Can we rely on imaging and biomarkers for preemptive antifungal therapy in hematological patients? Claudio Viscoli Professor of Infectious Disease, University.

Can we rely on imaging and Can we rely on imaging and biomarkers for preemptive biomarkers for preemptive

antifungal therapy in antifungal therapy in hematological patients?hematological patients?

Claudio ViscoliClaudio ViscoliProfessor of Infectious Disease, University of GenovaProfessor of Infectious Disease, University of Genova

Chief, Division of Infectious Disease, San Martino University Chief, Division of Infectious Disease, San Martino University Hospital, Genova, ItalyHospital, Genova, Italy

Laboratory Clinical aspects

Imaging

Diagnosis

A A comprehensive approach to the comprehensive approach to the diagnosis of IFIdiagnosis of IFI

Host

Underlying disease in invasive Underlying disease in invasive aspergillosisaspergillosis

7%

25%

28%

9%

8%

6%

9%

6% 2% BMT/Auto

BMT/Allo

Hematologic

SolidTransplant

AIDS

OtherImmune

Pulm

Other

None

595 patients

Patterson et al, Medicine, 2000

Underlying disease phase and Underlying disease phase and primary site of infectionsprimary site of infections

2%

6%

7%

4%

11%

6% 59%

5%

1st Induction 2nd Induction ConsolidationMaintenance AHSCT HSCTOther None

Pagano et al, Haematologica 20016%

1%

1%

1%

69%

15%

7%

Sino nasalCNS involvementDisseminatedGastrointestinalBloodSkinLung

n° 391 patients

CHARACTERISTIC PATTERNS OF INVASIVE ASPERGILLOSIS IN COMMONLY AFFECTED PATIENT GROUPS

Early during neutropenia (20-30%);Late (median 100 days) (75%), mainly related to severe GVHD and high-dose steroids

Allogeneic bone marrow or PSC transplantation, especially if matched unrelated or mismatched donor

During induction chemotherapy (75%);During maintenance or consolidation treatments (25%).Maily related to neutropenia

Acute Leukemia; Multiple Mieloma, stage II/III; Chronic leukemia in blast crisis; aplastic anemia; autologous bone marrow or PSC transplantation

TIMING OF INVASIVE ASPERGILLOSIS

UNDERLYING CONDITION

• 8988 admissions

• 71 positive cultures for Aspergillus

• Incidence rate 0.4% (37 proven/probable diseases as from EORTC-MSG criteria)

A comprehensive approach to the A comprehensive approach to the diagnosis of IFIdiagnosis of IFI

Laboratory Clinical aspects

Imaging

Diagnosis

Host

AspergillosisAspergillosis syndrome syndrome

• Cough (92%)

• Thoracic pain (76%)

• Hemoptysis (54%)

• Fever

• Neurological signs

• Nasal bleeding

• Nasal discharge

• Skin lesions

Fever 34/45 (75%)Cough 12/45 (27%), Dyspnoea 12/45 (27%) Chest pain 9/45 (20%). No sign or symptom 3 (positive GM with multiple pulmonary nodules on CT scan). Radiological pulmonary lesions were mainly represented by nodules (8/42, 19%), cavitations (10/42, 24%) and wedge-shaped consolidations (4/42, 10%). Notably, the halo sign was never found.

CLINICAL SYMPTOMS IN 45 CASES OF IA IN HSCT PATIENTS

Mikulska et al, BMT 2009

A comprehensive approach to the A comprehensive approach to the diagnosis of IFIdiagnosis of IFI

Laboratory Clinical aspects

Imaging

Diagnosis

Host

Invasive pulmonary aspergillosis

www.aspergillus.man.ac.uk

Normal lungIPA

IPA occurs in ~7% of acute leukaemia patients, 10-15% allogeneic BMT

patients

Unequivocal ‘Halo sign’ surrounding a noduleUnequivocal ‘Halo sign’ surrounding a nodule

Herbrecht, Denning et al, NEJM 2002;347:408-15.

