1. Solange BRESSON-HADNI
Reference-Centre Network for Care Management of Alveolar Echinococcosis.
Solange BRESSON-HADNI
Besançon University Hospital and Franche-Comté University.
Chronoenvironment, UMR CNRS 6249.
WHO Collaborative Centre for Prevention and Treatment of Human Echinococcosis.
Alveolar Echinococcosis French National Reference Centre.
BESANCON, FRANCE. 1

2. The French Alveolar Echinococcosis (AE) Network
Background:
1997 : European Network EurEchinoReg1
2003: French Network FrancEchino2,3
supported by the National Institute of Health Surveillance : InVS
« Institut de Veille Sanitaire »
collect AE cases exhaustively
inform on clinical and therapeutic changes
1.Kern P et al. Emerg Infect Dis 2003;9 :
2.Piarroux M et al. J Hepatol 2011;55:
3.Piarroux M et al. Emerg Inf Dis 2013; 19:

3. « Terms of reference » 2012-2016 :
WHO COLLABORATIVE CENTER FOR PREVENTION AND TREATMENT OF ECHINOCOCCOSIS
From 1995
« Terms of reference » :
To develop molecular, serological, and morphological methods for diagnosis and follow-up of echinococcosis
To provide professionals, researchers and institutions from WHO member countries with methodological support and expert advice in the field of echinococcosis
To develop eco-epidemiological investigations on Echinococcus spp. transmission to human and animal hosts at regional and continental scales
To participate in the organisation of meetings with WHO member states and in the production of WHO guidelines and manuals

4. « Terms of reference » 2012-2016 :
WHO COLLABORATIVE CENTER FOR PREVENTION AND TREATMENT OF ECHINOCOCCOSIS
From 1995
« Terms of reference » :
To develop molecular, serological, and morphological methods for diagnosis and follow-up of echinococcosis
To provide professionals, researchers and institutions from WHO member countries with methodological support and expert advice in the field of echinococcosis
To develop eco-epidemiological investigations on Echinococcus spp. transmission to human and animal hosts at regional and continental scales
To participate in the organisation of meetings with WHO member states and in the production of WHO guidelines and manuals

5. exhaustively collecting AE cases spreading expertise
1997 : European Network EurEchinoReg From 1995:
2003: French Network FrancEchino WHO Collaborative Center
exhaustively collecting AE cases spreading expertise
French informal network

6. exhaustively collecting AE cases spreading expertise
1997 : European Network EurEchinoReg From 1995:
2003: French Network FrancEchino WHO Collaborative Center
exhaustively collecting AE cases spreading expertise
French informal network
. 2012: National Reference Centre (CNR)
for Alveolar Echinococcosis
Dept of Parasitology/Besançon University Hospital .

7. National Reference Centre (CNR) for Alveolar Echinococcis
financial and human resources helpful in : - strengthening the physician network. - optimizing links among different structures concerned by this disease.

8. Besançon University Hospital
method
European Center for Disease Prevention and control
French Institute for Public Health Surveillance
InVS-Zoonosis department
Establishment for
the control of
zoonoses
ELIZ
National Agency for Food Safety, Environment and Labor ; ANSES
Competence Centres
Referral physicians from University Hospitals and/or General Hospitals in endemic areas
Specialized and general practitioners
FrancEchino/
National Reference Centre
Parasitology, Pathology and Pharmacy departments from French University Hospitals
Large national private medical analysis laboratories
Besançon University Hospital
WHO-CC
Franche Comté University
Hepatology
Parasitology
Visceral Surgery
Pharmacology
Radiology
Nuclear Medicine
Pathology
Endoscopy 8

9. 1982 -2013 : annual incident AE cases
FrancEchino Registry
: annual incident AE cases
573 AE cases

10. Time Space Evolution of the Distribution of AE Cases
221 cases
230 cases
NANCY
BESANCON
DIJON
LYON
CLERMONT-FERRAND km

11. Time Space Evolution of the Distribution of AE Cases
REIMS
230 cases
NANCY
BESANCON
STRASBOURG
DIJON
LYON
CLERMONT
FERRAND
GRENOBLE km

12. Time Space Evolution of the Distribution of AE Cases
Charleville
REIMS
230 cases
Metz
NANCY
BESANCON
STRASBOURG
Mulhouse
DIJON
Bourg en Bresse
LYON
CLERMONT
FERRAND
GRENOBLE km
Thonon
Chambéry
Rodez

13. For the last 3 years : annual meeting in Besançon :
offers all these physicians an opportunity to get together and exchange views on the registration and care management of AE patients.

