Hepatitis E virus (HEV) infection is an underdiagnosed disease in the developed world. In pediatric and adult organ transplant patients HEV infection can cause chronic hepatitis, which can lead to cirrhosis. Extra-hepatic manifestations, such as neurological symptoms and kidney injury, have been also reported in transplant patients. In this comprehensive minireview, we summarize the current knowledge on HEV infection in transplant patients, that is, its prevalence, incidence, natural history and therapy.
Hepatitis E virus (HEV) is a single-stranded RNA virus containing a 7.2-kilobase-long genome that belongs to the genus Hepevirus in the Hepeviridae family. Four major genotypes have been described. HEV genotypes 1 and 2 have been mainly found in humans in Asia (HEV1) and in Africa and Mexico (HEV2), and both cause epidemics in the developing world. HEV 3 and HEV4 have been found in humans and various animal species. Cases of HEV 3 have been mainly reported in western countries whereas HEV 4 is mainly found in China, Japan and Taiwan (1).
In the developed world, until very recently, only sporadic travel-associated cases of HEV1 and 2 or locally acquired HEV3 and HEV4, have been reported. However, recent data suggest that some areas of the developed world have hyperendemics, for example, the South of France (2). It had been assumed that HEV caused acute but not chronic cases of hepatitis. However, within the last couple of years, it has been shown that HEV infection can lead to chronic hepatitis in solid-organ transplant (SOT) patients (3), HIV-positive patients (4) and hematology patients receiving chemotherapy (5). Chronic HEV infection has been defined as a persistent increase in liver-enzyme levels plus the presence of HEV RNA in the serum and/or stools for at least 6 months after the acute phase (3). In this comprehensive minireview, we summarize the current knowledge on HEV infection in transplant patients.
In immunocompetent patients, anti-HEV IgM can be detected in the blood after an incubation period of 2–6 weeks, which then leads to an anti-HEV IgG response. During the incubation period and the early phase of HEV infection, HEV RNA is detected in both the serum and stools. However, HEV RNA then becomes undetectable in the serum in ∼3 weeks after the onset of symptoms, although it remains detectable in the stools for two additional weeks (1). A diagnosis of HEV infection can be made either by detecting HEV RNA or by indirectly detecting anti-HEV IgM directed against a range of recombinant viral antigens using enzyme immunoassays or immunochromatographic kits (6). All four genotypes elicit similar antibody responses and seem to represent a single serotype (7). Drobeniuc et al. compared six immunoassays that detect IgM antibodies to HEV and found significant variability between the sensitivity, specificity and interassay agreement of the anti-HEV-IgM immunoassays (8). An acute diagnosis can be confirmed by detecting HEV RNA using an immunoblot IgM assay or by detecting an increase in reactivity in a specific IgG assay (9). However, no commercial nucleic-acid-based assay is available that detects HEV RNA in the serum and/or stools, and no HEV RNA detection test has been approved, as yet, by the FDA. All available HEV RNA data have been obtained using in-house PCR tests. However, commercial assays are being developed to detect and quantify HEV RNA (10,11). Until these are available, HEV RNA must be tested in reference centers. It is also important to note that there is considerable variability in the accuracy of these tests between laboratories (10). In addition, phylogenetic analyses are needed to determine HEV genotype. In organ transplant patients, because HEV seroconversion may never occur (see later), anti-HEV IgM and, ideally, HEV RNA, should be also tested for.
Determining previous exposure to HEV, that is, detecting anti-HEV IgG, is problematic. It is not known whether HEV seroprevalence differs between different regions or whether it reflects problems in detecting HEV IgG. Indeed, there is great variability between the effectiveness of different enzyme immunoassays (12). This may explain the low rate of HEV seroprevalence reported in developed countries. For example, in the Midi-Pyrénées (southwest France), anti-HEV IgG seroprevalence among blood donors was found to be 16.6% when the Adaltis assay was performed and was 52.2% when using the Wantai assay (2,13). The specificity of IgG immunoblots, which have been used to confirm the results of anti-HEV IgG tests, was found to be poor (9). Hence, the sensitivity of serological assays needs to be increased so that a true picture of its seroprevalence in developed countries can be obtained.
