Chronic hepatitis E and hepatitis E seroprevalence in immunosuppressed patients: a prospective study

Introduction

Hepatitis E virus (HEV) is an RNA virus with eight known genotypes (HEV-1 to HEV-8). Of these, five genotypes (HEV-1 to HEV-4 and HEV-7) have been identified as capable of infecting humans. HEV-1 and HEV-2 exclusively infect humans and are primarily transmitted via fecal-oral contamination, being most prevalent in developing countries. In contrast, HEV-3 and HEV-4 are zoonotic and often associated with the consumption of undercooked meat, such as pork, wild boar, or deer (1). These genotypes are the leading cause of acute hepatitis in high-income countries (2).

Although most acute HEV infections resolve spontaneously with symptomatic management, immunosuppressed individuals face a heightened risk of progressing to chronic HEV infection, which is defined by the presence of HEV RNA or a positive HEV antigen test for more than 3 months (1).

In Europe, HEV-3 is the predominant genotype associated with chronic infections (3). Among solid organ transplantation (SOT) recipients, approximately 1% to 2% exhibit active HEV infection, as indicated by detectable HEV RNA (4). The progression to chronic infection varies between studies but is typically observed in about two-thirds of cases (2). However, this proportion might be overestimated. Recent prospective studies suggest that asymptomatic immunosuppressed patients often fail to develop antibody responses despite HEV infection. Thus, studies relying solely on anti-HEV immunoglobulin M (IgM) testing to confirm HEV RNA positivity may underestimate the prevalence of silent, self-limiting infections (5).

Chronic HEV infection in immunosuppressed individuals can lead to chronic hepatitis and liver cirrhosis, with potentially severe outcomes such as the need for new transplantation or death (6,7).

Despite these potentially severe outcomes, HEV infection is underdiagnosed. In Belgium, HEV seroprevalence has been studied exclusively in healthy populations. Historical serum bank analyses conducted in 2014 estimated an HEV seroprevalence of 5.8%, while a 2015 study reported a prevalence of 8.71% among Flemish blood donors (8,9). However, to our knowledge, no prevalence or incidence studies have been conducted in Belgium focusing on chronic HEV infection.

To address this gap, we conducted a single-cohort, prospective interventional study to assess the prevalence of chronic hepatitis E and seroprevalence in immunosuppressed populations, including SOT recipients and patients with hematological diseases (HDs), at a single tertiary center in Belgium. We present this article in accordance with the STARD reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-154/rc).

Methods

Study design, population, and data collection

This research was a single-cohort interventional study conducted prospectively. Between May 1, 2022, and April 30, 2023, data were collected from a cohort of immunosuppressed patients attending the outpatient clinics of the liver transplantation (LT), cardiac transplantation, kidney transplantation (KT), and hematology departments at University Hospital Saint-Luc, Brussels.

The collected data included demographic information, medical history, the indication for and type of immunosuppressive therapy, routine clinical examination findings, and standard blood test results, including liver function tests. Additionally, all patients underwent complementary blood tests to assess HEV serological markers [immunoglobulin G (IgG) and IgM], HEV polymerase chain reaction (PCR), and genotyping if PCR was positive. In cases where HEV PCR was positive, a liver Doppler ultrasound and FibroScan^® were performed. These patients were enrolled in a specific hepatological follow-up, and a second HEV PCR test was conducted 3 months later.

Inclusion criteria included patients aged 18 years or older at the time of enrollment who agreed to participate in the study, as documented by a signed and dated informed consent form. Eligible participants were required to be under regular follow-up at University Hospital Saint Luc for at least one annual visit due to SOT or a hematological condition requiring maintenance immunosuppression for at least 3 months.

Exclusion criteria included patients under 18 years old, those unable to attend follow-ups or undergo evaluations due to personal or medical circumstances, and any other contraindications at the discretion of the investigator.

This study received ethics approval from the Ethics Committee of the University Hospital Saint-Luc (approval No. B4032021000127), and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent was obtained from all patients.

Case definition

The diagnosis of chronic hepatitis E relies on two positive HEV PCRs 3 months apart. Patients were considered cured if they had negative HEV PCR in blood and normal liver function tests.