Halo sign

Neutropenia PMN >> 500

CT scan evolution during IPACT scan evolution during IPA

High value notspecific delayed

Peripheral halo triangolar shape Air-crescent sign

d0 - d5 d5 - d10 d10 - d20

Caillot et al. J Clin Oncol. 2001; 19: 253-9.

Early use of high-resolution CT Early use of high-resolution CT scan for the diagnosis of scan for the diagnosis of pulmonary aspergillosispulmonary aspergillosis

• Allows significantly earlier diagnosis and therapy (5-10 days)

• Associated with overall improved survival

• Allows early surgical resection

Caillot et al, JCO, 1997 Heussel et al, JCO, 1999

Improved management of invasive pulmonary aspergillosis in Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic neutropenic patients using early thoracic computed tomographic

scan and surgeryscan and surgery ((CAILLOT et al. J Clin Oncol 1997)CAILLOT et al. J Clin Oncol 1997)

Improved management of invasive pulmonary aspergillosis in Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic neutropenic patients using early thoracic computed tomographic

scan and surgeryscan and surgery ((CAILLOT et al. J Clin Oncol 1997)CAILLOT et al. J Clin Oncol 1997)

SURVIVAL

0 50 100 150 200 days

systematic CT-scan

CT-scan on indication

RETROSPECTIVEANALYSIS

n = 37

RETROSPECTIVEANALYSIS

n = 37

DAYS TO DIAGNOSISFROM HOSPITAL ADMISSIONFROM FIRST SUSPICIONSUGGESTIVE CT-SCAN PRE-DIAGN

31 ± 9 7 ± 5

1 / 8

21 ± 5 2 ± 1

23 / 25

SYSTEMATIC CT-SCANBEFORE AFTER

0

20

40

60

80

100

120

Fever 34/45 (75%)Cough 12/45 (27%), Dyspnoea 12/45 (27%) Chest pain 9/45 (20%). No sign or symptom 3 (positive GM with multiple pulmonary nodules on CT scan). Radiological pulmonary lesions were mainly represented by nodules (8/42, 19%), cavitations (10/42, 24%) and wedge-shaped consolidations (4/42, 10%). Notably, the halo sign was never found.

CLINICAL SYMPTOMS IN 45 CASES OF IA IN HSCT PATIENTS

Mikulska et al, BMT 2009

A comprehensive approach to the A comprehensive approach to the diagnosis of IFIdiagnosis of IFI

Laboratory Clinical presentation

Imaging

Diagnosis

Host

Aspergillosis: obtaining a diagnosisAspergillosis: obtaining a diagnosis

Fine needle biopsy

Fine needle biopsy

SputumSputumBroncho-alveolar lavage

Surgical biopsy

Surgical biopsy

CT scan

Galacto-mannan, glucan,

PCR

(adapted from Ben de Pauw, 2001)

Galactomannan,glucan,

PCR

Traditional methodsTraditional methods

• Positive blood culture• Candida, Fusarium, Cryptococcus and others; not

Aspergillus, Mucor

• Positive histology from site of infection• allows generic diagnosis of fungal infection• requires positive culture for etiological definition

• Positive culture from site of infection• limitation due to contamination/colonization problems• may require positive histology for confirmation, depending

on site

NON INVASIVE DIAGNOSTIC TESTS NON INVASIVE DIAGNOSTIC TESTS FOR FUNGAL INFECTIONSFOR FUNGAL INFECTIONS

NON INVASIVE DIAGNOSTIC TESTS NON INVASIVE DIAGNOSTIC TESTS FOR FUNGAL INFECTIONSFOR FUNGAL INFECTIONS

EORTC EORTC IFICGIFICG

PCRPCR

PCRPCR

galactomannangalactomannanmannanmannan

capsular antigencapsular antigen

Panfungal-PCRPanfungal-PCR

(1(13)-ß-D-glucan3)-ß-D-glucan

C-Reactive Protein (CRP),C-Reactive Protein (CRP),procalcitonin (PCT),procalcitonin (PCT),interleukin-6 (IL-6)interleukin-6 (IL-6)

Species specific

Genus specific

Fungi

Fungi and bacteria

(13)-ß-D-glucan (BDG)

It’s a component of the fungal cell wall

There are 4 differnt commercial systemFDA approved 2004 as a support for the diagnosis of IFI