HEV Transmission in Transplant Patients
HEV1 and 2 are mostly transmitted via a fecal and/or oral route. HEV3 and HEV4 infections are spread via zoonosis: anti-HEV antibodies have been detected in several animals, that is, pigs, wild boars, deer, rabbits, etc. (1). In nontransplant patients, HEV3 infection has been observed in patients who have consumed animal products, that is, undercooked pork, offal, sausages and mussels (1). Genotype-3 HEV RNA has been detected in several types of pork sausages (2). In organ transplant patients, a case-controlled study revealed that eating pork products, mussels and game meat was associated with HEV infection (14). In addition, eating game meat was the only independent predictive factor for HEV infection in SOT patients (14). However, it has been shown that HEV is inactivated when heated above 70°C (15).
Can HEV infection be transmitted by blood transfusion?
Only a few cases of HEV infection have been reported to be transmitted by blood transfusions (1). Among 34 SOT patients who presented with HEV infection, two patients had received a blood transfusion within the 3 months before HEV infection. Blood from the 10 involved blood donors was screened for HEV using serological and molecular tests. Anti-HEV IgM was detected in only one donor, and all patients had negative anti-HEV IgG and serum HEV RNA (16). To date, the screening of blood donors for HEV is not recommended.
Can HEV infection be transmitted via the transplant organ?
In the Midi-Pyrénées area, where the seroprevalence of anti-HEV IgG is 13.5% in organ donors, 15 organ donors for 17 SOT patients, who experienced an HEV infection within the first year posttransplant were screened for HEV using a serological assay and molecular tests (16). Anti-HEV IgM was detected in only one donor in whom anti-HEV IgG and serum HEV RNA were negative. All other donors had negative anti-HEV IgG, anti-HEV IgM and serum HEV RNA. Hence, in this hyperendemic area of France, no case of HEV transmission via the graft has been found.
Conversely, Schlosser et al. reported a first case of occult HEV transmission through a liver transplant (17). A liver transplant patient developed acute hepatitis a few days after transplantation, which evolved into chronic hepatitis and cirrhosis in <1-year posttransplant. Retrospective analysis of frozen sera revealed that the HEV serology and serum HEV RNA, which were negative before transplantation, became positive after transplantation. The HEV serology and serum HEV RNA were negative in the organ donor. However, HEV RNA was detected in a liver biopsy obtained from the donor before transplantation. Phylogenetic analysis showed that the donor's and recipient's HEV strains were identical. The risk of transmission of HEV infection by nonhepatic organs is still unknown.
Prevalence and Incidence of HEV Infection in Transplant Patients
There are few data regarding the prevalence and incidence of HEV. Furthermore, because most studies have been performed using serological assays with poor sensitivity, these data should be cautiously considered. In southwest France, among 700 patients who had undergone a liver, kidney or a simultaneous kidney–pancreas transplantation, 89 patients (12.7%) were anti-HEV IgG positive and 10 patients had isolated anti-HEV IgM antibodies (16). After a median follow-up period of 22 months posttransplantation, none of these patients experienced HEV reactivation. Among the 601 remaining patients, 34 patients had developed a de novo HEV infection, which was confirmed by detecting HEV RNA in the serum and/or stools. The incidence of HEV was 3.2 cases/100 person-years (16).
In the Netherlands, the incidence of HEV infection among 331 liver transplant patients was 2% (18). In Germany, 2.9% of liver transplant patients, with increased alanine aminotransferase levels of unknown origin, had detectable HEV RNA in their serum (19). In Spain, a 2.1% anti-HEV IgG seroprevalence was reported (20). Further studies using sensitive assays are required to determine the true seroprevalence and incidence of HEV infection in transplant populations. To date, it is not recommended to screen for HEV infection in patients who are waiting for organ transplantation.
