
Sensitivity
Specificity PPV NPV LR+ LR- DOR
Proven, probable vs No IFD
PCR or GM EIA
Single 98.1 47.8 17.4 99.6 1.88 0.04
47.6
multiple
79.2 76.7 27.6 97.1 3.41 0.27
12.6
PCR and GM EIA
single 90.6 84.4 39.3 98.8 5.79 0.11
51.76
multiple
56.6 94.9 55.6 95.1 11.16 0.46
24.4
By EORTC/MSG criteria
Proven/probable disease versus no IFDDiagnostic odds ratio
Ascertainment biasE
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0
10
20
30
40
50
60
70
80
90
EORTC EORTC minus GM EORTC plus PCR
Performance of PCR
Utility in proven/probable n=53 First marker positive
PCR in 23 EIA in 15 PCR and EIA simultaneously positive in 7 radiological features in 8
In 85% biomarkers preceded specific radiological signs (range 1-118d)
Diagnostic accuracy Screening by PCR AND GM EIA can enable a
diagnosis of IA to be excluded
Positive PCR +GM EIA or multiple positive PCRs or EIAs can be used to accurately diagnosis IA
specificity 84.4%; sensitivity >90% DOR>50
Biomarkers are earliest markers in 85% of cases
Use antifungals more cost effectively
Antifungal expenditure
Similar units typically spending £1-2 mill pa
2005 2006 2007 2008 2009 2010 £0.00
£50,000.00
£100,000.00
£150,000.00
£200,000.00
£250,000.00
£300,000.00
£350,000.00
£400,000.00
Total Antifungal expenditure
Linear (Total Anti-fungal expendi-ture)
Cost of testing
Linear (Cost of testing)
Use of biomarkers
Regular screening throughout period or risk
Screening during fever only Diagnostic testing during
refractory fever only Confirmation when specific
radiological signs are present None - empiric therapy
Strategy Used
Influenced by Risk of IFD
Prevalence affects utility of diagnostic tests
ECIL recommend screening if IFD 5-10%
Prophylaxis used Mould active reduces utility of diagnostic
tests Availability of
Diagnostic tests Protective environments/HEPA filtered air
Incidence of IFD after posaconazole therapy
Pagano et al Haematological 2012; 97:963
Effect of antifungal therapy
Group
Days post infection
1 2 3 4 5
Test
qPCR
GM PCR GM PCR GM PCR GM PCR GM
Infected controls
2/3 0/3 3/3 1/3 3/3 3/3 3/3 3/3
Amphotericin B 2/3 1/3 3/3 3/3 3/3 3/3 3/3 3/3
Caspofungin 1/3 1/3 1/3 3/3 2/3 3/3 3/3 2/3
Posaconazole 1/3 0/3 1/3 2/3 3/3 3/3 1/3 2/3
Uninfected controls
0/3 0/3
McCulloch et al J Clin Path 2012; 65:83 Marr K A et al. Clin Infect Dis. 2005;40:1762-1769
Example
High risk patientPrevalence8- ≥10%
No Mould active prophylaxis – Screening regime
Mould active prophylaxis used – Diagnostic regime
Twice weekly screening of blood samples:
Galactomannan,And Aspergillus PCR
HRCT and BAL when infection suspectedDiagnostic testing during refractory fever with Beta D glucan
(serum) and Aspergillus PCR (BAL and blood or serum), galactomannan
(BAL and serum)
Targeted antifungal therapy for clinically diagnosed infection only with
biomarker confirmation
Single Positive biomarkerContinue screening process
>1 biomarker positive* triggers diagnostic workup to include relevant radiology and BAL if
indicated
No consistent clinical signs or symptoms indicates need for possible
pre-emptive therapy
Any consistent clinical signs or symptoms indicates need for antifungal
therapy
*For example: PCR and GM, or Multiple GM