Detection of anti-HEV antibodies and HEV RNA

HEV virus infection was diagnosed based on the positivity of anti-HEV antibodies determined by the recomWell HEV IgG and IgM enzyme-linked immunosorbent assay (ELISA) Kit on the Analyzer I platform (Mikrogen, Neuried, Germany). Nucleic acids were extracted by using NucliSens^® easyMAG™ (Biomérieux, Marcy l’Étoile, France) extraction kit by following manufacturer instructions. HEV RNA detection was performed for quantification purposes. Real-time quantitative PCR (RT-qPCR) was further performed on all pre-screened positive samples by using RealStar^® HEV RT-PCR kit 2.0 according to manufacturer instructions (Altona Diagnostics GmbH, Hamburg, Germany). HEV genotype was finally determined by Sanger sequencing by using the protocol described in Boxman et al. (10), amplifying 493 base pairs fragment of ORF2, was used, and the obtained sequences were aligned against HEV reference genomes.

Statistical analysis

Categorical variables were presented as numbers and percentages. Continuous variables, such as age, laboratory results, the number of immunosuppressants, and the duration of immunosuppression, were reported as mean ± standard deviation (SD). Proportions were compared using the χ² test, and independent sample t-tests were used to compare HEV IgG-positive and HEV IgG-negative groups.

To identify independent risk factors associated with positive HEV IgG, binary logistic regression analysis was performed, reporting adjusted odds ratios (ORs) with 95% confidence intervals (CIs) and P values.

All statistical analyses were conducted using SPSS version 29, with statistical significance defined as a P value <0.05.

Results

Characteristics of the subjects

A total of 782 patients were enrolled in the study, of whom 740 were included in the statistical analysis. Forty-two patients were excluded due to having dual causes of immunosuppression, which made inter-group comparisons impossible.

The 740 patients were distributed as follows: 335 patients were followed for KT, 136 for heart transplantation (HT), 200 for LT, and 69 for HD (Table 1). Within the HD group, 19 patients were treated for lymphoma with over 3 months of immunosuppressive therapy, 30 had received allogeneic hematopoietic stem cell transplantation in the past year, and 20 had received allogeneic hematopoietic stem cell transplantation more than a year ago. Additionally, 12 patients in the HD group had received immunoglobulin substitution prior to inclusion.

Of the 740 patients, 28% were on single immunosuppressive therapy, 36% were on double immunosuppressive therapy, and 36% were on triple immunosuppressive therapy.

Table 1 displays their demographic characteristics and laboratory data. The mean age of total population was 57.05 years old, with a sex ratio female/male (F/M) of 1/3. No difference in age or sex ratio was found between the groups. Table 1 presents the seroconversion rate (IgG positivity) across the different immunosuppressed groups. Only six patients in the entire cohort were IgM-positive, and five of them also had a positive HEV RNA PCR. As IgM positivity and/or HEV RNA viremia were only observed in these cases, they are described in detail later in the manuscript. Comparative analysis between groups showed a significative difference for lab tests, mean number of immunosuppressive medications and mean time between the beginning of immunosuppression and the time of inclusion. Table 2 describes the type of immunosuppressive medications according to the pathology.

HEV seroprevalence

The HEV seroprevalence of the total population is 9.9%. In subgroup analysis, the HEV seroprevalence is 11% for the HT, 8.4% for the KT, 14% for the LT, and 2.9% for the patients followed for a HD (Figure 1).

Figure 1 HEV seroprevalence in % according to the cause of immunosuppression. HEV, hepatitis E virus; IgG, immunoglobulin G.

When looking at subgroup analysis, there was a significant difference for HEV seroprevalence between the HD and HT groups (P=0.046) and between the HD and LT groups (P=0.01).

Description of the HEV seropositive population

The mean age of HEV seropositive population is 63.3 years old, with a sex ratio F/M of 2/3.

There was no significant difference between the characteristics of the different groups except for the mean number of immunosuppressants.

Table 3 displays the demographic characteristics and laboratory data of the HEV IgG+ population with subgroup according to the type of immunosuppression.

Using independent sample t-test to compare the means of HEV seropositive population with HEV seronegative population, there was a significant difference in age, aspartate aminotransferase (AST) levels and total bilirubin between the two groups. The results are shown in Table 4. No difference was found for mean number of immunosuppressive medications between HEV IgG+ and IgG− patients.