Natural History of HEV Infection in SOT Patients
In nonimmunosuppressed patients, the clinical features of HEV range from asymptomatic infection, to mild hepatitis, to subacute liver failure (1). However, the majority of patients present with jaundice (1). A multicenter retrospective study was performed in 17 European transplant centers to determine the natural history of HEV infection after organ transplantation (21). Data from 85 patients were collected, which included 47 kidney transplant patients, 26 liver transplant patients, 2 simultaneous kidney–liver transplant patients, 6 simultaneous kidney–pancreas transplant patients, 1 islet transplant patient, 2 heart transplant patients, and 1 lung transplant patient. At HEV diagnosis, only 32% of patients were symptomatic. Fatigue was the main symptom observed. Only one patient was icteric. Liver-enzyme levels were increased but were much lower than those usually observed in immunocompetent patients. Indeed, ALT levels were 260 ± 38 IU/L, whereas ALTs were ∼3000–5000 IU/L in nontransplant patients. Serum HEV RNA was positive in all patients, and phylogenetic analysis found that HEV strains belonged to genotype 3. Interestingly, HEV seroconversion may have been delayed and or may not have occurred.
Twenty-nine of the 85 patients (34.1%) had spontaneous clearance of HEV within the 6 months after HEV diagnosis (21). None of these patients went on to present with reactivation of HEV. The 56 remaining patients (65.9%) evolved to chronic hepatitis. Nine of the 85 patients (9.4%) developed cirrhosis, that is, 9 of the 56 patients with chronic hepatitis (16%; Ref. 21). Chronic HEV3 infection and HEV-induced cirrhosis have been also reported by other groups who did not participate in this multicenter study (22,23). Thus, the risk of chronicity of HEV1-, HEV2- and HEV4-infections still needs to be determined.
Impact of HEV infection on liver fibrosis
Sixteen organ transplant patients underwent sequential liver biopsies (1–5 liver biopsies/patient) after HEV infection (24). The median time between the first and last liver biopsy was 22 (10–96) months. Activity scores increased from 1 (1–2) to 2 (1–3) Metavir units (p = 0.08), and fibrosis scores increased from 1 (0–2) to 2 (1–4) Metavir units (p = 0.04). In three patients, liver fibrosis had evolved to cirrhosis at 28, 32 and 50 months after HEV diagnosis. Two of the three patients presented with decompensated cirrhosis and portal hypertension: they died, respectively, from hemorrhagic and septic shock (24).
Predictive Factors for Chronic HEV Infection in SOT Patients
In the first report on chronic HEV infection in SOT patients, CD2, CD3 and CD4 T-cell subsets were significantly lower in patients with chronic hepatitis compared to those with resolved hepatitis (3). Since then, the predictive factors for chronic hepatitis have been searched for in larger numbers of SOT patients (Table 1). The use of tacrolimus (compared to cyclosporine A) and a low platelet count were the only two independent predictive factors for chronic hepatitis in SOT patients (21).
Table 1. Predictive factors for chronic hepatitis (21)
Resolving group (n = 29)
Chronic group (n = 56)
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
Time since transplantation (months)
70.3 ± 52.8
41.4 ± 38
Peak AST level (IU/L)
Peak ALT level (IU/L)
Serum creatinine (μmol/L)
168 ± 69
130 ± 51
Platelet count (/mm3)
225 655 ± 62 521
190 384 ± 79 903
HEV Infection in Pediatric SOT Recipients
Until very recently, no case of HEV infection had been reported in pediatric liver transplant patients. Then, Halac et al. looked for HEV infection in Canadian pediatric liver transplant patients (23). Among patients with normal liver-enzyme levels (n = 66), anti-HEV IgG seroprevalence was 15%. However, in a group of patients with increased liver-enzyme levels and histological features of chronic hepatitis (n = 14), anti-HEV IgG antibodies were detected in 36% of patients before and in 86% after liver transplantation, suggesting that two-thirds of patients experienced a de novo HEV infection after transplantation. Of these, an 8-year-old girl with a liver transplant developed chronic HEV infection (23). Another case of acute HEV infection has been recently reported in a 9-year-old liver transplant patient (25). These recent data suggest that HEV infection should be considered as a cause of hepatitis in pediatric transplant patients.