14. AE PATIENTS DIAGNOSIS Still imperfect management situations
Wrong or delayed diagnosis :
atypical AE lesion:
- immunosuppressed patients++
- purely extra-hepatic localization
Unrecognized familial cases
Diffusion of information about these particular forms of the disease :
- dedicated website
- publishing general reviews
in largely diffused journal
- diffusing information on
opportunistic AE to concerned specialists
- giving lectures to general practionners/radiologists/
gastroenterologists
Inform on CNR offer :
- slides re-examination/PCR
- patient’s file discussion in
periodic multi-disciplinary meeting
With this network, we wish to optimize AE patients diagnosis. In fact, there are still (plutôt que already comme indiqué sur la dia?) imperfect management situations such as wrong or delayed diagnosis. Recent examples concerned AE in immunosuppressed patients which is currently emerging, also the very rare situation of a purely extra-hepatic localization, that is often associated to delayed diagnosis. Ignored familial cases is another example.

15. AE PATIENTS DIAGNOSIS Still imperfect Means to optimize
management situations
Means to optimize
Wrong or delayed diagnosis :
atypical AE lesion:
- immunosuppressed patients++
- purely extra-hepatic localization
Unrecognized familial cases
Disseminating information about these particular forms of the disease :
- creating a dedicated website
- publishing general reviews
in widely-read journals
- providing information on
opportunistic AE to concerned specialists
- giving lectures to general practitioners/radiologists/
gastroenterologists
Informing on CNR offer :
- slides re-examination/PCR
- patient’s file discussion in
periodic multi-disciplinary meetings
We can certainly optimize management at the diagnosis level by disseminating information about these particular form of the disease. Here are listed different measures : creating a dedicated website, publishing general reviews in widely-read journals, providing information on opportunistic AE to concerned specialists, giving lectures to general practitioners, radiologists, gastroenterologists. It is also important to inform on CNR offer, for examples, slides re-examination, specific PCR analysis and patient’s file discussion in periodic multidisciplinary meetings. We have established this meeting 2 years ago, on a every 2 months frequency.

16. AE PATIENTS TREATMENT Still imperfect management situations
Lack of precise loco-regional and
extra-hepatic extension evaluation
Palliative/debulking hepatectomies
Lost of follow-up after « curative
hepatectomy »
Sequential use of ABZ
Prompt ABZ interruption in case
of increased liver enzymes
Promote PNM staging classification
Diffusion of information about AE
Tt: - dedicated website
- publishing general reviews in
largely diffused journals
- giving lectures in UH/GH of
endemic AE areas/ distant areas
- periodic multi-disciplinary meeting in the CNR : possibility to send patient’s file
ABZ-sulphoxide plasma concentration monitoring: possibility to send samples to CNR
After the diagnosis, there also remains imperfect management situations for treatment : lack of precise loco-regional and extra-hepatic extension evaluation, palliative hepatectomies, lost of follow-up after presumed curative hepatectomy , without any adjuvant albendazole therapy, sequential use of albendazole, or prompt albendazole interruption in case of increased liver enzymes.

