Pathogeny and epidemiology E. Carreras MD, PhD

Fungal infections

Pathogeny and epidemiology

1

3

• physical barriers • neutrophil • T lymphocytes • antibodies • spleen 100 % months Aspergillus T lymphocytes antibodies

spleen antibodies spleen

Candida barriers neutrophil T lymphocytes antibodies spleen Protective mechanisms JM

IFI in HSCT

TRANSNET (2001-2006) 24 USA centres 16.390 HSCT (Allo 41%, Auto 59%) Median age: 50 y.

Kontoyiannis et al. CID 2010

58 ₅₂ 0 20 40 60 80 100 Aspergilosis Candidiasis

Mortalidad global a los 90 días

Overal mortality at 90 days

IFI: 998

Fungal infections

prophylaxis

Wald et al. JID 1997

Invasive Aspergillosis in HSCT

-

Epidemiology -

20 40 60 80 100 120 140 160 > 180 Days after-SCT 0 5 10 15 20 Patien ts alloHSCT autoHSCT

Retain fungi, bacteria & virus

HEPA or LAF rooms

Filter

Retain

Pre-filter dust

High-efficiency 90% particles >0,3 μ HEPA 99.97% particles >0,3 μ

Complements to HEPA rooms

Portable HEPA

FFP3 (N95)

masks

HEAPA and LAF isolation and

survival after HSCT

Passweg, et al. BMT 1998



bacteria



fungi

• 288 allo-HSCT (112 unrelated or mismatch)

• cotrimoxazole, cipro, NO antifungals

• free circulation in/out hospital

deaths by IFI: 4 Aspergillus (<1%) (2 after ICU)

Calgary experience Rusell, et al. BB&MT 2000 latitude Calgary: 51º 1’

Stockholm experience

• 36 allo-HSCT at home vs 54 inpatient

• free in/out hospital, no HEPA

deaths by IFI: 2.2%

Svahn, et al. Blood 2002

latitude Estocolmo: 59º 21'

Ottawa experience

• 178 allo-HSCT at home vs 196 in hospital

• only cotrimoxazole

infectious-deaths 3. 2% vs. 8.9% (p=0.03)

McDiarmid et al. EBMT meeting 2007

Fungal infections

prophylaxis

Risk groups for IFI

Risk group (%) Prophylaxis Neutropenia / disease / treatment Low (1-4%) Not indicated <7days MM, NHL, CLL Auto-HSCT Intermediate (5-10%) To be considered 7-14 days AML consolidation Allo-HSCT (standard) High (>10%) Recommended 14 days AML/MDS induction* Allo-HSCT (high-risk)** GvHDa>II, GVHDc ext. Candida colonization***

* Or refractory or in relapse; ** unrelated, >40 y, CBT; *** tropicalis in one or other spp. in >2 localizations

SEQ/AEHH consensus, De la Cámara et al Med. Clin (Barc.) 2010

IF:

PRD >2 mg/kg >2 w Severe mucositis CD34+ selection /

TCD / Campath

Prophylaxis with fluconazole

in HSCT recipients

Marr et al. Blood 2000

Survival Allogeneic Fluco Placebo Autologous Survival Fluco Placebo

Multicentre* Seattle#

IFI incidence

- Global  Itra =

- Breakthrough  Itra  Itra - Moulds  Itra  Itra - Candida  Itra = Toxicity - GI  Itra  Itra - Hepatic =  Itra Mortality - Global = = - Due to IFI  Itra =

Itraconazole

solution

vs. fluconazole for

prophylaxis in HSCT

Micafungin

vs. fluconazole for

prophylaxis in HSCT

Van Burik et al. CID 2005

Micafungin Fluconazole Overall efficacy 80% 73% Colonization Breakthrough infecc. Toxicity Mortality

Voriconazole

for fungal prophylaxis

in allo-HSCT

Randomized, Double-Blind (2003-2006)

• Fluconazole 400 mg/day

• Voriconazole 400 mg/day till day

+ 100 or +180 (if PDR or TCD y <200 CD4+

Wingard et al, Blood 2010; 116: 5111

Cumulative incidence IFI

Posaconazole

or fluconazole for prophylaxis

in severe graft-versus-host disease

Voriconazole

vs itraconazole for

Prophylaxis (IMPROVIT)

Azole plasma levels / Posaconazole

Bryant et al, Int J Antimicrob Ag 2010 90.5% of patients failed to reach the higher putative target of 0.7 microg/mL,

PROS

•

oral

•

oral, good biodisponibility (?)

•

broad spectrum

•

Proved efficacy against

aspergillus

•

limited toxicity

•

acceptable price

Prophylaxis with new azoles

CONS

•

Emergent Mycoses

Candidas no-albicans -- fluconazole

Mucormicosis – voriconazole (?) Candida glabrata -- micafungin

•

Cardiotoxicity

Voriconazole - posaconazole

•

Interference with CsA and Tacro

•

Variability of their levels

•

Role on galactomannan?

