Traitements antifongiques  : prophylaxie, préemptif, empirique chez les patients immunodéprimés

Florence ADER Service des Maladies Infectieuses et Tropicales, Hospices Civils de Lyon

Inserm1111 Centre International de Recherche en Infectiologie Université Claude Bernard Lyon 1, CNR Légionelles

Lyon HEMINF study group

Lyon

study group

Gestion du risque infectieux

Complications non infectieuses

Profil: intensité, durée

Dysimmunité

VIH

TOS

Transplantation CSH

Onco-Hémato. CHTh

séquentielles

Maladies auto-immunes

CST long cours IS / Biothérapies

IMMUNO- DÉPRESSION/ SUPPRESSION

Aspléniques Hépatopathies

OH chnq IRC REA

Muqueuses (mucite, GvHD,…)

FRANCHISSEMENT

/RUPTURE de BARRIERE

Profil de dysimmunité /reconstitution immunitaire

SEUIL

Environnement

AÉRO- CONTAMINATION

Dysbiose microbiote

Commensalisme/colonisation

Translocation hématogène Virulence/Résistance

Latence

Réactivation

Infections d’acquisition

Opportunistes/invasifs

Mécanismes des complications infectieuses chez les immunodéprimés

Virulence/Résistance Réactivation Opportunistes/invasifs

Bactéries Entérobactéries

Strepto/entérocoques Staph aureus/coag nég BGN non fermentants

Virus HSV1/2

VZV EBV CMV

HHV-6/7/8 Adénovirus

BK virus Parvovirus B19

Parasites Toxoplasma

Bactéries

Mycobacterium TB complex

Bactéries Streptococcus pneumoniae

Legionella spp. Nocardia spp.

Virus

Influenza/parainfluenza VRS

Champignons Candida spp.

Champignons Pneumocystis jirovecii

Aspergillus spp. Mucorales

Fusarium spp. Scedosporium spp.

Liste non exhaustive…

Prophylaxie primaire

Stratégie préemptive

Traitement empirique

Neutropénie fébrile

Traitement étiologique

Prophylaxie secondaire

Stratégies anti-infectieuses programmatiques des immunodéprimés

Terrain Terrain +

Biomarqueur(s) Imagerie

Terrain +

Biomarqueur(s) +

Clinique = fièvre++

± statut sérologique pré-interventionnel

Stratification du risque

Focus 1. Stratégies prophylactiques des infections à Candida spp.

Ecologie: Microbiome digestif

Dysbiose/Translocation Ecologie sélectionnée

F de R : Colonisation

Mucite KTC (biofilm)

CC Nutrition parentérale totale

Chirurgie digestive compliquée

Transplantation hptq Néonatologie

Réa

Mycologie : Rendement HC faible

Monitoring colonisation Biomarqueurs indirects

(peu sb, peu spcfq) Résistances

Prophylaxie anti-Candida spp. et transplantation organe solide Al

l-cau

se m

ortal

ity

Outco

me pr

oven

IFI

Playford et al., Cochrane database 2004

Focus on liver transplantation

TRANSNET cohort, Pappas et al., Clin Infect Dis 2010

Kidney (unrelated

donor) 33%

Kidney (related donor)

19%

Liver 27%

Pancreas 7%

Lung 7%

Heart 7%

Small bowel 0%

Other 0%

TRANSNET cohort of multi-center transplantation network, transplant types 5-year “incidence cohort” n=16 808

Focus on liver transplantation

TRANSNET cohort, Pappas et al., Clin Infect Dis 2010

11.6%

8.6%

4.7% Candidasis 68%

Aspergillosis 11%

Zygomycoses 3%

Other mold 2%

Unsepcified mold 2%

Cryptococcosis 6%

Endemic mycoses

5%

Other yeast 2%

Unspecified yeast 1%

IFI type in liver transplant recipients n=378

Liver transplantation

All-cause mortality was not significantly affected

Fluconazole – 400 mg/jour – ≥ 4 sem (> 10 sem ?)

