1. Hepatitis E Virus and Chronic Hepatitis in Organ-Transplant Recipients
Nassim Kamar, M.D., Ph.D., Janick Selves, M.D., Jean-Michel Mansuy, M.D.,Leila Ouezzani, M.D., Jean-Marie Peron, M.D., Ph.D., Joelle Guitard, M.D.,Olivier Cointault, M.D., Laure Esposito, M.D., Florence Abravanel, Pharm.D.,Marie Danjoux, M.D., Dominique Durand, M.D., Jean-Pierre Vinel, M.D.,Jacques Izopet, Pharm.D., Ph.D., and Lionel Rostaing, M.D., Ph.D.
N Engl J Med 358: february 2008
Jae Jun Sim
So Yeoun Park

2. INTRODUCTION - Acute hepatitis caused by the HEV
HEV : agent responsible for acute hepatitis that does not become chronic
- not routinely sought in cases of acute hepatitis in recipients of solid-organ transplants
anti-HEV IgG antibodies : 6 to 16% of renal-transplant recipients
- only three cases of acute HEV infection have been reported in organ-transplant

3. Acute hepatitis caused by the HEV
agent responsible for acute hepatitis that does not progress to chronic hepatitis
14 cases of acute hepatitis E infection in organ-transplant recipients
→ suggest that HEV infection may evolve to chronic hepatitis in immunocompromised
patients

4. PATIENTS AND METHODS January 1, 2004 - December 31, 2006
STUDY SUBJECTS
- all recipients of liver, kidney, kidney and pancreas transplants were screened for HEV infection by serologic and molecular tools
The exclusion criteria
1) chronically infected with hepatitis B, C, D viruses
2) Biliary-tract complications
3) Toxin- and drug related causes of abnormal LFT
--> Fourteen of 217 patients (6.5%) tested positive for serum HEV RNA .
STUDY PROTOCOL
1) Anti-HEV status : enzyme immunoassay (HEV EIA, Abbott)
2) HEV RNA in serum and stool : real-time PCR amplification (TaqMan, Applied Biosystems) of a 189-bp product located in the ORF2 region
3) The grades and stages of chronic hepatitis : Metavir classification
DATA ANALYSIS
1) chi-square test or Fisher’s exact test
2) Quantitative variables: Friedman and Wilcoxon tests
3) P value < 0.05

5. Results 1 Prevalence of anti-HEV IgG 2
Clinical and Biologic Presentation 3
Diagnosis of HEV Infection 4
Liver Histologic Findings during the Acute Phase 5
Course of HEV Infection 6
Resolving versus Chronic HEV Infection

6. RESULTS - 1 Prevalence of anti-HEV IgG
- January 1, 2004, and December 31, 2006
- kidney transplant (241recipients) ,liver transplant (86 recipients)
→screened for HEV infection at the time of transplantation
* The prevalence of anti-HEV IgG
13.5% for all recipients
14.5% for kidney recipients
10.4% for liver recipients

7. Table 1. Demographic Features of Transplant Recipients at Diagnosis of Acute HEV Infection.

8. RESULTS - 2 Clinical and Biologic Presentation
acute hepatitis episode
1) asymptomatic in 7 of the 14 patients
→ tested for HEV
2) seven other patients : fatigue, diffuse arthralgias, myalgias that had evolved over a period of 1 to 2 weeks
acute rejection episode after undergoing transplantation: zero
Immunosuppressive therapy : remained in all patients for at least 6 months before acute episode
Liver-enzyme levels : higher than the levels 3 to 4 months before the diagnosis of HEV infection

9. Table 2. Liver Function in Patients with HEV Infection.

11. RESULTS - 3 Diagnosis of HEV Infection
classic causes of hepatitis: ruled out
At diagnosis, HEV RNA : PCR amplification products of the serum HEV of 12 patients
Phylogenetic analysis :all the strains belonged to genotype 3 (GenBank accession numbers,EU to EU221003)
failed to sequence the strains of the remaining two patients
→ No correlation between HEV RNA concentration and either liver-enzyme levels , liver-activity scores at diagnosis

