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Hepatitis E virus in animals, food and where else? Nicole Pavio Anses Laboratoire de sant animale, UMR 1161 INRA,ENVA, Anses, France nicole.pavio@anses.fr Hepatitis E virus infection in human HEV1 to HEV4 Every year : 20 million hepatitis E

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Hepatitis E virus in animals, food and where else?

Nicole Pavio Anses Laboratoire de santé animale, UMR 1161 INRA,ENVA, Anses, France nicole.pavio@anses.fr

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Hepatitis E virus infection in human

 Liver enzyme X 10 Anti-HEV IgM +  HEV RNA +

  • Incubation time

40 days (2-9 weeks)

  • Acute Hepatitis

enteric transmission (similar to hepatitis A)

  • Fulminate Hepatitis

1%-4%. Pregnant women: 15%-25%

  • Chronic Hepatitis

Immuno-suppression (solid organ transplant recipient) RNA+> 6 Mo

  • Neurologic syndroms

Guillain-Barré, Parsonage-Turner (CSF+ chronic infection)

  • Extra-hepatic

Kidney dysfunction, pancreatisis

  • Hepatocellular carcinoma (Amougou Atsama, 2017; Borentain P et al 2017)

HEV1 to HEV4

Every year : 20 million hepatitis E infections 3 million symptomatic cases 56 600 hepatitis E-related deaths.

IAFP Europe April 24-26 2019

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Water, spoiled foods HEV Genotypes 1, 2 HEV Genotypes 3, 4 Endemic Regions Tropical, subtropical Authochtonous sporadic or grouped cases Europe, Japan HEV Genotypes 3, 4

Virale hepatitis E epidemiology

Animal reservoirs

Food

IAFP Europe April 24-26 2019

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HEV Phylogeny: HEPEVIRIDAE family

Cutthroat Trout

A Orthohepevirus Piscihepevirus D B

C1

C

3ra 7 5-6 2 1 4 3 C2 1 2 3 4

Doceul et al 2016 IAFP Europe April 24-26 2019

Zoonotic transmissions

HEV-3ra HEV-7 HEV-3 -4

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IAFP Europe April 24-26 2019

Anti-HEV antibodies HEV RNA

Animal reservoirs of HEV

Anti-HEV antibodies and HEV RNA

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Spain and France (Clemente-Casares et al, EID 2003) Switzerland (Masclaux et al 2013) Italy (Iaconelli et al 2015)

Waste Water Treatment Plant

(Rutjes SA, EID 2009)

Surface water in non endemic region (The Netherlands)  Strawberries (Fields) Berry fruit

(Brassard J, et al, 2012) (Maunula et al, 2013)  Corbicula Japonica, Japan (Li et al Am J Trop Med Hyg. 2007)  Outbreak on Cruise Ship (Oyster HEV-3) (Said et al 2009)  UK Mussels up to 92% HEV RNA (Crossan et al EID 2012)  Bioaccumulation in Oyster (Grodski et al 2014)

 Shell fish  Herb and Spices (Loisy-Hamon 2015)  Green leafy salads (Kokkinos et al 2012)

Animal reservoirs

Food

Sources/vehicules of HEV3 and HEV4

IAFP Europe April 24-26 2019

 Swine Slurry  Slaughterhouse

 Personnel (hands)  Surfaces, ustensiles (knife, hook)  Effluents  Transportation vehicules Di Bartolo et al, 2012 Nantel-Fortier et al, 2016

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USA (Feagins et al., 2007) 11% RNA+; 2/3 infectious The Netherlands (Bouwknegt et al., 2007) 6.5% (Boxman, et al 2019) 12,7% Japan (Yazaki et al., 2003) 1.9% Korea (Jung et al., 2007) 10.8% India (Kulkarni et al., 2008) 0.83% France (Rose et al 2011) 4% Germany (Wenzel JJ, 2011) 4% Italy (Di Bartolo et al 2012) 6% Canada (Wilhelm et al 2014) 3,5%

Pork Liver contaminated with HEV : grocery stores, slaughterhouse Pork Liver sausages contaminated with HEV

France (Pavio et al 2014) 30% Germany (Szabo et al et al 2015) 22% Italy (Di Bartolo et al 2014) 24% Switzerland (Moor et al 2018) 19% The Netherland (Boxman, et al 2019) 70%

Pork sausages

UK (Berto et al 2012) 10% Germany (Szabo et al 2015) 20% Switzerland (Moor et al 2018) 6%

