Clinical aspects of hepatitis e virus infection

Hepatitis E

Overview of clinical aspects

Harry DaltonEuropean Centre for Environment & Human Health

University of Exeter Medical School

Cornwall, UK

Talk outline

Acute & chronic HEV

Epidemiology

Extra-hepatic HEV

HEV in developing countries

• Major health issue• Large outbreaks

• Genotypes 1 & 2

• Faeco-oral route via infected

water

• Affects young adults

• Mortality in pregnant women

25%

HEV in developed countries:

received wisdom

• A bit like HAV

– Acute illness

– Self-limiting

• Mainly seen in travellers

• v. rare in non-travellers

• Of little relevance in developed countries

HEV in developed countries: received

wisdom

• A bit like HAV

– Acute illness

– Self-limiting

• Mainly seen in travellers

• v. rare in non-travellers

• Of little relevance in developed countries

Cornwall

• Good location to do epidemiological studies

• <0.5% immigrants

Jaundice hotline clinic: 1998-2015

(n > 2,900)

Diagnoses in over 60's

CBD stones

pancreatic/biliary cancer

decompensated chronic

liver disease/alcohol

metastatic cancer

drug-induced liver injury

miscellaneous

unknown

Acute viral hepatitis in Cornwall, UK

1. Acute HEV

2. Seronegative hepatitis

3. EBV hepatitis

4. Acute HBV

5. HAV

6. Acute HCV

Dalton et al EuroJMicro 2008, Vine et al APT 2012, Donaghy et al EJGH 2013

Acute HEV3:Cornish experience

• Commonest cause of acute hepatitis

– 146 cases of HEV in non-travellers

• Genotype 3

– M:F = 3:1

– Median age 63.5 years (range 32-92)

Dalton et al J Viral Hepatitis 2007, Dalton et al EurJGastro 2008, Vine et al APT 2012., Woolson et al 2014, APT

Acute HEV3: symptoms

COMMON

• Jaundice

• Anorexia

• Lethargy

• Abdominal

• pain

• Vomiting

• Fever

• Myalgia

LESS COMMON

• Pruritis

• Weight loss

• Headaches

• Arthralgia

• Neurological

• No symptoms

Dalton et al EJGH 2008, Woolson et al APT 2014

Acute HEV3: Spectrum of severity

• Asymptomatic – mild hepatitis –liver failure

• Most recover 4-6 weeks

• High mortality in patients with pre-existing chronic liver

disease : Dalton et al Lancet 2007

Peron et al JViralHepat 2007

Blasco-Perrin et al, APT 2015

HEV misdiagnosed as Drug-induced liver injury (DILI)

• 13% of patients with DILI have HEV3

Dalton et al APTherap 2007

• Diagnosis of DILI not secure without testing for HEV

HEV: Other developed countries

• USA Drobenuic EID 2013

• Japan Miuzo ClinMicro 2002

• France Mansuy JMedVirol 2004

• Netherlands Widdowson JMedVirol 2004

• Spain Buti JVirolMethods 1995

• Italy Romano J Hepatol 2010

• New Zealand Dalton JGastHepatol 2007

• Denmark, Germany, Hungary, Sweden 2009-

Chronic HEV infection: Transplant recipients

Chronic HEV3 infection in transplant patients • No symptoms, anicteric, ALT 200-300IU/L

Kamar et al NEJM 2008

Chronicity occurs in 60% of HEV3 infections• Genotype 3

• Genotype 4 (n=1)Kamar et al Gastro 2011

Cirrhosis rapidly progressive Kamar et al Transplant 2010

Prevalence of chronic HEV• High in French transplant centres

• Other European transplant centres: 1-2%Pas et al EID 2012

Koning et al J Heart Lung Tran 2013

Moal et al JMV 2013

Halac et al Gut 2012

Pischke et al Am J Transpl 2012

HEV/HIV co-infection

Incidence of HEV infection in patients with HIV is low

Few PCR-proven cases (all HEV3) have been documented

Chronic HEV infection & cirrhosis uncommon

low CD4 count <250

Dalton, NEJM 2009, Colson, J Clin Virol 2009, Kenfak-Foguena, Emerg Infect Dis 2011