12. RESULTS - 4 Liver Histologic Findings during the Acute Phase
assessment of disease activity: Metavir score
0 -no activity
1- mild activity
2- moderate activity
3- severe activity
assessment of fibrosis : Metavir score
0 - no fibrosis
1- portal fibrosis without septa
2 -a few septa
3- numerous septa without cirrhosis
4- cirrhosis
RESULTS - 4 Liver Histologic Findings during the Acute Phase
9 ~ 14 patients : liver biopsy to evaluate the severity of the acute episode of hepatitis
liver-transplant recipients: liver biopsy to detect acute rejection
mean (±SD) Metavir activity : 1.3±1.0 , fibrosis scores : 0.9±0.6
dominant lesions : lobular, with inflammation , with spotty necrosis that included acidophilic bodies
portal tract : expanded and included an inflammatory infiltrate composed mainly of lymphocytes
piecemeal necrosis : six patients

13. RESULTS - 5 Course of HEV Infection
Immunosuppressive therapy and target immunosuppressive trough levels : not modified after the diagnosis of HEV infection
1) 6/14 patients (43%) : HEV infection resolved
→ serum & stool HEV RNA : undetectable within 6 months after diagnosis
→ undetectable until the last f/u :mean of 12 months (range, 5 ~36)
2) 14/8 patients (57%) : HEV infection evolved to chronic hepatitis
→ persistently elevated liver-enzyme levels
→ detectable HEV RNA : mean of 15 months (range, 10 ~24) after the acute phase
3) resolving HEV infection
→ AST & ALT : returned to preinfection values within 1 month (five patients) , 3 months(one patient) after diagnosis
→ γ-GT & ALP : returned to baseline levels within 3 months after diagnosis
Among those with chronic HEV infection, liver enzyme levels remained above the upper limit of normal at the last follow-up

14. HEV seroconversion
- four patients : resolving HEV infection (two at 1 month , one each at 3 and 6 months after diagnosis)
seven patients with chronic infection (one at 3 months, two at 6 months, two at 12 months, and one each at 13 and 15 months after diagnosis)
6/8 patients with chronic infection : second liver biopsy
2 patients declined liver biopsy
Histologic lesions :features of chronic viral hepatitis - fibrosis with dense lymphocytic infiltrate and variable degrees of piecemeal necrosis
less severe than those typically seen in nonimmunocompromised patientsbiopsy specimens
: the Metavir activity scores progressed from 1.0±0.8 to 2.2±0.9 and the fibrosis scores from 1.2±0.5 to 1.5±0.5

15. RESULTS - 6 Resolving versus Chronic HEV Infection
<acute phase>
1. median serum HEV RNA concentrations : no significant differences
(range, 5.79 to6.44 log10 copies of RNA per milliliter and range,4.92 to 7.28 respectively)
2. peak liver-enzyme levels :no significant differences
3. Hepatitis developed later after transplantation in patients with resolving HEV infection than in those in whom the infection progressed
< chronic hepatitis>
2. significantly lower serum creatinine levels at baseline and significantly lower counts of leukocytes, total lymphocytes, platelets,and CD2, CD3, and CD4 lymphocytes
2. time from transplantation to the development of infection : significantly shorter
3. total lymphocyte counts and the CD2, CD3, and CD4 lymphocyte counts were significantly lower — than in patients in whom HEV infection resolved

16. Table 3. Patients with Resolving HEV Infection and Those in Whom the Infection Evolved to Chronic Hepatitis.

17.  HEV infection can evolve to chronic
HEV should be considered an etiologic agent of hepatitis in organ-transplant recipients
 HEV infection can evolve to chronic
hepatitis, at least in organ-transplant recipients