Risk factors of HEV seropositivity

Logistic regression analysis identified two independent risk factors for HEV seropositivity: older age (OR =1.039; 95% CI: 1.018–1.060) and LT (OR =5.356; 95% CI: 1.197–23.963). Neither sex nor the mean number of immunosuppressive medications was found to be significant. The specific types of immunosuppressive medications could not be conclusively linked to HEV seropositivity. Information regarding potential risk factors such as dietary habits (e.g., consumption of pork or game meat) or international travel was not available in the medical records.

Description and outcome of the patients with positive HEV RNA and chronic HEV

Among the total population, 6 patients (0.8%) were positive for HEV RNA, all of whom were infected with HEV genotype 3, subtype 3c. Of these, 5 patients were KT recipients and had persistent HEV RNA positivity 3 months after the initial test, meeting the criteria for chronic HEV infection (0.6%). A summary of these cases is presented in Table 4. Patient 6 was followed by the hematological department and died before follow-up PCR testing could confirm chronic infection. Consequently, this case was not classified as chronic HEV.

Hereunder is a description of the six HEV RNA+ patient, as summarized in Table 5.

• Patient 1: a patient followed for a KT since 1999 due to Goodpasture syndrome, treated with tacrolimus, corticosteroids, and mycophenolic acid. HEV serology in March 2022 revealed HEV IgG and IgM positivity with a viral load of 2.7×10⁶ IU/mL, which remained detectable after 3 months despite immunosuppressive adjustments. FibroScan showed 17.1 kPa stiffness, and a liver biopsy confirmed F3 fibrosis. Ribavirin treatment was initiated in November 2022, with a gradual dose increase to a dose of 800 mg/day. The treatment had to be discontinued after 2 months due to anemia. HEV RNA became negative within 2 months of treatment and remained so, with a FibroScan in November 2023 showing improved stiffness (5.4 kPa).
• Patient 2: a patient followed for a KT since 2007 due to antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, treated with tacrolimus, corticosteroids, and mycophenolic acid. HEV serology in February 2022 was positive for IgG and IgM, with a viral load of 5.1×10⁶ IU/mL. Despite immunosuppressive adjustments, the viral load remained positive after 3 months (3.1×10⁵ IU/mL). Ribavirin treatment was initiated in March 2023 at a dose of 200 and 400 mg alternately in view of impaired renal function. Ribavirin treatment reduced the viral load but failed to clear the infection, necessitating a second treatment course, which managed to clear the infection.
• Patient 3: a patient followed for a KT since 2016 due to Alport syndrome, treated with tacrolimus, corticosteroids, and azathioprine. HEV serology in August 2022 revealed IgG and IgM positivity with a viral load of 1.7×10⁶ IU/mL, still positive after 3 months despite tacrolimus dosing reduction. Ribavirin therapy with a target dose of 800 mg/day led to HEV RNA clearance after 3 months.
• Patient 4: a patient followed for a KT since 2004 due to focal segmental glomerulosclerosis, treated with tacrolimus, corticosteroids, and mycophenolic acid. HEV serology in October 2022 revealed IgG and IgM positivity with a viral load of 9.7×10³ IU/mL, which remained detectable after 3 months despite immunosuppressive adjustments. Ribavirin treatment with a target dose of 800 mg/day cleared HEV RNA within 3 months.
• Patient 5: a patient followed for a KT since 2012 due to postpartum hemolytic uremic syndrome, treated with tacrolimus, corticosteroids, and mycophenolic acid. HEV serology in November 2022 revealed IgG and IgM positivity with a viral load of 9.7×10⁵ IU/mL, which remained detectable after 3 months despite immunosuppressive adjustments. Despite ribavirin treatment at the dose of 400 mg/day (because of renal impairment), HEV RNA remained detectable, requiring a second treatment course, which managed to clear the infection.
• Patient 6: a hematology patient with myelodysplastic syndrome, treated with azacytidine after relapse post-allogeneic transplantation in 2019. HEV RNA was detected in December 2022 (viral load: 4.6×10⁵ IU/mL), but the patient died in February 2023 due to macrophage activation syndrome before follow-up testing could confirm chronic infection.

Discussion

This prospective, monocentric study represents the largest series in Belgium to date evaluating HEV seroprevalence and chronic HEV infection in immunosuppressed patients. Limited data exist on prospective screening of the immunosuppressed population for HEV infection, which is essential to understanding true seroprevalence and the progression to chronicity.