HEV Infection in Hematopoietic Stem Cell Transplant Patients
Very little data regarding the incidence of HEV infection in stem cell transplant patients exist. Koenecke et al. did not find any cases of chronic HEV infection among 52 hematopoietic stem cell transplant patients with elevated liver-enzyme levels of unknown cause (26). However, Tativian et al. reported a case of persistent HEV infection in a patient that had received vincristine/adriamycin/dexamethasone, followed by autologous stem cell transplantation for a myeloma (27). Very recently, Halac et al. reported a first case of HEV-related cirrhosis in a child post bone marrow transplant (28). In addition, a case of HEV reactivation was reported in a patient with acute lymphoblastic leukemia after allogeneic stem cell transplantation (29).
Management of HEV Infection in SOT Patients
The available data regarding the management of HEV infection in transplant patients are only found in small series and case reports (Figure 1).
Reduction of immunosuppressive drug doses
A first report showed that reducing immunosuppressive drug dose achieved HEV clearance in 4 of 16 SOT patients with chronic HEV infection. Tacrolimus trough levels and daily doses of steroids were significantly lower in patients with chronic hepatitis who had been cleared of the virus compared to those who remained viremic at, respectively, 3.25 (2.5–6.5) versus 7.35 (3.8–11.2) ng/mL (p = 0.02) and 0.035 (0.03–0.04) versus 0.1 (0.06–0.1) mg/kg/d (p = 0.04; Ref. 24). In a large cohort of transplant patients, 32.1% of patients with chronic hepatitis cleared the virus after reducing immunosuppressant dose (21). These clinical observations are in line with recent data, which show that HEV-specific T-cell proliferative responses are decreased in transplant patients, particularly in those with chronic hepatitis (30). Furthermore, a Th2 profile was more frequently observed in transplant patients with chronic hepatitis (30). Hence, in cases of chronic HEV infection, it is recommended to reduce immunosuppressant dose, particularly for those that target T cells. However, the target levels have not yet been defined.
Three liver transplant patients with chronic HEV infection, who were not cleared of the virus after reducing immunosuppressant dose, were given a 3-month course of pegylated interferon (135 μg/week). A sustained virological response was then observed in two of the three patients (31). A 12-month course of pegylated-interferon has also been given successfully to a liver transplant patient with chronic HEV infection (32). The main major side effect observed after giving pegylated-interferon to liver transplant patients has been antibody-mediated acute rejection: but this only occurred in one patient at the end of therapy when tacrolimus trough levels were maintained at very low levels (31). Hence, when pegylated-interferon is given in this setting, tacrolimus trough levels should be maintained at therapeutic levels.
Because interferon therapy is contraindicated for kidney transplant patients, as it has been associated with a high risk of acute kidney rejection, and despite a lack of in vitro data showing that ribavirin has an anti-HEV effect, the latter has been given to kidney transplant patients with chronic HEV infection. Eight HEV RNA-positive kidney transplant patients were given oral ribavirin monotherapy for 3 months (600–800 mg/day, according to the patient's creatinine clearance; Ref. 33). All eight patients were cleared of the virus under this therapy. Among the six patients who had a 6-month follow-up after ribavirin was stopped, a sustained virological response was observed in four. Mallet et al. reported on a simultaneous kidney–pancreas transplant patient who was successfully treated with a 3-month course of ribavirin (34). More recently, Chaillon et al. successfully treated a heart transplant patient with chronic HEV infection with a 3-month course of ribavirin (35).
Hemolytic anemia is the main side effect of ribavirin therapy in transplant patients who have impaired kidney function. According to the manufacturer, ribavirin therapy is contraindicated when creatinine clearance is <50 mL/min. However, it has been also shown that ribavirin can be given if the dose is adapted to creatinine clearance.
How to manage transplant patients with HEV infection?