17. AE PATIENTS TREATMENT Still imperfect Means to optimize
management situations
Means to optimize
Lack of precise loco-regional and
extra-hepatic extension evaluation
Palliative/debulking hepatectomies
Lost of follow-up after « curative
hepatectomy »
Sequential use of ABZ
Prompt ABZ interruption in case
of increased liver enzymes
Promoting PNM staging classification
Disseminating information about AE
Tt: - dedicated website
- publishing general reviews in
widely-read journals
- giving lectures in UH/GH in
endemic AE areas/ distant areas
Informing on CNR offer :
- periodic multi-disciplinary meeting in the CNR : possibility to send patient’s file
- ABZ-sulphoxide plasma concentration monitoring: possibility to send samples to CNR
- training for physicians
Means to optimize in this field : promote PNM staging classifiaction, disseminate information about treatment , inform on CNR offer woth the possibility to discuss therapeutic option in our multi-disciplinary meeting, availibility to measure albendazole sulfoxide plasma concentration in our centre and training for medical doctors as well as surgeons;

18. AE PATIENTS TREATMENT Still imperfect Means to optimize
management situations
Means to optimize
Lack of precise loco-regional and
extra-hepatic extension evaluation
Palliative/debulking hepatectomies
Lost of follow-up after « curative
hepatectomy »
Sequential use of ABZ
Prompt ABZ interruption in case
of increased liver enzymes
Prospective multi-centric studies
Finally, another mean to optimize AE patients’ care is, of course, to promote prospective multi-centric studies

19. The Echino VISTA Project Principal investigators:
« Alveolar echinococcosis :
Parasite viability and innovative markers
for the follow-up of patients treated
with Albendazole »
Principal investigators:
Carine Richou, Solange Bresson-Hadni
Coordinator: Frédéric Grenouillet
And I will finish by presenting you in few slides The EchinoVista project : « alveolar echinococcosis : parasite viability and innovative markers for the follow-up of patients treated witrh albendazole » is a prospective clinical study

20. The Echino VISTA Project
Prospective clinical study
Hospital Clinical Research Program
Inter-regional funding : Ministry of Health
Six French centres: Besançon, Dijon, Lyon, Nancy, Reims, Strasbourg -UH-
It is a prospective clinical study, within the framework of the Hospital Clinical Research Program, supported by an inter-regional funding of the Ministry of Health. The project includes 6 French centres :Besançon, Dijon, Lyon, Nancy, Reims and Stasbourg University Hospitals

21. The Echino VISTA Project
Biologist partner: Parasitology Institute of Bern, Switzerland (B.Gottstein)
development of serum markers
Ethical Agreement: Committee for the Protection of People, Franche-Comté Region; March 1st 2012
The Parasitology Institute of Bern participates as a biologist partner for the development of serum markers.
The project has received Ethical agreement in March 2012.

22. Echino VISTA Optimally manage AE pts treated with
Main objective :
Optimally manage AE pts treated with
ABZ and to make appropriate and
timely decision of Tt withdrawal.
Its main objective is to optimally manage AE patients treated with albendazole and to make appropriate and timely decision of treatment withdrawal.

23. Echino VISTA
Exploratory analysis of existing and newly developed biological and imaging exams, for diagnosis and follow-up
Study of the relationship of these markers to the viability of the parasite and/or the activity of the parasitic lesions
It also includes an exploratory analysis of existing and newly developed biological and imaging exams for diagnosis and follow-up and a study of the relationship of these markers to the viability of the parasite and/or the activity of the parasitic lesions.

24. Echino VISTA Two groups of patients prospectively included:
Operated pts Non-operated pts
ABZ withdrawal ABZ withdrawal
after 1-year TT from the 4th year TT
negative PET-CT and serology
Two groups of patients are prospectively included in the study: patients with radical operation with the prospect of evaluating the possibility of albendazole withdrawal after 1year of treatment on the basis of negative PET-CT and serology. Non operated patients, with the prospect of evaluating the possibility of albendazole withdrawalfrom teh 4th year of treatment.

25. Echino VISTA
Additional studies associated with the prospective follow-up of patients :
- ABZ pharmacokinetics
- cytokines and other immunological markers
- prognostic value of the respect of a « safety margin » at operation
Additional studies on albendazole pharmacokinetics, on cytokine and other immunological markers and on the pronostic value of the respect of a safety margin by surgeons at operation are associated with the prospective follow-up of patients.