Over 1 year, we included 740 immunosuppressed patients followed after LT, cardiac transplantation, or KT, or for a HD. In this cohort, the HEV seroprevalence was 9.9%, and chronic HEV infection was detected in 0.6% of patients.

Previous studies in Belgium have investigated HEV seroprevalence in healthy subjects. Vercouter et al. screened 38,137 blood donation samples in May-June 2015, finding an HEV RNA positivity rate of 0.018% and an anti-HEV IgG prevalence of 8.71%. They observed a strong association between HEV IgG positivity and older age, with 90.32% of IgG-positive individuals being over 45 years old, confirming older age as a significant risk factor (8).

Another study analyzed historical serum banks from 2006 and 2014 in Belgium, reporting HEV IgG seroprevalence rates of 4.1% (95% CI: 3.1–5.1%) in 2006 and 5.8% (95% CI: 4.8–6.9%) in 2014, showing stability over time. This study also confirmed a significant increase in seroprevalence with age (9).

We were not able to statistically compare our population to these healthy Belgian population, our cohort being not large enough to match them with the other samples.

We also analyzed HEV seroprevalence according to the cause of immunosuppression and the type of SOT.

In LT, the HEV seroprevalence was 14% in our study which is consistent with the literature. A 2013 review by Zhou et al., covering studies from France, Germany, the Netherlands, Canada, and Iran, reported an average HEV IgG seroprevalence of 7.4% (11). A later review by Buescher et al. in 2020 analyzed 16 studies including 4,915 LT patients, finding a seroprevalence of 27.4% (95% CI: 18.33–38.86%) (4).

In HT, we observed an HEV seroprevalence of 11% of the patients which is lower than that reported in the meta-analysis by Buescher et al. which included five datasets from 2012 to 2019 covering 955 patients, revealing a much higher seroprevalence of 36.5% (95% CI: 20.24–56.63%) (4). One possible explanation for higher seroprevalence in certain studies is the increased use of blood product transfusions in HT patients (12).

In KT, the HEV seroprevalence in KT recipients in our cohort was 8.4%, with 1.49% testing HEV RNA positive. In Buescher et al.’s review, including 27 studies and 7,604 KT patients worldwide, the anti-HEV seroprevalence was 33.94% (95% CI: 23.97–45.56%), higher than our population. However, the HEV RNA positivity rate of 1.17% was consistent with our findings (4).

In patients with HDs, HEV IgG seroprevalence was only 2.9% in our HD group, lower than reported in other studies. 12 patients in our HD had received immunoglobulin substitution before inclusion, but the only two HEV IgG+ patients in the HD group were not in this category. There are insufficient data available regarding the seroprevalence and incidence of HEV with hematological malignancies. In Switzerland in 2023, the HEV seroprevalence of a cohort of 292 patients was 21.9% before bone marrow transplantation. In Italy, 34 of 563 patients were tested positive for HEV IgG pre-HSCT, defining a seroprevalence of 6.04% (13,14). In Sweden in 2020, they searched for HEV infection 6 months after HSCT. The prevalence of anti-HEV IgG and/or IgM was 4.7% (15). The difference observed before and after hematological treatment can be explained by the hypogammaglobulinemia and lymphopenia often observed after treatment in these specific patients. In those post-treatment studies, no data were given regarding the immunoglobulin substitution. It should be noted that our HD HEV RNA+ patient was not seropositive for IgG or IgM, which underlines the importance of PCR screening for HEV RNA in this specific population.

Differences in HEV seroprevalence between studies may reflect variations in the sensitivity and specificity of commercially available assays. Pas and colleagues show varying clinical specificity ranging from 84% to more than 99% and sensitivity ranging from 52% to 79% among the tested assays for both IgM and IgG (16). Importantly, testing for antibodies in immunocompromised patients may be unreliable, as they may not develop antibodies (17). This was also observed in our study for Patient 6, who was positive for HEV RNA but negative for HEV IgG and IgM.

In University Hospital Saint-Luc, liver transplant recipients receive reduced-dose tacrolimus monotherapy, whereas kidney transplant patients typically undergo triple immunosuppressive therapy. This higher immunosuppressive burden may explain the increased prevalence of chronic HEV infection in kidney transplant recipients. Conversely, the lower immunosuppression in liver transplant patients might contribute to the prolonged presence of HEV IgG antibodies after HEV exposure. Additionally, this population in our study has a higher mean age compared to the general Belgian population, which could explain the higher prevalence of HEV seropositivity.

