prophylaxie, préemptif, empirique chez les patients

Lyon
study group
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
VIH
Aspléniques
Hépatopathies
OH chnq
IRC
REA
Maladies autoimmunes
CST long cours
IS / Biothérapies
Dysimmunité
Onco-Hémato.
CHTh
séquentielles
Profil:
intensité, durée
TOS
Transplantation
CSH
IMMUNODÉPRESSION/ Complications
SUPPRESSION non infectieuses
Gestion du
risque infectieux
Mécanismes des complications infectieuses chez les
immunodéprimés
Muqueuses
(mucite, GvHD,…)
FRANCHISSEMENT
/RUPTURE de
BARRIERE
Dysbiose microbiote
Profil de
dysimmunité /
reconstitution
immunitaire
SEUIL
Environnement
AÉROCONTAMINATION
Latence
Infections d’acquisition
Réactivation
Opportunistes/invasifs
Commensalisme/colonisation
Translocation hématogène
Virulence/Résistance
Liste non exhaustive…
Virulence/Résistance
Réactivation
Opportunistes/invasifs
Bactéries
Virus
Bactéries
Entérobactéries
Strepto/entérocoques
Staph aureus/coag nég
BGN non fermentants
HSV1/2
VZV
EBV
CMV
HHV-6/7/8
Adénovirus
BK virus
Parvovirus B19
Champignons
Candida spp.
Parasites
Toxoplasma
Bactéries
Mycobacterium TB complex
Streptococcus pneumoniae
Legionella spp.
Nocardia spp.
Virus
Influenza/parainfluenza
VRS
Champignons
Pneumocystis jirovecii
Aspergillus spp.
Mucorales
Fusarium spp.
Scedosporium spp.
Stratégies anti-infectieuses programmatiques des
immunodéprimés
Prophylaxie
primaire
Stratégie
préemptive
Traitement
empirique
Neutropénie fébrile
Traitement
étiologique
Prophylaxie
secondaire
Terrain
± statut sérologique
pré-interventionnel
Stratification
du risque
Terrain
+
Biomarqueur(s)
Imagerie
Terrain
+
Biomarqueur(s)
+
Clinique = fièvre++
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
Outcome proven IFI
All-cause mortality
Prophylaxie anti-Candida spp. et transplantation organe solide
Playford et al., Cochrane database 2004
Focus on liver transplantation
Small bowel
0%
Lung
7%
Pancreas
7%
Liver
27%
Other
0%
Heart
7%
Kidney
(unrelated
donor)
33%
Kidney (related
donor)
19%
TRANSNET cohort of multi-center transplantation network, transplant types
5-year “incidence cohort” n=16 808
TRANSNET cohort, Pappas et al., Clin Infect Dis 2010
Focus on liver transplantation
Cryptococcosis
6%
11.6%
8.6%
Endemic Other yeast
mycoses
2%
5%
Unspecified
yeast
1%
Unsepcified mold
2%
Other mold
2%
Zygomycoses
3%
Aspergillosis
11%
4.7%
Candidasis
68%
IFI type in liver transplant recipients n=378
TRANSNET cohort, Pappas et al., Clin Infect Dis 2010
Liver transplantation
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
All-cause mortality was not significantly affected
Playford et al., Eur J Clin Microbiol Infect 2006
Fluconazole – 400 mg/jour – ≥ 4 sem (> 10 sem ?)
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. 
2. 
3. 
4. 
5. 
6. 
7. 
8. 
9. 
Score de MELD ≥ 30 (controversial)
Re-transplantation
Transplantation for fulminant hepatic failure
CST ≥ 2 w within 4 w preceding transplantation
H° ≥ 48h in the ICU at the time of transplantation
Colonization with Candida spp. ≥ 2 sites within 4 w preceding transplantation
High RBC transfusions and operative time > 6h
Renal replacement therapy at the time or within 7d of transplantation
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
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
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.
Focus on liver transplantation
Issue 4: differential efficacy of antifungal agents : optimizing IFI prophylaxis ?
Echinocandine
2014-2015
Winston DJ et al., Am J Transplantation 2014
Referential comparator vs. new echinocandins
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
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.
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
Echinocandin use = careful consideration to cost,
resistance and lack of all cause survival benefit.
Singh N, Am J Transplant 2013
Winston DJ et al. Am J Transplant 2014
Huprikar S. Am J Transplant 2014
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
Inhalation de
conidies/spores aspergillaires
Colonisation
Hypersensisbilité
Asthme
ABPA
PHS
Immunocompétence
Immunodépression
modérée
Immunodépression
Sévère
Aplasie
Clairance
Cavités
préexistantes
Aspergillome
APC
cavitaire
APC
nécrosante
APC
subaigue
API
continuum
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
High risk : graft versus host disease
≈ 40%
40-70%
CHRONIC
J0
Inj° Greffon
J+100
CC forte dose ± IS (ciclo/tacro)
Décroissance lente (6 mois minimum)
Risque d’effet rebond
30% de mortalité reliée
(directe/indirecte)
ACUTE
Prouvée
Probable
Possible
Preuve histo-pathologique ou culture mycologique
milieu stérile
Critères de terrain
Critères clinico-radiologiques
Critère(s) mycologique(s)
Critères de terrain
Critères clinico-radiologiques
HOST CONDITION
Neutropenic host
Non-neutropenic host
LUNG CT SCAN
Early inflammation
Days
Hours
Bronchial and alveolar involvement
DIAGNOSTIC-DRIVEN
APPROACH
Bronchial phase
Angioinvasive phase
Culture-based diagnosis
GM antigenemia-based diagnosis
PCR-based diagnosis ?