Renou, AIDS 2010, Kaba, J Med Virol 2011, Thoden AIDS 2008, Colson, J Vir Hep

2011, Jardi, HIV Med 2012, Crum-Cramcianflone, Emerg Infect Dis 2012

HEV infection in haematological patients

Chronic HEV infection reported in: T-cell lymphoma:

non-Hodgkin lymphoma (Rt Rituximab)

hairy cell leukemia

idiopathic T CD4 lymphopenia

chronic myelomonocytic leukemia

B-cell chronic lymphocytic leukemia

Cases of chronic HEV infection after stem-cell transplantation commonly mistaken for:

Graft-versus-host disease

Drug-induced liver injury

Kamar et al., Lancet 2012

HEV

treatment and prevention

Acute HEV• No treatment required, ribavirin in severe cases

Chronic HEV Kamar et al, NEJM 2014

• Wait (3 months)

• Reduce immunosuppression

• Ribavirin monotherapy

» 3 months

» Longer if stool still PCR +ve

HEV vaccineZuo et al Lancet 2010

Peron et al, Liver Int 2015

HEV3: Source and route of infection

Dalton et al Lancet Inf Dis 2008

HEV3: incidence

• UK: 0.2% Ijaz et al JClinVirol 2009

Ijaz et al JID 2014

100,000 infections per year

• USA: 0.7%Faramwi et al EpiInf 2011

• Netherlands: 1.1% Slot et al Eurosurv 2013

• SW France: 3.2%

Abravenal et al JID 2014

Asymptomatic infection

Clinically apparent acute & chronic hepatologicalinfection

• England and Wales:

– 869 lab confirmed cases of HEV ( 2014)

• England:

– incidence HEV: 100,000/yr

Hewitt et al Lancet 2014

HEV IgG seroprevalence: developed countries

• Mostly < 5%

• =► HEV is not an

issue in Europe

Wantai vs Genelabs HEV IgG assay

• PCR proven HEV3 cases (n=18)

• Serial samples n=50 (up to 7 years)

