Hepatitis E (Re-)Emerging in the Netherlands

Presented by Wilfrid van Pelt

CIb-RIVM EPI Agnetha Hofhuis, Wilfrid van Pelt, Roan Pijnacker, Rody Zuidema, Susan Hahné, Sofie Mooij

IDS Erwin Duizer, Harry Vennema

Z&O Saskia Rutjes, Martijn Bouwknegt

LCI Madelief Mollers, Jim van Steenbergen

NVWA (Dutch FSA) Aloys Tijsma, Ingeborg Boxman

Sanquin Hans Zaaijer, Boris Hogema

Anses (FR) Nicole Pavio

VVVL (BE) Isabel De Boosere

Bfr (DE) Reimar Johne

Acknowledgements

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

Alleen tekst

● Considered a travelers disease until the end of the last century

● 1 serotype, genotypes 1-4, with different transmissionroutes

Kamar et al. Lancet 2012; 379: 2477–88

Hepatitis E

Alleen tekst

Hepatitis E

Kamar et al. Lancet 2012; 379: 2477–88

● Liverinfection (O/B)

● Mostly asymptomatic, or

very mild complaints.

● Symptoms look like

hepatitis A:

jaundice, fever, abdominal

pain, fatigue…

● Underlying disease increases

risk symptomatic infection,

serious course and chronic

infection (GB, NA/PTS)

Guillain-Barré, Neuralgic amyotrophy/Parsonage-Turner S

●

Hepatitis E

(A) Acute icteric hepatitis (B) Chronic infection (C) Drug-induced injury (D) Neurological injury (E) Miscellaneous clinical

syndromes

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

Alleen tekst

Sanquin bloeddonor tests, 18-21 jaar, Hogema, 2014, Transfusion

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

HEV Inreasing in NL?

Alleen tekst

Virological laboratories 2012-2015 (patients)

Viremie Sanquin donoren 1:1800 (‘13) 1-800 (‘14,’15)

Viraemic Sanquin donors 1:1800 (‘13) 1-800 (‘14,’15)

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

HEV Inreasing in NL?

Alleen tekst

All large lab’s show

increase 2014

Many labs started in

2015 after joining

the Ca-Co study

0 50 100 150

Erasmus MC Rotterdam

Izore Friesland

LUMC

UMC Groningen

Streeklab Hengelo

UMC Utrecht

Vir Infectieziekten Groningen

HagaZiekenhuis

Veldhoven

Diakonessenhuis Utrecht

Streeklab Zeeland

Rijnstate Ziekenhuis Arnhem

VieCuri Venlo

UMC Nijmegen

Vumc

Maasstad Ziekenhuis Rdam

AZM Maastricht

MCH

GGD Amsterdam

AMC Adam

Streeklab Tilburg

SSDZ Delft

Laurentius Ziekenhuis Roermond 2012

2013

2014

2015

RIVM: all type 3

(3a,3c(mainly),3e,3f)

No regional clusters

No molecular clusters

HEV Inreasing in NL?

Seroprevalence

● Nederland

– Bloeddonors Sanquin 2012: 26,7% (23,6%-30,5%)

› 5239 sera

› Wantai anti-HEV IgG

– Livestock Farming & Resident Health Study (VGO), 2013-2014

› ~2500 sera residents

› Wantai anti-HEV IgG

› Preliminary seroprevalence 28,7%

● Europe

› Large differences, also dependent on assay

● France (october 2011)

› Dependent geography 20% - 71,3% Ariège Zuid Frankrijk

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

No association proximity of pig livestock farms Age: OR 20-30yrs vs ≥60 yrs 5.43 [2.14-13.78] Sex: OR Males vs Females 1.36 [1.16-1.64]

% HEV RNA positive donations in Europe

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

HEV RNA positive blood donors

a) Baylis,Vox 2012; b) Vollmer, JCM 2012; c) Slot, EuroSurv. 2013; d) Cleland, Vox 2013;

e) Hewitt, Lancet 2014; f) Gallian, EID 2014; g) Sauleda, Transfusion 2014; h) Fischer, PlosOne 2015;

i) Ikeda, ISS 2009; j) CBS Surveilance Report 2014;

k) pers. communication J.S. Epstein; l) Hogema, Transfusion 2015

What we know about sources in the Netherlands

● HEV RNA in animals – Pigs (>90% seropositive; 50% RNA positive)

– Wild game, Veluwe (wild boar 25% seropositive, 8% RNA positive, deer lower)

– HEV RNA shown in oysters and mussels, Oosterschelde (5%)

› Other countries in oysters, mussels, cockles

– Not shown in faeces from muskrat (2007), veals (1999), dairy cattle (1999) and poultry (1999)

● HEV RNA in food – Pigmeat (6% in livers, 50% meats tested infectious, 2% meats in EU-study)

– Wildgame (prevalence in liver and meats <5% in NL, higher abroad)

– Raspberries (frozen) EU study (not NL) 3%

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

USA (Feagins et al., 2007) 11% RNA+; 2/3 infectious

The Netherlands (Bouwknegt et al., 2007) 6.5%

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

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)

France 44% (Chaussade et al 2013)

Germany 32 % (Krumbholz et al 2014)

Direct contact with infected animals. High HEV seroprevalence in personnel with

swine occupation (veterinarians, butchers, slaughterhouse).