Issue 1: is yeast-active prophylaxis (vs. placebo) relevant in LT ?

Historically, mortality rates of 71% in invasive candidiasis following LT Nieto-Rodriguez JA et al., Ann Surg 1996

Playford et al., Eur J Clin Microbiol Infect 2006

Liver transplantation Issue 2: does antifungal prophylaxis reduce IFI-related mortality in LT ?

Antifungal prophylaxis reduced the rate of proven or suspected IFI and mortality due to IFI when compared to placebo.

All-cause mortality is not significantly affected.

Playford et al., Eur J Clin Microbiol Infect 2006 Cruciani M, et al. Liver Transplant 2006

Evans JD et al, Am J Transplant 2014

Liver transplantation Issue 3: risk stratification: high-risk LT recipients ?

1.  Score de MELD ≥ 30 (controversial) 2.  Re-transplantation 3.  Transplantation for fulminant hepatic failure 4.  CST ≥ 2 w within 4 w preceding transplantation 5.  H° ≥ 48h in the ICU at the time of transplantation 6.  Colonization with Candida spp. ≥ 2 sites within 4 w preceding transplantation 7.  High RBC transfusions and operative time > 6h 8.  Renal replacement therapy at the time or within 7d of transplantation 9.  Re-operation involving the intra-abdominal cavity

Winston DJ et al. Ann Intern Med 1999;131: 729–737 Collins LA, et al. J Infect Dis 1994; 170: 644–652 Patel R, et al. Transplantation 1996; 62: 926–934 Sun HY, et al. Clin Transplant 2011; 25: 420–425

Saliba F, et al. Clin Transplant 2013; 27: E454–E461 Lichtenstern C, et al. Mycoses 2013; 56: 350–357 Huprikar S. Am J Transplant 2014; 14: 2683–2684

Model for End-stage Liver Disease (MELD) BIC 3.78 x (bilirubinémie (mg/dL))+11.2 x (INR)+9.57 x (créatininémie (mg/dL))+6.43

P. Kamath et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33(2):464-470

Guidelines

Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the IDSA. Clin Infect Dis 2009; 48: 503–535.

Silveira FP, Kusne S; AST Infectious Diseases Community of Practice. Candida infections in solid organ transplantation. Am J Transplant 2013; 13 (Suppl 4): 220–227.

fluconazole (200-400mg daily) : preferred antifungal drug or liposomal amphotericin B (L-AmB) (1-2 mg/kg daily) as post-operative antifungal prophylaxis for liver transplant recipients at high-risk of IFI Duration centre-dpdt : 21d to 4 w

Focus on liver transplantation

Echinocandine 2014-2015

Issue 4: differential efficacy of antifungal agents : optimizing IFI prophylaxis ?

Winston DJ et al., Am J Transplantation 2014

Referential comparator vs. new echinocandins

TENPIN trial (Liver Transplant European Study Into the Prevention of Fungal Infection) Randomized trial of micafungin for the prevention of invasive fungal infection in in high-risk liver transplant recipients.

Randomized, double-blind trial of anidulafungin versus fluconazole for prophylaxis of invasive fungal infections in high-risk liver transplant recipients.

-  Aspergillus infection or colonization p=0.08 (3% vs. 9%) -  Fluconazole-R Candida spp. isolates 5 vs. 0 -  Breakthrough IFIs (no prophylaxis prior to transplantation) p=0.96 (2.3% vs. 2.4%)

Winston DJ et al., Am J Transplantation 2014

Saliba F et al. Clin Infect Dis 2015

Focus on liver transplantation Issue 5: when using an echinocandin in LT ?

Increased risk : -  for invasive aspergillosis -  for developing an IFI resistant to fluconazole -  or having received fluconazole before transplantation

< 10% of LT recipients

Singh N, Am J Transplant 2013 Winston DJ et al. Am J Transplant 2014

Huprikar S. Am J Transplant 2014

Echinocandin use = careful consideration to cost, resistance and lack of all cause survival benefit.