On the basis of the small number of published papers, it seems reasonable, when acute HEV infection occurs in transplant patients, to wait for 3–6 months before modifying immunosuppressive therapy or giving an antiviral therapy as nearly 40% of patients will clear the virus spontaneously (21). In the absence of spontaneous clearance of HEV, immunosuppressive drugs that target T cells may be reduced. After 3 months, in the absence of HEV clearance, ribavirin therapy can be then given for a 3-month period. In low immunological-risk patients, immunosuppression dose reduction can be started as soon as HEV infection is diagnosed. In patients where immunosuppressants cannot be reduced, that is, highly sensitized patients or patients grafted with donor-specific antibodies, ribavirin therapy can be given without the previous step of reducing immunosuppressive drug dose. Ribavirin should be preferred to pegylated-interferon because of its better tolerance and the absence of an increased risk of acute rejection.
Management of HEV Infection in Patients Who are Candidates for Organ Transplantation or Retransplantation
Fulminant HEV infections have been reported in patients with chronic liver disease whatever is the cause of liver disease. In developed and in developing countries, it has been shown that “acute on chronic hepatitis” is responsible for 70% of mortalities in the absence of liver transplantation (36). In cases of fulminant hepatitis in transplant recipients, retransplantation may be required. However, HEV infection may recur after retransplantation, leading again to chronic hepatitis in patients who are not cleared of the virus before retransplantation (37). In the setting of “acute on chronic hepatitis” with severe fulminant hepatitis, a short course of ribavirin has been shown to obtain complete recovery and avoids the need for liver transplantation (38).
In hemodialysis patients with chronic HEV infection, who are previous recipients of a kidney transplant, who are not cleared of the virus after immunosuppressant withdrawal, and who are candidates for kidney retransplantation, a 3-month course of pegylated-interferon alpha 2a (135 μg/week) has induced a sustained virological response (39).
Interestingly, kidney transplant patients infected with HEV, who are then cleared of the virus and then maintain sustained clearance, that is, HEV clearance for at least 6 months, do not relapse after retransplantation despite receiving an immunosuppressive regimen that includes an induction therapy (40). Hence, dialysis patients previously infected by HEV can be proposed for retransplantation.
Extra-Hepatic Manifestations of HEV Infection in Transplant-Patients
It has been suggested that neurological manifestations are associated with acute HEV-infection. Recently, among 126 patients from the United Kingdom and France, with locally acquired acute and chronic HEV genotype-3 infection, neurological complications were seen in seven patients (5.5%; Ref. 41). Of these, three patients who were chronically infected by HEV3 were recipients of an organ transplant and presented with inflammatory polyradiculopathy (n = 1), encephalitis (n = 1), and ataxia/proximal myopathy (n = 1). Interestingly, HEV RNA was detected in the cerebrospinal fluid of all three patients. Furthermore, in one of these patients, clonal HEV sequences were analyzed in both the serum and cerebrospinal fluid. The discovery of quasispecies compartmentalization and its temporal association suggests that neurological symptoms could be linked to the emergence of neurotropic variants (42). However, the mechanism of HEV-induced neurological symptoms is unknown. Hence, in cases where there are neurological symptoms and increased liver-enzyme levels of unknown origin, HEV infection should be suspected.
It has been recently shown that HEV infection may induce kidney injury. Indeed, at HEV diagnosis, a significant decrease in glomerular-filtration rate has been observed in organ transplant patients (43). Furthermore, glomerular injuries, that is, membranoproliferative glomerulonephritis, have been described in kidney transplant patients with acute and chronic HEV infections (43). Nephrotic syndrome has been also reported in a liver transplant patient with chronic HEV infection (43). Interestingly, proteinuria decreased or disappeared in these cases after HEV clearance. Further studies are required to confirm these preliminary data.
HEV infection should be suspected in organ transplant patients with unexplained hepatitis with or without extra-hepatic manifestations, that is, neurological symptoms or glomerular disease. HEV diagnosis in transplant recipients should be based on the detection of HEV RNA, as testing for antibodies may give false negative results due to immunosuppression. Chronicity rates are not known, but at least one study has found them to be as high as 60%.
Immunosuppressive dose reduction and antiviral therapy (ribavirin or pegylated-interferon) have been found to obtain a sustained virological response. Further studies are required worldwide to assess the frequency of HEV infections, to improve our understanding of its natural history, and to evaluate the therapeutic options.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.