Age was identified as the main risk factor for HEV seroprevalence in our population, consistent with most studies on SOT recipients, hematology patients, and healthy individuals (4,8,14,18).

Being liver-transplanted was also a risk factor for HEV seroprevalence, though it was not significant in other series (19). Our findings may be influenced by the minimal immunosuppressive regimen used in our LT population (low dose of tacrolimus monotherapy in most of the patients).

As 92% of our patients were on tacrolimus, we could not identify the use of this drug as a risk factor for HEV infection, contrary to what has been shown by Kamar et al. in 2011 (20).

After identifying five chronic HEV patients, a liver function test assessment showed that the highest RNA levels were found in patients with elevated liver enzymes. However, three of the five patients had normal or slightly elevated liver enzymes (one to two times the upper limit normal). This emphasizes the fact that systematic screening for HEV should be organized in immunosuppressed patients, more specifically in those with impaired liver function tests. However, chronic HEV infection can still occur despite normal or borderline normal enzymes.

In these patients, non-invasive evaluation of fibrosis using elastography is crucial to provide information on severity and prognosis of liver disease. However, as chronic hepatitis E is rare, there are no established cut-off values that have been reported.

One of our chronic HEV patients showed elevated liver elastography values and liver tests at diagnosis, which normalized at 1 year after ribavirin treatment. To discuss this point, we can only rely on case reports or small cohorts. Certain case reports have shown a similar evolution of fibrosis (21), while others small cohorts showed values that remain high even after successful viral clearance (22). This is in line with the observation after other chronic viral hepatitis eradication (23,24).

All five chronic HEV patients were infected with HEV subtype 3c, the most common subtype in Belgium (25). Subtype classification, as shown by Peeters et al., may influence disease severity, with certain clades associated with worse outcomes (26). None of our patients required hospitalization, suggesting a milder course of infection with HEV 3c.

In the case of chronic HEV infection, the European Association for the Study of the Liver (EASL) guidelines suggest the initial approach to treatment is the reduction of immunosuppression. If HEV replication continues three months after detection of HEV RNA, EASL recommends a 12-week course of ribavirin monotherapy (1). In our five chronic HEV patients, decreasing immunosuppression didn’t manage to achieve HEV clearance. After 3 months of ribavirin, HEV clearance was obtained in 3/5 patients, the other two needing an extra 3 months of ribavirine to clear HEV. Progress in the understanding of the biology of HEV and the pathophysiology underlying the occurrence of chronic infection in some specific patients would help us in a better control and treatment of these patients.

There were some limitations in our study.

First, it was a monocentric study. We could unfortunately not screen all the SOT patients followed in our institution during this 1-year study because of logistic considerations (many different doctors, patients not always keen in participating, etc.) Due to the 1-year window of the study, we may have missed viremic cases diagnosed before the beginning of the study.

Besides, not all data regarding host risk factors, such as pork and game meet consumption and a systematic review of blood product transfusion were gathered during the course of the study.

Conclusions

In conclusion, this single-cohort study found an HEV IgG seroprevalence of 9.9% in immunosuppressed patients, with chronic HEV detected in 0.6% of cases, all in kidney transplant recipients requiring ribavirin treatment. These findings highlight the importance of considering HEV infection in post-transplant patients with unexplained liver abnormalities. Our results support systematic HEV screening in immunosuppressed patients, particularly using molecular testing in those with altered liver function tests.

More prospective data and more insights on the virus biology and hosts’ immune response are awaited to draw conclusions on the importance of systematic screening in these immunosuppressed populations.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-154/rc

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-154/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-154/prf

Funding: This work was supported by a Gilead Grant (to G.D.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-154/coif). M.C.B. received support for attending ESC-HF 2023 (Prague), with costs paid through the institution; and also participated in the Acoramidis Advisory Board, with compensation paid through the institution. S.B. participated in the Advisory Board of Astra-Zenecca, Roche, Abbvi, Beigene, with compensation paid through the institution. G.D. received a scholarship in her name from Gilead. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study received ethics approval from the Ethics Committee of the University Hospital Saint-Luc (approval No. B4032021000127), and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent was obtained from all patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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