Sources/vehicules of HEV3 and HEV4

IAFP Europe April 24-26 2019

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Hepatitis E Virus dynamic in pigs

anti-HEV IgG anti-HEV IgM HEV fecal excretion

2 4 6 8 10 12 14 16 18 20 22 24

Age in weeks Maternal Anti-HEV antibodies HEV Infection ALT Cholesterol Triglycerides AST Theoretical HEV infection in natural setting HEV experimental infection in pigs IAFP Europe April 24-26 2019

Rogée et al 2015

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Hepatitis E Virus dynamic in pig herds

IAFP Europe April 24-26 2019

Salines in revision

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Days post-infection Days post-infection Log(ge HEV) / g feces Log(ge HEV) / g feces Inoculated pigs Contact pigs

Co-infection with Hepatitis E and Porcin Reproductive and Respiratory Syndrom viruses

 HEV + PRRSV : HEV chronic infection  Increased risk of HEV in other organs (muscles)

Salines et al 2015

IAFP Europe April 24-26 2019

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Co-infection with Hepatitis E and Porcin Reproductive and Respiratory Syndrom viruses

Salines et al 2018

Viremia kinetic (RNA copies/mL serum) HEV RNA in muscle at 49 dpi (RNA copies/g) HEV RNA in feces at 49 dpi (RNA copies/g) HEV RNA in liver at 49 dpi (RNA copies/g) dpi 7 14 21 28 35 42 49 FB PM DP Control nd nd nd nd nd nd nd nd nd nd nd nd Control nd nd nd nd nd nd nd nd nd nd nd nd Group 1 Inoculated nd nd nd 3.56.103 1.43.104 1.91.104 1.70.103 nd nd nd 1.49.107 1.46.106 Inoculated nd nd 4.22.104 3.85.104 7.70.104 2.14.104 4.02.103 nd nd nd 5.85.107 1.87.106 Inoculated nd nd 1.33.104 2.92.104 7.49.104 5.21.104 2.15.104 nd nd 1.43.104 6.40.107 1.02.106 Contact nd nd nd nd 2.12.104 2.80.104 9.44.103 nd nd nd 4.87.107 8.72.105 Contact nd nd nd nd nd nd nd nd nd nd 3.49.105 nd Contact nd nd nd nd nd nd nd nd nd nd 1.20.106 nd Group 2 Inoculated nd nd 4.51.103 2.07.104 2.24.104 nd nd 4.33.103 nd 6.23.103 1.45.105 1.56.103 Inoculated nd nd 2.16.104 2.43.104 2.05.104 1.24.104 nd nd 2.18.104 2.70.103 6.80.106 2.42.106 Inoculated nd nd 6.31.104 1.69.104 5.55.104 2.80.104 nd 8.14.103 3.55.103 5.40.103 4.86.106 3.59.105 Contact nd nd nd nd nd 2.64.104 7.33.103 5.91.104 6.75.105 6.42.103 5.55.107 1.12.106 Contact nd nd nd nd nd 2.65.104 6.82.103 2.12.104 2.28.103 3.72.103 5.24.106 1.69.106 Contact nd nd nd nd 1.76.104 6.64.104 2.94.103 6.92.103 nd nd 3.07.108 3.44.106 Group 3 Inoculated nd nd nd 4.40.103 2.08.104 2.11.104 1.22.104 nd nd nd 2.08.108 3.24.106 Inoculated nd nd nd nd 8.68.103 1.72.104 1.92.104 nd 1.59.104 6.17.103 5.75.107 2.04.104 Inoculated nd nd 4.10.104 1.95.104 1.46.104 1.00.104 1.15.103 nd 1.09.106 1.62.104 5.61.107 9.63.105 Contact nd nd nd nd nd nd nd nd nd nd 7.39.105 nd Contact nd nd nd nd nd nd nd 5.32.103 nd nd 1.03.108 5.87.105 Contact nd nd nd nd nd nd nd nd nd nd 8.29.105 nd

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HEV-PRRSV

During intercurrent infection (PRRSV): HEV is detected in pork meat muscles Biceps femoris (Ham) Psoas Major (Filet Mignon)

  • Risk assessement in Public Health:

Inactivation procedure: heating time/temperature Drying, curing

  • Recommendation: deep cooking of pork meat
  • Survey at slaughterhouse: test faecal samples to detect pig at risk of HEV positive meat
  • Up to 106/g = possible transmission

Food consumption

71°C during 20 min

Barnaud et al 2012 IAFP Europe April 24-26 2019

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Hepatitis E Virus in Muscle at Slaughterhouse

Sample size positive samples Prevalence estimate (%) 95% Confidence interval HEV serology 1034 629 60 57.8-63.7 HEV RNA (muscles) 1034 0-0.003 HEV RNA (liver) 1034 29 2.8 1.9-3.9