PANFUNGAL TEST

Positive in Doe’nt detect

Aspergillus Cryptococcus Candida ZygomicetesPneumocystis carinii FusariumTrichosporonSaccharomyces cerevisiaeAcremoniumHistoplasma capsulatum

CHARACTERISTICS

(13)-ß-D-glucan (BDG)LIMITS

•Need of glucan-free tools;•Important risk of contamination (glucan is ubiquitarious)

FALSE POSITIVE

Emodyalisis membranes (Miyazaki 1995, Yoshioka 1989)

Albumin (Usami 2002, Ohata 2003)

Immunoglobulins (Ogawa 2004)

Gauzes (Kimura 1995)

Hyperbilirubinemia, hypertriglyceridemia (Pickering 2004)

Antibiotics (amoxicillin-clavulanate) (Mennink-Kersten 2006)

Pseudomonas aeruginosa infections (Mennink-Kersten 2008)

Obayashi et al. CID 2008: 46 (15 June)

(13)-ß-D-glucan (BDG)

• PCR screening twice weekly during stay in hospital and once weekly after discharge until D100

• Antifungal therapy initiation– PCR group: in PCR+ patients with signs of infection and in patients with 2

consecutive PCR +– Empirical treatment group: 5d of febrile neutropenia

PCR based Empiricn = 196 n = 207

Antifungal therapy 109 (56%) 76 (37%)

(p<0.05)Proven invasive aspergilosis 11 16

• Reduction in early mortality (D30) in patients receiving PCR-based therapy but no difference in mortality at D100 and D180

Comparison of empirical and PCR-based preemptive antifungal therapy in 408 allogeneic

stem cell transplant recipients

(Hebart et al. ASH 2004)

Clinical Infectious Disease 2005; 41:1242-50

136episodes

136episodes

10 positive GM antigen

10 positive GM antigen

9 cases positive CT

9 cases positive CT

8282 defervesencedefervesence

8282 defervesencedefervesence

19 cases for pre-emptive antifungals

19 cases for pre-emptive antifungals

16%16%16%16%

1919 no feverno fever

1919 no feverno fever

117 febrile episodes

117 febrile episodes

++

136episodes

136episodes

11 unexplained relapses

11 unexplained relapses

30 persistent fever

30 persistent fever

8282 defervesencedefervesence

8282 defervesencedefervesence

1919 no feverno fever

1919 no feverno fever

117 febrile episodes

117 febrile episodes

41 candidates empirical antifungals

41 candidates empirical antifungals

35%35%35%35%

PREVERT Study Design• Prospective multicentric, unblinded, randomised (1:1)

trial run in 12 French centers between April 2003-February 2006

• Non-inferiority trial (< 8% difference in ITT and PP)• Randomisation stratified on center, induction vs

consolidation, and antifungal prophylaxis• Proven and probable IFI: EORTC-MSG definitions• Primary endpoint: survival either 14 days after

recovery from neutropenia or at 60 days if persistent neutropenia

Cordonnier et al. ASH 2006

Empirical v. Preemptive antifungal therapy in high risk neutropenic patients

PREVERT STUDY

*p<0.02*p<0.02p=ns

Overall survival Invasive fungal infections

Current situation

• Pre-emptive therapy logical, feasible, safe and probably cost-effective

• However, not all centers can perform lung CT scan and GM monitoring as often as required

• For this reason, empirical therapy remains standard practice in some smaller centers

• Big centers start approaching pre-emptive therapy• No drug has been tested in a comparative way for this

indication• Drugs approved for empirical or targeted therapy are likely

working (caspo, L-AmB, vorico).

My opinionMy opinion• Diagnosis of IFI is a complex intellectual exercise leading to

different degrees of diagnostic certainty and requiring experience, prudence and the availability of relatively sophisticated and/or invasive diagnostic tools (culture, biopsy, CT, GM, glucan?)

• The lower the risk (host factors) the higher the evidence required

• The strategy of how using the antigen-detection tests and/or PCR is still controversial and subject to personal interpretations

• Pre-emptive therapy has been shown to be safe and effective