Annemiek van der Eijk - Virology...
Transcript of Annemiek van der Eijk - Virology...
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
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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