Angioinvasion
Lung infarction
Statut immunitaire de l’hôte conditionne 2 typologies
Neutropénique
Non neutropénique
Angio-invasive
Endobronchique
Leucémies aigues
Chimioth intensives
Allogreffe de CSH
en pre-engraftment
Allogreffe de CSH
en post-engraftment
GvHD
Transplanté org. solide
ANGIO-INVASIVE
Caillot et al., J Clin Oncol 1997 – typologie princeps
BRONCHIAL- or
AIRWAY-INVASIVE
Bergeron A et al., Blood 2012
Imaging
Nodule with halo
Air crescient-Cavity
Dissemination
Consolidation
Ground glass opacities
Fungal
burden
Tree-in-bud opacities
Bronchiectasis
Pattern
Bronchial or Airway-invasive
Angio-invasive
Galactomannan (GM)
serum
BALF
Time
Adapted from Nucci et al., Haematologica 2013
Prophylaxie anti-aspergillaire et patients hématologiques
haut risque
Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia
Cornely OA et al., N Engl J Med 2007; 356: 348-359
LAM + SMD
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%)
*proven or probable
Prophylaxie anti-aspergillaire et patients hématologiques
haut risque
Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease
Ulmann AE et al., N Engl J Med 2007; 356: 335-347
POSACO n=301
FLU n=299
96
99
Chronic extensive
64
60
Acute GvHD III-IV
138
137
Acute GvHD I-II
Fixed 112-day treatment period
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%)
16
12 (4%)
0.046
4 (1%)
IFI-related mortality
*proven or probable
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
Standard-risk HCT recipients
Little or no GvHD
Primary endpoint IFI p=0.11
Cumulative incidence of presumptive, probable,
and proven invasive fungal infection
Wingard JR et al, Blood 2010
Overall survival by treatment arm
Guidelines
ECIL-4 guidelines, Maertens J et al. Bone Marrow Transplant 2011
Patients at
high-risk for IPA
No prophylaxis
Mould-inactive
prophyalxis
(fluconazole)
Mould-active
prophyalxis
(posaco-vorico)
Issue 1: performance of culture and
non-culture diagnostic tools ?
Issue 2: performance of CT scan ?
IPA
diagnosis
Proven
Probable
Possible
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 ?
Diagnostic-driven approach: antigène Aspergillus
Galactomannane (Ag GM)
ANGIO-INVASIVE
Bronchial side
Vascular side
BRONCHIAL- or
AIRWAY-INVASIVE
Aspergillus GM
Aspergillus GM
Correlation inverse PNN/serum Ag GM
PNN
Serum Ag GM
Prophylaxie ATF ?
Sérum
LBA
Neutropénie
Pas de neutropénie
x 2/sem
Sb diminuée++
valeur cutt-off 0,8-1
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
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
Guidelines
ESCMID 2016 ?
Issue 1: diagnostic tools
The GM controversy
Antifungal therapy decreases sensitivity of the Aspergillus GM enzyme
immunoassay
Marr et al., Clin Infect Dis 2005
Maertens, Nucci & Donnely. Haematologica 2012
Girmenia & Perrone, Haematologica 2012
Issue 2: performance of CT scan
Non-neutropenic allogeneic HSCT-chronic GvHDcorticosteroids-posaconazole-cough and mild fever
Serum GM = 0.1 – BAL GM 3.7
Courtesy of J. Maertens
Issue 2: performance of CT scan
Solitary nodule under mould-active prophylaxis
Possible IPA or alternative invasive mould infection ?
(Mucormycosis,….)
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
n=117
Daily GM and clinical monitoring
OD index ≥ 0.5x2
≥ 5d ATB-refractory
n=30
fever
Infiltrats Rx
Fungal
positive culture
Thoracic CT Scan ± Sinus CT
Thoracic CT scan
BAL
Halo sign
Atypical sign
Endoscopie/BAL
+
Broad-spectrum
n=9
(7.7%)
ATF
therapy
_
Continued monitoring
no ATF therapy
Normal
“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
Empirical vs. preemptive antifungal therapy for high-risk, febrile, neutropenic
patients: a randomized, controlled trial
Cordonnier C et al. Clin Infect Dis 2009
Non-inferiority
Serum GM x 2/w – HR CT scan within 24h
Decrease cost 35%
Cordonnier C et al. Clin Infect Dis 2009
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
± statut sérologique
pré-interventionnel
Stratification
du risque
Terrain
+
Biomarqueur(s)
TDM HR
Terrain
+
Biomarqueur(s)
+
Clinique = fièvre++
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.
MERCI !
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.