2 4 6 8 10 12 14 [10^3 - 10^4] [10^4 - 10^5] [10^5 - 10^6] [10^7 - 10^8] [10^8 - 10^9]

Number of livers copies of HEV RNA per gram Feurer et al 2017

 Different muscle: gluteus medius or semi-membranosus  No indication PRRSV status

Perspectives:

  • Larger sampling
  • HEV, PCV2 and PRRSV status
  • Biceps or Psoas

IAFP Europe April 24-26 2019

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IAFP Europe April 24-26 2019 HEV RNA +: 33/36 batches of (non- heated) liquid products 7/24 spray dried powder products

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Berto et al.2013 EID

Food category number of samples analyzed (394 total) RNA Quantification (Min-Max in copies of HEV RNA/g)* Prevalence and [ 95% CI] Figatelli and fitone 140 1.7 102-6.9 105 30 [23, 38] Dried salted liver 30 6.9 105 3 [0, 1] Quenelle and quenelle paste 55 2.6 102-2.83 105 25 [15, 37] Dried or fresh liver sausages 169 1 102 -2.3 106 29 [22, 36]

Pavio et al 2014 EID

Frequent Hepatitis E Virus Contamination in Food Containing Raw Pork Liver, France

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Phylogeny of HEV sequences present in raw pork liver foods.

Pavio et al EID 2014

All HEV genotype 3 High sequence identity : 99% (n=16) Food/ human sequences (France, UK, Spain) Food/pig sequences (France)

Swine Human (France) Human (other) Food

Food/pig Food/pig Food/ human SPAIN Food/ human UK Food/ human FRANCE

IAFP Europe April 24-26 2019

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Direct foodborne transmission of HEV

IAFP Europe April 24-26 2019

Guillois et al CID 2015

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Foodborne transmission of HEV

IAFP Europe April 24-26 2019

Yapa et al 2016

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Foodborne transmission of HEV

IAFP Europe April 24-26 2019 Case-control study among hepatitis E cases (n=270) aged 18 years or

  • lder notified between January 2012 and January 2014 and matching

controls (n=1,159). => Consumption of undercooked pork liver, pork, wild boar meat, frankfurters, liver sausage and raw vegetables; contact with waste water (occupational).

Faber et al 2018

Pork liver>Wild boar>Pork>Liver sausage or liver pâté>Boiled sausage>Raw vegetables

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Foodborne transmission of HEV

IAFP Europe April 24-26 2019

Tulen et al 2019

A nationwide case-control study June 2015 and October 2017 (n=597). Traditional Dutch dry raw sausages of pork muscle meat, called “cervelaat”, “snijworst”, and “boerenmetworst”were reported by 72% of the patients, and 46% of controls (OR 3.0; 95% CI 2.2–4.1) Direct contact with pigs and working with a septic tank were strong risk factors (aOR 3.1; 95%CI 1.3–7.3 and aOR 6.9; 95%CI 1.2–40.8, respectively),

,

Kamar et al 2012

75 % foodborne origin of HEV

Van Cauteren et al, 2018

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IAFP Europe April 24-26 2019

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HEVnet HEVnet net networ

  • rk &

k & da data taba base se

Sharing ring se sequences s & me meta tadata ta of hepatiti titis s E vir virus Online database for sharing HEV sequences with metadata. International network of hepatitis E virus (HEV) experts, fostering collaboration to perform supranational and interdisciplinary studies.

Public health Veterinary health Food safety Blood safety Environmental research www.hevnet.nl

HEV expert scientists are invited to join HEVnet. Email to hevnet@rivm.nl with a short explanation: What can you contribute to the network and the establishment of a worldwide reference set of HEV?

IAFP Europe April 24-26 2019

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Thanks to

CHU Purpan CNR VHE Jacques Izopet Jean-Michel Mansuy Florence Abravanel Santé Publique France Elisabeth Couturier Julie Figoni Henriette de Valk Anciens CNR VHE Elisabeth Nicand Sophie Tessé Anne-Marie Roque -Afonso ANSES Ploufragan Nicolas Rose Matthieu Andraud Morgane Salines Virginie Dorenlor Florent Eono Frederic Paboeuf Institut du Porc Carole Feurer HEV Team UMR 1161 Virologie Laboratoire de santé animale Virginie Doceul Elodie Barnaud Gaël Stéphant Antonin Demange Eugénie Bagdassarian Léa Meyer Marie Pellerin Stephan Zientara Jennifer Richardson IAFP Europe April 24-26 2019