(in all prophylaxis)

Prophylaxis with new azoles

Liposomal AmB inhalated

Rijnders et al. CID 2008; 46: 1409

Invasive pulmonary aspergillosis

Recommended antifungal

prophylaxis in AML/MDS - HSCT

- Summary - ECIL 3 recommendations Acute Leuk Allo SCT Allo+ GvHD Fluconazole (400 mg qd oral) CI AI CI

Itraconazole (200 mg bid oral solution) CI BI BI

Posaconazole (200 mg tid oral) AI id AI

Voriconazole (200 mg bid oral) AI AI

Equinocandins (IV) id -- id

Micafungin (50 mg qd IV) -- CI --

Polyenes (IV) _{CI CI CI}

AmphoB-L (inhalated+fluco oral) BI BII id

ECIL3 Bone Marrow Transplantation 2010 Jul 26.

IFI diagnosis

•

Histopathology

•

Imaging techniques

- Chest x-ray, CT, MRI - Biopsy guided by TC

•

Microbiology

- Direct examination, fluorescence - Culture

- Serological: Ag and Ab detection - PCR techniques

Histopathology

An unremarkable chest x-ray should be

followed by a CT scan to reliably detect or to accurately exclude early pulmonary

infection in these patients.

A “positive” chest x-ray is enough to establish the diagnosis.

CT findings

in invasive

pulmonary

aspergillosis

Halo sign Crescent sign

Reverse halo sign

Zygomycosis

Angio-invasive AL - neutropenia

Airway-invasive

Allo-SCT immunosup

Bergeron et al, Blood 2012

CID 2007

Air-crescent

Nonspecific

Imaging findings in acute invasive

pulmonary aspergillosis: clinical

significance of the halo sign

Greene et al. Clin Infect Dis. 2007

halo sign

no halo sign

9 days

Brodoefel H, et al

Long-Term CT Follow-Up in 40 Non-HIV Immunocompromised Patients with Invasive Pulmonary Aspergillosis: Kinetics of CT Morphology and Correlation with Clinical Findings and Outcome

IFI diagnosis

•

Histopathology

•

Imaging techniques

- Chest x-ray, CT, MRI - Biopsy guided by TC

•

Microbiology

- Direct examination, fluorescence - Culture

- Serological: Ag and Ab detection - PCR techniques

Direct examination:

in BAL sputum, CRL

, ...

Gram

calcofluor silver stain

Serological methods

Detection of fungal components:

- Galactomannan  Platelia Aspergillus

(only in aspergillus and penicilium)

- Glucan  Glucatell (G test)

(all but cryptococcus and zygomycetes)

- Others  mannan + antimannan Ab

 Germ tubes Ab

(C. Albicans)

“Cut off” 0.5 GM first Days before X-ray thorax 12/15 (80%) 8 HRTC 12/15 (80%) 6 Cultures + 16/18 (89%) 9 Diagnostic 16/18 (89%) 14 Treatment 16/18 (89%) 6 Death 17/18 (94%) 14

First GM+ and other events

Maertens et al. J Infect Dis 2002

Antifungal therapy decreases sensitivity of

Aspergillus

Galactomannan

Without prophylactic

or empirical therapy With therapy or _prophylaxis

Galactomannan in Broncoalveolar lavage

GM index

≥

0.8

Sensitivity: 86%

Specifiocity: 91%

Galactomannan / false positive

Wheat. Transpl Infect Dis 2003

Allo-HSCT  mucositis / food

Children  Bifidobacterium

Pollution cotton  glucopiranose

Other moulds  same galactomannan

Cyclophosphamide  crossed reaction

Antibiotics  Pipera-Tazob / Amoxi

Pre-emptive

antifungal based on lab

or imagine tests

Therapeutic approaches to IFI in

neutropenic patients

Prophylaxis antifungal to all patients (primary or secondary) Empirical antifungal due to fever unresponsive to antibact. Treatment antifungal based on proven IFI

Probability of IFI

0% 100% Anticipated Early treatment

~ 80% unnecessary treat. (IFI incidence <20%)

Fungal infections

Preemptive antifungal therapy

Early treatment when:

• Patients with high risk of IFI (HSCT or AL)

(proved only in neutropenic w/o prophylaxis)

+

• GM positive 2 x >0.5

(2 x week, be careful w false positive) or

•

GM(-ve) but HRVT(+ve) + GM(+ve) in BAL [if HRCT (+) and both GM (-ve)  caution: treat

as a non-aspergillus infection]

Maertens et al. Clin Infect Dis. 2005

Galactomannan (GM) and computed tomography (CT)

-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection.

2 c. glabrata 1 zygomycosis were not correctly treated GM+ GM- CT+ BAL+ Antifungal treatment GM- CT+ BAL- GM- CT- NO Antifungal treatment 41/116 (30%) episodes would have had classical

empirical therapy Only 9/41 (22%)

Delayed preemptive

therapy!!

Role of the preemtive antifungal therapy in the era of systematic prophylaxis with azoles??

- Decreased sensibility of galactomannan - Higher incidence of zygomycoses

Fungal infections

Directed treatment

Random: Vorico + placebo Vorico + anidulafungin

• CNS affectation

• respiratory failure or severe sepsis criteria

• pulmonary cavitation or extensive lesion (?)

Combination of antifungals for IA treatment?

association of

voriconazole + anidulafungin

(or AmB + caspo) (CI) monotherapy w

voriconazole

(or AmB liposomal)

YES

NO

Pneumocystis jiroveci

(formerly carinii)

E. Carreras