Prophylaxie anti-Candida spp. et réanimation Prophylaxie anti-Candida spp. en néo-natologie etc…

Lavage chlorhexidine quotidien en réanimation adulte : diminution incidence des infections (bactériennes et fongiques) liées aux cathéters

Huang SS, et al. N Engl J Med 2013; 368:2255–65 Climo MW, et al. N Engl J Med 2013; 368:533–42

Montecalvo MA, et al. Am J Med 2012; 125:505–11

Focus 2. Stratégies prophylactiques des infections à Aspergillus spp.

Immuno-pathological spectrum of Aspergillus spp.

Park & Mehrad Clin Microbiol Rev 2009

Hypersensisbilité Immunocompétence Immunodépression modérée

Immunodépression Sévère Aplasie

Asthme ABPA PHS

Clairance Cavités

préexistantes

continuum

API Aspergillome APC

subaigue APC

nécrosante APC

cavitaire

Inhalation de conidies/spores aspergillaires

Colonisation

Focus Hématologie

Ecologie: Moisissures environnementales Seuil d’aérocontamination Secteur stérile

F de R : Neutropénie

CC IS, SAL, anti-TNF-α,

Fludarabine, alemtuzumab, etc…

GvHD

Mycologie: Rendement culture faible

Pb de contamination Biomarqueurs : Ag, PCR

Investigations: TDM HR

Endoscopie bchq

J0 Inj° Greffon

ACUTE

CHRONIC

J+100

30% de m

ortalité reliée (directe/indirecte)

≈ 40% 40-70%

CC forte dose ± IS (ciclo/tacro) Décroissance lente (6 mois minimum)

Risque d’effet rebond

High risk : graft versus host disease

Poss

ible

Prob

able

Prou

vée

Preuve histo-pathologique ou culture mycologique milieu stérile

Critères de terrain Critères clinico-radiologiques Critère(s) mycologique(s)

Critères de terrain Critères clinico-radiologiques

Neutropenic host Non-neutropenic host

Early inflammation

Bronchial and alveolar involvement

Bronchial phase Angioinvasion

Angioinvasive phase

Lung infarction

Days

Hours

LUNG

CT

SCAN

DI

AGNO

STIC

-DRI

VEN

APPR

OACH

GM antigenemia-based diagnosis

Culture-based diagnosis

HOST CONDITION

PCR-based diagnosis ?

Statut immunitaire de l’hôte conditionne 2 typologies

Neutropénique Non neutropénique

Angio-invasive

Leucémies aigues Chimioth intensives Allogreffe de CSH en pre-engraftment

Endobronchique

Allogreffe de CSH en post-engraftment

GvHD Transplanté org. solide

ANGIO-INVASIVE

BRONCHIAL- or AIRWAY-INVASIVE

Bergeron A et al., Blood 2012

Caillot et al., J Clin Oncol 1997 – typologie princeps

Fungal burden

Bronchial or Airway-invasive Angio-invasive Pattern

Imaging

Bronchiectasis

Ground glass opacities

Nodule with halo

Air crescient-Cavity Dissemination Consolidation

Galactomannan (GM)

serum BALF

Time

Adapted from Nucci et al., Haematologica 2013

Tree-in-bud opacities

Prophylaxie anti-aspergillaire et patients hématologiques haut risque

n FLU n=240 p POSA n=304 p ITRACO n=58 IFI* 32 19 (8%)) < 0.01 7 (2%) < 0.01 6 (10%) IA 22 15 (6%) < 0.001 2 (1%) < 0.001 5 (9%)

Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia Cornely OA et al., N Engl J Med 2007; 356: 348-359

LAM + SMD

*proven or probable

Prophylaxie anti-aspergillaire et patients hématologiques haut risque

n FLU n=299 p POSA n=301 IFI* 43 27 (9%) < 0.07 16 (5.3%) IA 28 21 (7%) < 0.006 7 (2.3%) IFI-related mortality 16 12 (4%) 0.046 4 (1%)

Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease Ulmann AE et al., N Engl J Med 2007; 356: 335-347

*proven or probable

Fixed 112-day treatment period

137

60

99

138

64

96

Acute GvHD I-II

Acute GvHD III-IV

Chronic extensive

POSACO n=301 FLU n=299

Prophylaxie anti-aspergillaire et patients hématologiques haut risque

Randomized, double-blind trial of fluconazole vs. voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation

Wingard JR et al, Blood 2010

Cumulative incidence of presumptive, probable, and proven invasive fungal infection Overall survival by treatment arm

Standard-risk HCT recipients Little or no GvHD Primary endpoint IFI p=0.11

ECIL-4 guidelines, Maertens J et al. Bone Marrow Transplant 2011

Guidelines

Patients at high-risk for IPA

Issue 1: performance of culture and non-culture diagnostic tools ? Issue 2: performance of CT scan ?

Proven Possible IPA diagnosis

Probable

No prophylaxis Mould-inactive

prophyalxis (fluconazole)

Mould-active prophyalxis

(posaco-vorico)

Issue 1: diagnostic tools Aspergillus culture

Positive cultures from respiratory secretions in IPA cases airway-invasive 83% vs. angioinvasive 17%

Bergeron A et al., Blood 2012

Non neutropenic patients (allo-HSCT) : agressive BAL strategy with direct exam + culture + GM

Nucci at al., Haematologica 2013

Impact of mould-active prophylaxis on cultural yield ?

ANGIO-INVASIVE BRONCHIAL- or AIRWAY-INVASIVE

Diagnostic-driven approach: antigène Aspergillus Galactomannane (Ag GM)

Aspergillus GM

Aspergillus GM

Bronchial side

Vascular side

Correlation inverse PNN/serum Ag GM

PNN Serum Ag GM

Meersmann et al., AJRCCM 2007 He et al., Crit Care 2011

Cordonnier et al., Clin Microbial Infect 2009 Hong Nguyen et al., ASBMT 2010

Zou et al., PloS One 2012 Nucci et al., Haematologica 2013

Neutropénie Pas de neutropénie Sérum x 2/sem Sb diminuée++

LBA valeur cutt-off 0,8-1

Cross-reactivity Fusarium spp./Aspergillus spp. GM assay Tortorano et al., Clin Microbiol Infect 2012

Intégration de la PCR dans les critères diagnostiques (?)

Guidelines IDSA 2016

Prophylaxie ATF ?

Guidelines ESCMID 2016 ?

Issue 1: diagnostic tools The GM controversy

Marr et al., Clin Infect Dis 2005 Maertens, Nucci & Donnely. Haematologica 2012

Girmenia & Perrone, Haematologica 2012

Antifungal therapy decreases sensitivity of the Aspergillus GM enzyme immunoassay

Non-neutropenic allogeneic HSCT-chronic GvHD-corticosteroids-posaconazole-cough and mild fever

Issue 2: performance of CT scan

Serum GM = 0.1 – BAL GM 3.7 Courtesy of J. Maertens

Solitary nodule under mould-active prophylaxis Possible IPA or alternative invasive mould infection ?

(Mucormycosis,….)

Issue 2: performance of CT scan

Wingard JR, Blood 2012

Une approche préemptive anti-IFI est-elle possible chez les neutropéniques haut risque d’Hématologie ?

1980 Pozzi et al. (1982)

Hémopathies myéloïdes/neutropénie fébrile = surmortalité par IFI

1990 Amphotéricine B empirique

Prophylaxie anti-levure (fluconazole) Emergence des IFI filamenteuses

2000 Optimisation pronostique: chb stériles/régimes CHth/transplantation de CSH…

Optimisation diagnostique: TDM HR/biomarqueurs/Endoscopie-LBA Prophylaxie anti-filamenteuse (posaco/vorico) + stratégie empirique

40-50% ttmt empirique vs. 10-15% vraie incidence IFI Changement de paradigme = considérer l’approche PRÉEMPTIVE ?

