Posttransplantation hepatitis E: transfusion-transmitted hepatitis rising from the ashes.

In developed countries, acute hepatitis E virus (HEV) infections are increasingly reported mostly due to zoonotic genotypes 3 and 4 strains (1). Risk factors for these sporadic cases include consumption of raw or undercooked infected meat or direct contact with infected animals (1). In immunocompromised patients, hepatitis E clearance can be inefficient, which can induce chronic liver disease and cirrhosis (2). Several cases of blood-transmitted hepatitis E have been described in Europe and Japan but of unevaluated magnitude, because HEV screening in blood donors remains not implemented (3–9). Here, we describe the first case of blood-transmitted hepatitis E after liver transplantation (LT). CASE REPORT A 55-year-old man underwent a LT on May 13, 2012, for a chronic hepatitis B virus (HBV)-induced cirrhosis (Child–Pugh A, MELD score 10), leading to a hepatocellular carcinoma. HBV viral load was undetectable with entecavir treatment. During surgery, he received 10 red blood cell units (RBCU). He also had three RBCU and one pool of platelet concentrates after LT. He was administrated steroids, mycophenolate mofetil, and tacrolimus as immunosuppressive treatment and anti-HBs immunoglobulin and entecavir as prophylactic regimen of HBV recurrence. He was complication-free and discharged at day 18 after LT. A month later, liver test abnormalities appeared (γ-glutamyl transferase 446 IU/L, alanine aminotransferase 206 IU/L, and aspartate aminotransferase 55 IU/L). Graft Doppler and ultrasonography were unremarkable. A liver biopsy showed a lobular hepatitis with moderate lymphocytic infiltrate, without signs of acute rejection. Serum markers for HBV reactivation remained negative and markers of ongoing hepatitis A, E, and C, cytomegalovirus, herpes simplex virus, and human herpes virus-6 were negative, with the exception of HEV viremia (Ceeram, La Chapelle sur Erdre, France), although HEV immunoglobulins G and M (Adaltis, Milan, Italy) were negative. HEV genotype, determined from ORF2 and ORF1 regions, was 3c (10, 11). A survey was then conducted by HEV RNA screening on stored samples, determining the patient had a detectable viremia from day 17. None of the known risk factors (dietary habits and environmental exposure) were found. HEV RNA tested on the liver graft donor serum was negative. A transfusion survey was performed by testing the donors involved in blood donations. Fifteen sera stored by the French Blood Agency were tested for HEV RNA. A single sample was detectable with an estimated viral load of 3.5 log10 IU/mL. This sample was used for a RBCU administrated during surgery. HEV serology (immunoglobulins M and G) of the blood donor’s serum was negative. Phylogenetic analysis showed a strict homology between the blood donor and the patient’s strain (Fig. 1). The donor was a 41-year-old man living in a rural area. Upon examination, no clinical findings were reported, except a contact with farm animals (chicken, rabbit, and sheep) and a consumption of raw pork products. Hence, the patient contracted HEV by blood transfusion.FIGURE 1: Phylogenetic analysis of partial ORF2 and ORF1 regions. Phylogenetic trees were constructed on the MEGA4 software using the neighbor-joining method from a Kimura two-parameter distance matrix based on partial nucleotide sequences of ORF1 encoding for RdRp (323 nucleotides) and ORF2 (315 nucleotides). Bootstrap values obtained from 500 resamplings are shown. A 100% sequence homology is observed between blood donor and the recipient sequences. GenBank reference sequences are indicated by their accession number.Because of the risk of evolution into a chronic infection, HEV viremia was closely monitored. Liver tests remained abnormal, and viremia was stable at 8 log IU/mL, driving to a ribavirin therapy initiation (800 mg/day) in early September. The patient was in good general condition and the liver tests have normalized. Because the HEV viremia was negative 4 months after ribavirin therapy initiation, we planned to purchase ribavirin for 3 months more. The tolerance remained excellent without hematologic or renal side effects. The HEV viremia was still negative in March 2013. DISCUSSION We report the first case of blood transmission of HEV in the setting of LT. Causes of liver test abnormalities in LT cases include acute rejection, surgical complications, drug-induced liver injury, and viral infections (12). HEV testing is not part of the usual screening process for acute hepatitis, leading to probable underestimation of HEV infections (13). In the setting of transplantation, persistent HEV infection is observed in 60% of patients and can lead to a rapid progression of fibrosis. A short delay between LT and HEV transmission as the use of tacrolimus is associated with increased risks of infection persistence (14), and the patient had both of these risk factors, which led to undertake a ribavirin-based therapy without delay. Although several cases of HEV blood-transmitted infections have been reported in France, HEV RNA detection and aminotransferase level dosage are not part of blood donors screening. As in previous reports, HEV RNA was the only detectable marker in blood donors’ samples (3, 5). The feasibility of nucleic acid testing on plasma pools has recently been documented (15). HEV RNA testing should thus be performed to reinforce blood transfusion safety in developed countries. In conclusion, LT patients presenting with acute cytolysis should systematically be screened for HEV RNA, and posttransfusion hepatitis must regain attention and concern. Audrey Coilly 1,2,3 Stéphanie Haïm-Boukobza2,3,4 Bruno Roche1,2,3 Teresa Maria Antonini1 Anthony Pause4 Camélia Mokhtari4 Aymeric Becq1 Hussein Farahmand5 Lisette Hauser6 Jean-Charles Duclos-Vallée1,2,3 Didier Samuel1,2,3 René Adam1,2,3 Anne-Marie Roque-Afonso1,2,3 1 AP-HP Hôpital Paul Brousse Centre Hépato-Biliaire Villejuif, France 2 Univ. Paris-Sud UMR-S 785 Villejuif, France 3 Inserm, Unité 785 Villejuif, France 4 AP-HP Hôpital Paul Brousse Laboratoire de Virologie Villejuif, France 5 AP-HP Hôpital Paul Brousse Site EFS Villejuif, France 6 Etablissement Français du Sang Ile de France Paris, France