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Hepatitis E: a curious Hepatitis E: a curious zoonosiszoonosis
Nicole Pavio (INRA, AFSSA LERPAZ, ENVA)
Ecole Nationale Veterinaire d’Alfort, France
2
Water, soiled food
Genotypes 1, 2
Genotypes 3 et 4
Endemic RegionsEndemic RegionsAsia, Africa, Central AmericaAsia, Africa, Central America
Sporadic CasesSporadic CasesUS, Europe, JapanUS, Europe, Japan
Genotype 3, 4
Environment ?????
????? (Japan: grilled Liver, Sushi)
Cas sporadiques
VHE (2)
VHE (3)
(2)
(1, 2)
VHE (3)
VHE (1)VHE (1) VHE (1)
VHE (1, 4)VHE (1)
VHE (1)
VHE (3, 4)
Régions d’endémie
• Acute Hepatitis * enteric transmission• Incubation time : 40 days • Fulminate Hepatite : 1 -4% (20% pregnancy)
*chronic in recipient transplants and HIV+
Hepatitis E VirusHepatitis E VirusHepeviridaeHepeviridae, , hepevirushepevirus
Q: Is the animal reservoir responsible for zoonotic transmissions ?
Possible animal Réservoirs
33% Japanese cats (n=135) Usui et al, 2004
Animals Countries Ab Prevalence
SwineSwine Worldwide 30-80%
Rat India, Brazil 50-80%
Cat Japan 33%
Dog Brazil 7%
Sheep India, China, Brazil
Goat India, China, Brazil
Wild boarWild boar Japan, France, Germany, Italy, Spain, Hungary
5-42%
Deer Japan, Hungary 2.6%
Chicken USA, Brazil, Australia 20-30%
Bovine Brazil 1.42%
Horse Egypt 13%
Mongoose Japan 8.3%
Crossing the Species Barrier
GenotypeGenotype Natural HostNatural Host Exp ModelsExp Models InfectionInfection
1 & 2 HumanHuman Macaque +
Swine -
Rat +
3 HumanHuman Macaque +
Swine +
SwineSwine Macaque +
Swine +
Chicken nd
Rat nd
Lamb +
Avian ChickenChicken Macaque -
Swine -
Chicken +
Rat nd
Turkey +
nd: not determined
Model of experimental infection in swine
Asymptomatic (few liver lesions, no increase of ASAT,ALAT, feces excretion,
seroconversion)
Extra-hepatic sites of multiplication : small intestine, colon, lymph nodes, high
excretion in bile, spleen, . (Williams et al JCM 2001).
No effect in pregnant gilts (Kasorndorkbua et al 2003).
Few differences of physiopathology between swine and human genotype 3 strains.
Highly contagious R0 = 8.8 (Bouwknegt et al Vet Res 2008)
Asymptomatic
Occurs around 10 weeks (after weaning, lost Ab maternal)
Viral excretion between 12 and 15 weeks, seroconversion at 16-20 weeks
> 90% herds are infected (USA, Europe, Asia)
HEPATITIS E IN SWINE
Natural infection
Model of experimental infection in swine
HEPATITIS E IN SWINE
Bouwknegt
et al Vet Res 2009
HEPATITIS E IN SWINE
Zoonotic transmissions through direct contact with swine or infected pork meat
Increased HEV sero prevalence in exposed personnel (veterinaries, butchers, slaughterhouse).USA 26% (Meng et al 2002)
Sweden 13% (Olsen et al 2006)
Moldavia 51.1% (Drobeniuc et al 2001)
The Netherlands 11% (Bouwknegt et al 2007)
Species of origin Mode of contamination Geno-type Reference
Sika deer Uncooked meat (sushi) 3 Tei et al, 2003
Wild boar Barbecue (partially undercooked) 3 Tamada et al, 2004
Wild boar Barbecue (partially undercooked) 3 Masuda et al, 2005
Pig Grilled or uncooked pig liver 3 Yasuyuki et al, 2003
Zoonotic transmissions through infected food product
Possible transmissions zoonotic with pork products
Confession Muslim Hindu
Prevalence 2% 20%Indonesian study(Surya et al 2005)
Evidence of Zoonotic transmissions
Food product infected by HEV: pork liver in grocery stores
USA (Feagins et al JGV 2007); ARN + = 14/127 (11%); 2/3 infectiousThe Netherlands (Bouwknegt et al J Food Prot 2007); ARN+ 4/62 (6.5%)Japan (Yazaki Y et al J Gen Virol 2003); ARN + = 7/363 (1.9%)
Source of HEV exposure
Inactivation of infectious hepatitis E virus present in commercial pig livers sold in local grocery stores in the United StatesR. Feagins, et al Int J Food Microbiol. 2008 March 31; 123(1-2): 32–37.
HEV-positive pig liverliver homogenate negative for HEV
56°C for 1 hr stir-fried at 191°C for 5 min
boiled in water for 5 min
Other risk factors:Consumption of offal or wild-boar meat (Wichmann O et al , J Infect Dis. 2008)
Japan (Li et al Am J Trop Med Hyg. 2007) Corbicula Japonica
Sea shell
US, Spain and France RNA +Clemente-Casares et al, EID 2003
Wastewater in non endemic regions
Source of HEV exposure
Surface water in non endemic regions (Rutjes SA, EID 2009)
>150 human indigenous cases per year (source: National reference centre)
http://www.cnr.vha-vhe.aphp.fr/cadrecnr.htm
1 to 2 cases of fulminate hepatitis/year
Chronic cases (transplant recipient)
Genotype 3 HEV strains
Seroprevalence : 3.2% in blood donors from Paris area and north west
Boutrouille et al JCM 2007 )
16.4% in blood donors from Toulouse area (30% in
hunters Mansuy et al JMV 2008)
Hepatitis E in France
sewage
Environment ?
