Klinische verschijningsvormen van Hepatitis E virus

Annemiek van der Eijk

1Viroscience lab, Erasmus MC, Rotterdam, the Netherlands

Clinical presentation of hepatitis E virus

- Fever - Fatigue - Loss of appetite - Nausea - Vomiting - Abdominal pain - Jaundice - Dark urine - Clay-colored stool - Reported range S:AS infection from 1:2 to 1:13. - Mortality gt1: overall 1-4%, pregnant women 15-25% - Neurological symptoms

asymptomatic

symptomatic

HEV infection in the immunocompetent

Dalton et al, Lancet 2008

Chronic HEV in transplant recipients

• Chronic HEV infection reported in the transplant setting • Persistent viraemia

• Persistently raised transaminases

• Histological features associated with chronic hepatitis

• Evidence of rapid development of cirrhosis

• Association with a more profound immunosuppression

Kamar,N Engl J Med 2008;358(8):811-7.

Haagsma, Liver Transplantation 2009;15(10):1225-8

Course of chronic HEV infection in LTX patient

0

5

10

15

20

25

30

35

40

450

100

200

300

400

500

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700

800

900

1000

jul-09 jan-10 aug-10 feb-11 sep-11

HEV

PC

R (c

t-val

ue)

ALAT

(U/L

)

ALAT ULN ALAT PCR hepatitis E LOD HEV PCR

IgG -

IgM - IgM +

IgG +

Riba

*

Individual Knodell score (HAI) of liver biopsy specimens

HAI score Periportal necrosis

Intralobular

Inflammation Portal

inflammation Fibrosis

1 0 1 0 0

4 1 1 1 1

6 1 1 1 3

10 1 3 3 3

10 1 3 3 3

10 1 3 3 3

Liver biopsy overview

Histopathology

Current status of HEV diagnostics - Histopathology

Reactivation in an alloHSCT recipient

Legend

ALT (U/L) HEV viral load (log IU/ml)

upper normal limit ALT (U/L) HEV LOD (2.16log IU/ml)

Patient characteristics of Hepatitis E confirmed patients (n=8)

Patient Sexe

Age at allo-

HSCT (yrs)

Diag-nosis

Stem cell

source living

at EOF

GVHD

initial diagnosis

at time of AlloHSCT

HEV gt

Time from

alloHSCT to

infection (mos)

Duration of infection

(mos)

Median (range) ALT levels during

infection (U/l) °

Immune-suppression at

time of infection

Hepatic fibrosis in liver

histology

hep in-volvement HEV RNA IgG status

1 M 44 AML UCB No Acute grade II-IV Chronic

extensive GHVD - - 3 2,7 12,5* 73 (24-577)

ciclosporin, prednisone,

mycophenolate

2 F 54 NHL MUD Yes yes GHVD - - 3 8,4 42,4 207 (31-1507) Ciclosporin F2

3 F 59 MDS MUD Yes yes GHVD - - 3 3,4 6,3 72 (36-215) ciclosporin, mycophenolate -

4 M 43 CLL MUD No - DILI - + 3 14,0 1,6* 66 (15-309) alemtuzumab -

5 M 66 AML MUD No - DILI - + 3 5,8 1,7* 39 (19-268) ciclosporin, prednisone,

mycophenolate -

6 M 58 NHL MUD Yes yes GHVD - + 3 18,3 11,3 208 (25-1130) sirolimus, prednisone F1

7 F 39 SAA UCB No - DILI + - 3 0 6,5* 70 (12-213) ciclosporin, mycophenol acid F0

8 M 59 AML UCB Yes yes GHVD + - 3 -2,0 2,1 and 4,9 27 (10-550) none -

Abbreviations: alloHSCT, allogeneic hematopoietic stemcell transplantation; AML, acute myeloid leukemia; CB, cord-blood; CLL, chronic lymphoid leukemia; GVHD, graft-versus-host-disease; HEV gt, hepatitis E virus genotype; MDS, myelodysplastic syndrome; MUD, matched-unrelated donor; NHL, non-Hodgkin lymphoma; SAA, severe aplastic anemia; SIB, sibling, EOF end of follow-up, DILI drug induced liver injury. * Patient died having a HEV viremia ° ALT Upper limited of normal, male = 40 U/l or female = 30U/l

SOT - recipients Median (range)

Allo-HSCT recipients Median (range)

ULN (F/M)

Peak ALAT (U/L) 329 (70-909) 430 (213 – 1507) 33/44

Peak HEV RNA (log IU/ml) 7.21 (6.15 – 8.30) 7.26 (5.34-8.49) NA

period of HEV RNA positivity (mos) 10.8 (6.3 -55.1) 6.4 (1.6 – 42.4) NA

time between the Tx and first HEV-RNA positive (mos) 23.9 (-3.6 – 240) 4.6 (-2.1 – 18.3) NA

Lag time PCR pos prior to HEV IgM (days) 64 (-35 – 842 ) 65 ( 0 -245) NA

Lag time PCR pos prior to HEV IgG (days) 129 (0- 842) 126 (-594 – 351) NA

Parameters of HEV confirmed cases of SOT and AlloHSCT group

Extra-hepatic manifestations of hepatitis E

acute pancreatitis

thrombocytopenia

aplastic anaemia

acute thyroiditis

glomerulonephritis

HEV-associated neurological illness

Bell's palsy

brachial neuropathy

peripheral neuropathy

Guillain–Barré syndrome

Results: Flowchart of included patients and HC

Anti-HEV antibodies in GBS patients vs healthy controls

Serum anti-HEV IgM

5.0% 0.5%

Serum anti-HEV IgG

45.8% 38.3% Sero- prevalence

GBS patients versus healthy controls

HEV serology Odds ratio (CI) p-value

Adjusted

Odds ratio (CI)

Adjusted

p-value

Anti-HEV IgM positive

10.5

(1.3-82.6) 0.011

9.7

(1.2-77.0) 0.032

Anti-HEV IgG positive

1.4

(0.9-2.0) 0.130

1.4

(0.9-2.1) 0.149

Conclusions

• Chronic HEV infection is reported in the transplant setting (both SOT and hematological patients)

• Persistent viraemia

• Persistently raised transaminase activity

• Histological features associated with chronic hepatitis

• Evidence of rapid development of cirrhosis

• PCR is superior to serology to detect infection in immunocompromised patients

• Therapeutic options for chronic HEV includes tapering immunosuppressiva and secondly ribavirine, (PEG-IFN)

Acknowledgements

Department of Cardiology

Dr. A.H.M.M. Balk

Department of Respiratory Medicine

Dr.P.Th.W. van Hal

Department of Internal Medicine,

Kidney Transplant Unit

Prof.Dr. W. Weimar

Department of Hematology

J. Versluis

Prof. Dr. J.J. Cornelissen

Department of Virology

S.D. Pas

M. Pronk

Prof.Dr. A.D.M.E. Osterhaus

Department of Gastroenterology and Hepatology

L. Koning

R de Man

R de Knegt8