Galactomannan and computed tomography–based preemptive antifungal therapy in neutropenic patients at high risk for IFI: a prospective feasibility study Maertens J et al., Clin Infect Dis 2005

High-risk neutropenic patients

Daily GM and clinical monitoring

OD index ≥ 0.5x2 ≥ 5d ATB-refractory fever

Infiltrats Rx

Thoracic CT Scan ± Sinus CT

Fungal positive culture

Thoracic CT scan BAL

Endoscopie/BAL

Halo sign Atypical sign Normal

Continued monitoring no ATF therapy

Broad-spectrum ATF therapy

+ _

n=117

n=30

n=9 (7.7%)

“Proof-of-concept” pilot feasibility study of consecutive patients : 41 episodes qualified for empirical antifungal therapy vs. 9 episodes treated with preemptive approach = 78% decrease in ATF use from an estimated 35% to 7.7% 10 afebrile episodes ATF-treated on the account of GM+ 12 w-survival = 63.6%

But: 1 case undiagnosed zygomycose Daily monitoring GM until resolution of neutropenia (4170 serum dosages) : time and money-consuming !!??!! Lack of medico-economical data. Real-time availibility of diagnsotic facilities: radiology, endoscopy, mycology

Cordonnier C et al. Clin Infect Dis 2009

Empirical vs. preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial

Non-inferiority

Serum GM x 2/w – HR CT scan within 24h

Cordonnier C et al. Clin Infect Dis 2009 Decrease cost 35%

185 high-risk patients with acute myeloid leukemia The multi-state model evidenced that the risk of IA is a complex time function of neutropenia duration and risk management. The quantitative PCR assay accelerated the early detection of IA (P = .010), independently of other diagnostic information used to treat, while B-glucan assay did not (P = .53). Our results provide strong rationale for prospective studies testing a preemptive antifungal therapy, guided by clinical, radiological, and bi-weekly blood screening with GM antigenemia and a standardized quantitative PCR assay.

Terrain Terrain +

Biomarqueur(s) TDM HR

Terrain +

Biomarqueur(s) +

Clinique = fièvre++

± statut sérologique pré-interventionnel

Stratification du risque

Synthèse

Diffiiculté pour l’infectiologue : avoir la connaissance du contexte (pathologie de fond) et la maitrise de l’évaluation du risque dans les domaines concernés (réa, TOS, Hématologie, Néo-nat, Neuro-ophtalmo, etc..) Contexte évolutif++ : révision de la stratégie, adptatation La maitrise du risque IFI à Candida spp. est lié à l’identification des patients à risque en amont (importance des données de colonisation) et à la gestion des problèmes de résistance. Le maitrise du risque IFI aspergillaire est lié à l’évaluation dynamique du risque avec une balance à trouver entre les approches prophylactiques, préemptives et empiriques en fonction des catégories de patients et des capacités logistiques de chaque centre.

Lyon

study group F. Ader, E. Bachy, M. Balsat, F. Barraco, N. Benech, A-L. Bienvenu, G. Billaud, F. Biron, A. Boibieux, C. Chidiac, A. Conrad, S. Ducastelle-Leprêtre, O. Dumitrescu, D. Dupont, V. Escuret, T. Ferry, G. Fossard, E. Frobert, L. Gilis, S. Goutelle, A. Grateau, Y. Guillermin, M. Heiblig, H. Labussière-Wallet, M. Le Maréchal, L. Lebras, B. Lina, G. Lina, P. Miailhes, A-S. Michallet, M. Michallet, G. Monneret, F. Morfin-Sherpa, F-E. Nicolini, E. Paubelle, T. Perpoint, M. Peyrouse de Montclos, S. Picot, F. Poitevin-Later, A. Quintela, M. Rabodonirina, S. Roux, J. Saison, G. Salles, C. Sarkozy, A. Sénéchal, M. Sobh, X. Thomas, F. Valour, F. Wallet, M. Wallon, E. Wattel.

MERCI !