Serology
Virology
0123456789
10
0 10 20 30 40 50 60 70 80 90 100
% positifs
N é
leva
ges
> 70% Swine Herds are infected (n=51)
Intra herd prevalence : 25% (2.5 to 80%)
HEV Prevalence in French swine herds
HEV RNA is present in individual fecal samples
HEV RNA is present in slurry manure storage
HEV RNA present in manure storage is infectious (as confirmed by experimental infection of pig)
HEV RNA sequences present in swine are closely related to human strains (Genotype 3c, 3e and 3f).
swJ1
-1 c
apsi
d
swJ1
-3 c
apsi
d
swJ2
-3 ca
psid
swST
HY40
HE-JA20
ORF2
HE-JA4 ORF2
swJL234 ORF2
H. E virus HEV-US1 ORF2
HE-JANGP2 ORF2HE-JA22 ORF2HE-JA7 ORF2
KOR1 capsid protein
UMC7A
H. E virus HEV-US2 ORF2
H. E virus FR45.3 capsid
NLSW36
NLSW20
Fr-4 capsid protein
Fr-11 capsid
SwE FR43 S5 capsid protein
HE MaR7307574 capsid protein
NLSW99
JMO-Hyo03L
JSO-H
yo03
L
JYO
-Hyo
03L
JDEE
R-H
yo03
LJT
H-H
yo03
L
HE
-JA
5 O
RF2
HE
-JO
-198
2 O
RF2
HE-
JA6
OR
F2sw
JL82
OR
F2HE
-JA2
3 O
RF2
HE-J
A9 O
RF2
swJ2
5-1
HE-JA11 ORF2
swJ681 ORF2
H. E vi
rus TW
12SW
H. E vir
us TW3SW nucle
ocapsid
H. E virus TW13SW
H. E vi
rus Fr-1
caps
id
S.HEV swJ791 ORF2
H. E virus FR18 12S capsid
swJ8-2 capsid
H. E virus UK 7518 capsid
S.HEV P143/11/02 capsidH. E virus UK 8734 capsid
H. E virus FR22.6 capsidH. E virus Fr-9 truncated
H. E virus Fr-10 capsidH. E virus Fr-5 capsidNLSW91NLSW85NLSW82NLSW28
H. E virus FR79 capsid
H. E virus Fr-2 capsid
H. E virus 6317147 ORF2
H. E virus VH1 putative capsid
H. E virus Fr-3 capsid
NLSW
97
H. H
EV VH2 putative capsid
protein
H. E
vir us Fr- 13 ca ps idH
. E virus FR
HP
105 capsidH
. E virus FRSPP05 capsid
NLSW
15H. E virus FRHPP305 capsid
H.HEV E11 putative capsidprotein
H. E virus Fr-6b capsid
H. E virus Fr-6a capsid
0.02
3e
3d
FR, UK, JP
3c
3a
3b
3f
FR, SP, NL
FR, NL
USA, CAN, KOR,JP
TW
JP
French HEV ORF2 PhylogenyNeighbors joining tree methodSwine strainsHuman strains
Molecular Virology : phylogenic analyses of French isolatesMolecular Virology : phylogenic analyses of French isolates
Epidemiology: study of Epidemiology: study of clinical cases of HEV within the ANGH networkclinical cases of HEV within the ANGH network
Renou et al, EID 2007 & Renou et al, APT 2008
French Guinea = 1 caseIndigenous cases (no Travel) = 47 cases (89%)1 case of fulminate hepatitisNo particular risk factor identified (private well)
85%(44/52 cases)
15%(8/52 cases)
Geographic Distribution of 53 cases: Increasing Gradient North-> South
12
9*
1
10*
1
21 1
2
11
1
11
1
5
11
Pet Pig (DDSV)
HEV RNA +CNR
HEV RNA +UMR Viro94% homology 94% homology ntnt
ORFORF--1 & ORF1 & ORF--22
Patient acute hepatitisQuestionnaire (DDASS)
85%
15%
Geographic distribution of swine herdsIncreasing Gradient South-> North
Genotypes 3c, 3e et 3f
Indigenous Hepatitis E
Serology 3.2 to 16.4 %>70% positive Herds
Environment
Genotypes3c, 3e et 3f? ?
?Food productscontact
sewagewater
Pigasymptomatic R0 = 8.8
ConclusionsConclusions
AcknowledgmentsAcknowledgments
UMR 1161 Eq VHE
Annie Boutrouille
Aurélie Lunazzi
Audrey Fraisse
Gaetana Di Liberto
Marc Eloit
AFSSA Ploufragan
Jean-Pierre Jolly
Virginie Dorenlor
Christelle Fablet
CHU Purpan
J. Izopet, JM. Mansuy
CHG Hyères
Christophe Renou
CNR VHE
E. Nicand
Inserm U618
P. Coursaget
InVS
E. Delarocque-A
DERNS
A. Thebault