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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 !