Pork Liver sausages contaminated with HEV

France (Pavio et al 2014) 30%

Germany (Johne R communication) 25%

Italy (Di Bartolo et al 2014) 22%

Sources abroad

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

HEV RNA in the environment in the Netherlands

● Drinking water HEV RNA shown in 2 water reservoirs with partly cleaned drinking water

● Sewage – HEV RNA shown in slaughterhouse sewage

› Other countries in city sewages and sewage of pig farms

● Surfacewater – In NL shown in the river Maas (17%)

› Other countries in irrigation water

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

Genetic relationship of HEV in the Netherlands

3c

3a

3f

3e

Prototype

Pig

Pig liver

Wild boar

Water

Human

Prototype

Pig

Pig liver

Wild boar

Water

Human

0 - 3 nt

4 - 11 nt

12 - 15 nt

16 - 20 nt

0 - 3 nt

4 - 11 nt

12 - 15 nt

16 - 20 nt

2004-2006

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

Alleen tekst

● HEV-infection is caused by consumption and/or direct or indirect contact with specific (pig-)(meat-)products

Patient-Control studies Working Hypothesis

Pilot patient-control comparison (n=50 patients, n=147 age-sex matched control person (continuous survey))

● Patients predominantly middle aged man

● People with underlying disease more often get a symptomatic HEV infection (Diabetes, Cardio-vascular disease, Immunodeficiency, Rheumatism)

● Medication, Meat and Food, Animal Contact: unclear

Riskfactor study, ideal

● Difference HEV IgM/PCR positive……IgG negatives

● Difference patients……asymptomatic viremic cases (medicatie-mod/cnt)

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

Vegetarians (bd 400) seroprevalence 15% lower at all ages (Sanquin p.c.)

Alleen tekst

Patients from 21 virological lab’s:

– Cases: HEV positive IgM or RNA Controls: HEV IgG negative

– June 2015 - june 2017

– Questionnair: from Laboratory –to- Treating Physician –to- Patient

– Sample: to RIVM for IgG testing and genotyping op IDS/VIR – ~15 invitations / month Cases; ~30 invitations / month Controls

– ~50% expected respons

Participants from Livestock Farming & Resident Health Study (VGO)

– Cases: HEV positive IgG Controls: HEV IgG negative

– June 2013 - june 2014; 2500sera and questionnairs

Blood donors Sanquin (predominantly middle aged man)

– Cases: HEV positive IgG Controls: HEV IgG negative

– November 2015 (Februari 2016)

– 2500sera and questionnairs; 60% expected respons

Patient-Control studies

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

Alleen tekst

● Questionnair: Complaints, Medication (pig derived) Medical history, General

health, SES, Education, Age, Residence

– Exposure (2month before illness):

travel history fruit & vegetables profession

meat consumption eating outside outdoor activities

shellfish/crustacean water contact

rawmilk products animal contact

Extra Controls from the general population

– No serological testing

– 100 invitations / month, general control study

Pig meat products in high detail

Patient-Control studies

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

“Hide(meat) Glue”

●Used for glueing pieces of meat:

› Steaks, Ham, Beefsteak, Pork tenderloin

●Thrombine and Fibrinogen derived from Cattle/Pig blood.

Dutch FSA approved animals (not-tested for HEV)

●No HEV-inactivating production step

●Endproduct not tested for HEV

●Risk-control: now (erronously) retailer/consumer

●Mandatory on productwrapper “Pig Protein” “Varkenseiwit”

●Production 2014: 175.000 kg

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

Spray Dried Porcine Plasma (SDPP)

● Hide (meat) Glue ≠ SDPP

● SDPP production (spray drying ~15 seconds 220 – 80 C): Inactivation HEV?

● SDPP is used for:

● binding fats and water

● colouring food products

● Animal feed (piglets)

● Total production 2014 SDPP (1 big producer):

13.000.000 kg

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

Spray Dried Porcine Plasma (SDPP)

● Pujols et al. Virology Journal 2014, 11:232: › 100 % tested SDPP batches HEV AB present

› 22,4% HEV RNA +

› HEV RNA in SDPP batches fed to pigs: no HEV seroconversion…….

– Meaning for Hide/Meat Glue and other pig blood derived products?

Action plan Dutch FSA, Hide Glue:

●HEV incorporating in the “foodsafetyplan”

●Monitoring-project, starting in 2016

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015

Recent (re-)emerging of Hepatitis E cases in the Netherlands, among blood donors as well

HEV RNA is present / found in the Netherlands in:

› domestic pigs and wild boars in NL

› meat products: pigmeat and wildgame in NL

› Sewage, surface water and drinking water in NL

Unknown:

› Why HEV is increasing in humans

› Role Hide/Meat Glue and SDPP in foods

› Relative importance of different transmission pathways (env/food)

› Risk factors for developing clinical disease (also dose-resp)

› Inactivation of HEV in foods

› Stability/Infectivity of HEV in food. Infectivity testing is difficult

Conclusions

ECDC- HEV-Exp meeting , Stockholm, 9,10 Dec 2015