• Genelabs underestimates true seroprevalence by a factor of 4

Bendall et al J Med Virol 2010

HEV seroprevalence recent data

Country Blood donors

HEV RNA

positive

HEV IgG

seroprevalence

Assay Reference

France

Midi-Pyrénées 52%

16%

Wantai

Genelabs

Gallian et al, 2014

Mansuy et al, 2011

Mansuy et al, 2008

Japan Fukuda et al, 2004

Germany

29.5%

18.0%

4.5%

Wantai

Mikrogen

MP diagnostics

Vollmer et al, 2012

Baylis et al, 2012

Wenzel et al, 2013

Netherlands 27.0%

1.1%

Wantai

Abbott

Slot et al, 2013

Zaaijer et al, 1993

Sweden9.2% Abbott

Baylis et al, 2012

Olsen et al, 2006

England

12.0%

5.3

Wantai

Abbott

Hewitt et al, 2014

Ijaz et al, 2012

Beale et al, 2011

Bernal et al, 1996

Scotland 4.7% Wantai Cleland et al, 2013

HEV and blood donors

Country Blood donors

HEV RNA

positive

HEV IgG

seroprevalence

Assay Reference

France

Midi-Pyrénées

1:1595

52%

16%

Wantai

Genelabs

Gallian et al, 2014

Mansuy et al, 2011

Mansuy et al, 2008

Japan 1:1781 Fukuda et al, 2004

Germany 1:1200

1:4525

29.5%

18.0%

4.5%

Wantai

Mikrogen

MP diagnostics

Vollmer et al, 2012

Baylis et al, 2012

Wenzel et al, 2013

Netherlands 1:2671 27.0%

1.1%

Wantai

Abbott

Slot et al, 2013

Zaaijer et al, 1993

Sweden 1:7986

9.2% Abbott

Baylis et al, 2012

Olsen et al, 2006

England 1:2848

1:7000

12.0%

5.3

Wantai

Abbott

Hewitt et al, 2014

Ijaz et al, 2012

Beale et al, 2011

Bernal et al, 1996

Scotland 1:14520 4.7% Wantai Cleland et al, 2013


HEV seroprevalence: varies within countries

Midi Pyrénées

41%

Ariege

71%

Aveyron &

Lot

23%

Mansuy et al Eurosurveillance 2015

HEV IgG seroprevalence: varies within countries

Midi Pyrénées

41%

Ariege

71%

Aveyron &

Lot

23%

Mansuy et al Eurosurveillance 2015

Chronic HEV in

transplant pts

++++


4.7%

12%

16%

Hartl et al, submitted


4.7%

12%

16%

Hartl et al, submitted

0/350 liver

transplants:

chronic HEV

Figure 3

HEV: global burden

• Genotypes 1 and 2

• 9/21 Global Burden Disease

regions• 20 million infections/year

• 70,000 deaths/year

• 3,000 stillbirths/year

Rein et al Hepatology 2012

HEV: global burden






Rein et al Hepatology 2012 Kmush et al AJTMH 2015

1.985.22

10.57

28.2831.71

33.33

38.81

54.55

32.81

43.40

30.77

38.8936.67

32.1435.71

40.00

0.002.13

10.0913.01

38.38

48.15

60.4960.61

77.9273.44

77.3676.9277.14

83.3378.57

71.43

90.00

75.00

100.00

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

1 - 5

6 - 1

0

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86

- 90

Pe

rce

nt

an

ti-H

EV

Pre

va

len

ce

Age Category (years)

AFRIMSTotal Ig…

Overall:

Overall:

46.7%

HEV: global burden






• UNDERESTIMATE ?100%

Rein et al Hepatology 2012 Kmush et al AJTMH 2015

1.985.22

10.57

28.2831.71

33.33

38.81

54.55

32.81

43.40

30.77

38.8936.67

32.1435.71

40.00

0.002.13

10.0913.01

38.38

48.15

60.4960.61

77.9273.44

77.3676.9277.14

83.3378.57

71.43

90.00

75.00

100.00

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

1 - 5

6 - 1

0

11

- 15

16

- 20

21

- 25

26

- 30

31

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36

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41

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86

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Pe

rce

nt

an

ti-H

EV

Pre

va

len

ce

Age Category (years)

AFRIMSTotal Ig…

Overall:

Overall:

46.7%

Hamish MacDonald

Extra-hepatic manifestations of HEV

Case reports

Case series

Controlled studies


Case reports• Autoimmune thyroiditis

• Myocarditis

• Cryoglubinaemia

Case series• Pancreatitis

• Thrombocytopenia

• Monoclonal gammopathy

• Renal disease

• Neurological syndromes

Controlled studies» Guillain−Barré syndrome


Case reports• Autoimmune thyroiditis

• Myocarditis

• Cryoglubinaemia

Case series• Pancreatitis

• Thrombocytopenia

• Monoclonal gammopathy

• Renal disease

• Neurological syndromes

Controlled studies» Guillain−Barré syndrome

“Association does not necessarily

imply causation………….”