26. Echino VISTA
First prospective collaborative clinical study ever performed in France in the field of AE care management: 21 patients included (8 operated)
Similar project being set up in Urumqi, China
May serve as pilot project for a more ambitious multicentric European trial to explore new therapeutic strategies in AE.
Until now, 21 patients (among them, 8 with radical operation) have been included in this project which is the first prospective collaborative clinical study ever performed in France in the field of EA care management.
A similar project is being set up in Urumqi, china.
EchinoVista may serve as a pilot project for a more ambitious multicenter European to explore new
Therapeutic strategies in EA.

27. THANK YOU FOR YOUR ATTENTION !

28. Pathology Parasitology Nuclear medicine L.Millon Hepatology
F.Grenouillet
Nuclear medicine
O. Blagosklonov
Hepatology
S.Bresson-Hadni
C.Richou
Visceral surgery
GA. Mantion
B. Heyd
Radiology
E.Delabrousse
Ph.Manzoni
N.Sailley
Environmental
Biology
P.Giraudoux
F.Raoul
Immunology
D.A Vuitton
Pharmacology
MP.Brientini
D. Montanges
Human registry
J.Knapp, F Demonmerot
P.Evrard, S.Capelle
Pathology
S.Degano
S.Felix

29. Follow-up of the NON-operated on patients
Date
Clinical exami
Imaging
Albendazole blood measurement
Biological follow-up)
(hepatic work-up HWU = ASAT/ALAT + PAL, GGT, T Bili)
Antibodiesand circ Ags
Tube for RNA extraction (Paxgene tube)
PCR
Treg TH1 TH2 TH17
CHUB
Urumqi?
Inclusion
Yes
US & CEUS
PET-CT
MRI
BC, HWU
yes
yes*
J15
Yes T4
BC, ASAT/ALAT
J30 (M1)
Yes T0 & T4
J45
J60 (M2)
J75
J90 (M3)
NFS, BHC M4 M5 M6
Yes T0 M7 M8 M9
Yes T0
M10
M11
M12 (An1)
Oui
Oui*

30. Follow-up of NON-operated on patients
Date
Clinical exam
Imaging
Albendazole blood measurement
Biological follow-up)
(hepatic work-up = ASAT/ALAT + AP, GGT, Total Bili)
Antibodies
and circ Ags
Paxgene tube for RNA extraction
PCR
Treg TH1 TH2 TH17
CHUB
Urumqi?
M15
BC, ASAT/ALAT
M18
Oui
yes T0
BC, HWU
yes
M21
M24 (An2)
US & CEUS
PET & RMI
M27
M30
Yes T0
BC, BHC
M33
NFS, ASAT/ALAT
M36
(An 3)
TEP & RMI
M39
M42 T0
NFS, BHC
M45
M48
(An 4)
T0 & T4

31. Follow-up of operated on patients
Date
POST OP
Clinical exam
Liver Imaging
Other imaging studies
ABZ
measurement
Biological follow-up)
(hepatic work-up = ASAT/ALAT + AP, GGT, Total Bili)
Antibodies and circulating Ags
Paxgene tube for RNA
PCR
Treg
Th1 Th2 Th17
CHUB and Urumqi?
Before surgery
Yes
US & CEUS
PET-CT & RMI
Thorax & Brain CT
Within the month before surgery
T0/T4
BC, HWU
yes
J30 (M1)
Yes Surgeon
Yes T0
J90 (M3) M6 M9
M12 (Yr1)
PET & RMI
Yes T0/T4
M15
BHC **
(+ NFS si ABZ 2 ans)
M18
M21
HWU **
(+BC if ABZ 2 years)
M24 (Yr2)
M30
M36
(An 3)
CEUS PET & RMI
Thorax & CNS CT
M42
Oui
M48
(An 4)
HXU **
Stop ABZ 
(except OLT and ID patients) Or
StopABZ 
If OLT or ID or early wihdrawal refusal