Anonymous referee,

New England Journal of Medicine

HEV infection and the kidney

Impairment of renal function at start of HEV infection

Membrano-proliferative & membranous glomerulonephritis during

acute & chronic infection

Cryoglobulinemia that disappears after HEV clearance

Regression of nephrotic syndrome after HEV clearance

Ali, Indian J Nephrol 2001

Kamar et al., AJKD 2005

Kamar et al., Transplantation 2012

Taton et al. Transplant Infect Dis 2013

HEV and neurological syndromes

HEV and neurological syndromes

HEV associated neurological syndromes:• Guillain−Barré syndrome

• bilateral brachial neuritis

• Encephalitis

• Mononeuritis multiplex, Bell’s Palsy, peripheral neuropathy, mysotitis, vestibular neuritis

5.5% of Toulouse/Cornwall patients with HEV have neurological injury

• LFTs only mildly abnormal and most cases anicteric

Occurs in:• acute and chronic HEV

• Developed and developing countries


Kamar et al Emerg Inf Dis 2011

Dalton et al Nature Rev Neurol, in press

Guillain-Barré Syndrome

(GBS)

• Post infectious immune-mediated polyradiculopathy

• Infectious triggers:

– Campylobacter: 35%

– Unknown: 50%

• 30% abnormal LFTs ? Cause

Oomes et al Neurology 1996


HEV & Guillain-Barré syndrome

Case control study of Dutch patients with GBS (n=201)

• 5% of GBS have HEV infection (10/201, p=0.01 vs controls)

• Mildly abnormal LFT’s: – normal bilirubin

– ALT: 70 (range 26-921); abnormal n=7

• Outcome:

– 1 required ventilation, 7 have significant disability at 6 months

• Some patients are viraemic (HEV3) at presentation

– ?role for early therapy with ribavirin

van den Berg et al Neurology 2014


HEV & Guillain-Barré syndrome

Case control study of Bangladeshi patients with GBS (n=100)

• 11% of GBS have HEV infection (genotype 1, n=1)

Worldwide HEV & GBS: n=36

• Age 2-73 years, 72% male

• All but one: immunocompetent

Geurtsvankessel et al Clin Infect Dis 2013



HEV & Guillain-Barré syndrome:

outstanding questions

30% of GBS have abnormal LFT’s:• Are the other 25% caused by re-infection with

HEV?

If HEV re-infection is 4 weeks prior to

symptom onset:

– IgM –ve

– IgG +ve

– PCR –ve

– Indistinguishable from distant infection



HEV & Guillain-Barré syndrome:

outstanding questions

30% of GBS have abnormal LFT’s:• Are the other 25% caused by re-infection with

HEV?

What are the pathogenic mechanisms?

Role of HEV in other neurological

syndromes?

If HEV re-infection is 4 weeks prior to

symptom onset:

– IgM –ve

– IgG +ve

– PCR –ve

– Indistinguishable from distant infection

van den Berg et al Neurology 2014


Dalton et al Nature Neurology Rev, in press

HEV & Neuralgic amyotrophy

(brachial neuritis, Parsonage Turner syndrome)

• LFTs abnormal in some patients, ? Cause

• Anglo/Dutch cohort study: 47 patients tested for HEV• 5 (10%) had HEV at the start of the illness

• Age 30-40 years

• Mildly abnormal LFT’s: ALT 100-300, normal bilirubin

• 4 PCR positive: HEV genotype 3

• Worldwide: • HEV & NA n=30, nearly all from Europe

• Genotype 3

• Median age 49 years, 88% males

• Bilateral symptoms +/- phrenic nerve involvement

Van Eijk et al, Neurology 2014



• Bilateral non-traumatic

shoulder pain

• Middle aged male

• Abnormal LFTs

Diagnosis = HEV

HEV & Meningo-encephalitis12 cases reported

• Europe, Asia, USA

• HEV RNA in serum and CSF (n=6)

• Immunocompromised, chronic infection (n=5)• Ataxic component

• Poor outcome

• 2 deaths



Bart Jacobs

Erasmus MC Rotterdam

Bart Jacobs

Erasmus MC Rotterdam

“Harry. Has this virus been

misnamed?”

“These patients have profound

neurological injury, but not much

of a hepatitis”

HEV & neurological syndromes:

evidence for causality

Number and homogeneity of cases• Over time and geographical location

Case-control data (GBS) van den Berg et al, Neurol 2014, Geurtsvankessel et al Clin Inf Dis 2013

• Netherlands (HEV3) & Bangladesh (HEV1)

HEV RNA• Serum and CSF

Kernow C1p6 Dalton et al NEJM 2009, Shukla et al PNAS 2011 & J Virol 2012

• Strain of HEV incorporating a section of host genome

• Isolated from a patient with HIV and chronic HEV infection

• Grows on a range of cell lines, including neurological

HEV & neurological syndromes:

evidence for causality

HEV crosses blood brain barrier in mice:

• HEV crosses blood-brain barrier in mice

•

HEV infects neurological cell lines:

eGFP-HEV

72 hrs

HEV plasma VL

HEV stool VL

CD4

ALT

July

-07

Aug-0

7

Sept-

07

Dec-0

8

Jan-0

9

Feb-0

9

Mar-

09

Apr-

09

May-0

9

Jun-0

9

Jul-

09

Aug-0

9

Sept-

09

Oct-

09

Nov-0

9

Dec-

09 Jan-1

0

Feb-1

0

Mar-

10

Apr-

10

May-1

0

Jun-1

0

Jul-

10

Aug-1

0

Sept-

10

Oct-

10

Nov-1

0

Dec-1

0

Jan-1

11.0E+00

1.0E+01

1.0E+02

1.0E+03

1.0E+04

1.0E+05

1.0E+06

1.0E+07

1.0E+08

0

50

100

150

200

250

300

350

135µg/week Peg α-interferon

135µg/week Peg α-interferon + 1000mg/day Ribavirin

135µg/week Peg α-interferon + 500mg/day Ribavirin

ALT

(IU

/L)

and C

D4 c

ount (c

ells

/mm

3)

HE

V V

iral Load (

GE

q/m

l)

HEV and neurology: response to treatment

Dalton et al NEJM 2009

Dalton et al Ann Int Med 2010

Interferon

Ribavirin

HEV: who should we test?

Immunocompetent• ALT >300 or Wallace et al, 2015, submitted

• Decompensate chronic liver disease

• Guillain-Barré Syndrome

• Neuralgic amyotrophy

• Acute neurological syndromes, with raised ALT

Immunosuppressed• Raised ALT

• Annual PCR

Dalton et al Nature Neurol Rev, in press

Kamar et al Liver Int, in press

Conclusions:

HEV in developed countries

• Common

• Porcine zoonosis

• Significant morbidity &

mortality• Acute and chronic

• Prognosis poor in chronic liver

disease

• Neurological injury

• Clinic phenotype of HEV is

still emerging

Acknowledgments

• Lemon Street Gallery, Truro

• Sheila Sherlock Travelling Bursary 2011

• Office of Chief Scientist Scotland

• Duchy Charity

• British Medical Association

research collaborators• Colleagues in SW England:

• Dr Richard Bendall

• Dr Frances Keane, Renal and Neurological physicians (Truro),

• Medical Students: UoE & PCMD

• Colleagues from Plymouth

• Dr Mark Gompels (Bristol)

• UK, national:• Malcolm Banks: Veterinary Laboratory Association (Surrey)

• Linda Scobie: Glasgow Caledonian University, Scotland

• Adrian Stanley: Glasgow Royal Infirmary

• Ken Simpson, Scottish Liver Transplant Unit, Edinburgh

• Prof Richard Tedder, Dr Samreen Ijaz: Health Protection Agency (London)

• Ellie Barnes: University of Oxford

• International:• Bob Purcell/Sue Emerson, NIH, Bethesda, Maryland, USA

• Bart Jacobs and colleagues, Erasmus MC and Nijmegen, The Netherlands

• Hans Zaaijer, Sanquin,Amsterdam, The Netherlands

• Alessandro Bartoloni, Florence, Italy

• Prof Ting Wu, Xiamen University, China

• Jacques Izopet, Nassim Kamar & colleagues, Toulouse, France

Clinical aspects of hepatitis e virus infection

Health & Medicine

Transcript of Clinical aspects of hepatitis e virus infection