The high burden of HEV infection in solid organ transplant recipients

Abstract

Background: HEV is an important cause of morbidity in solid organ transplant (SOT) recipients. However, the total burden of hepatitis E, including subclinical infections in this group, is not well defined. We compared hepatitis E exposures in SOT recipients to non-transplant controls. We also examined the prevalence of rat HEV (rHEV), an emerging hepatitis agent, in this population.

Methods: This study was conducted in the main SOT center in Hong Kong. Quantitative HEV IgG, RT-PCR, IgM, and IgG avidity assays were used to measure conventional HEV and rHEV exposures in 669 SOT recipients and 667 non-transplant hospitalized controls. Follow-up samples from a subset of SOT recipients were assessed to measure longitudinal HEV exposures.

Results: Age-adjusted HEV IgG seroprevalence in SOT recipients (236/669; 35.3%) was significantly higher than non-transplant controls (185/667; 27.7%; p=0.001). Across baseline and follow-up samples, 25 (3.7%) SOT recipients had viremia (n=3) or serological evidence (n=22) of recent hepatitis E. The latter had IgM positivity (n=5), IgG seroconversion (n=16), or a 5-fold increase in longitudinal HEV IgG concentrations (n=1). Chronic hepatitis occurred in all 3 viremic individuals, while transient hepatitis was observed in 10/22 (45.4%) SOT recipients with serological evidence of recent hepatitis E. rHEV IgG levels were similar between SOT recipients and controls (p=0.424), but 2 viremic infections in the SOT group were due to rHEV and both turned chronic.

Conclusions: SOT recipients have higher hepatitis E seroprevalence than the non-transplant population. Increased exposure is driven by viremic infections and a significant burden of subclinical infections in Hong Kong. rHEV is an important cause of chronic hepatitis E in SOT recipients.

Keywords: follow-up studies; hepatitis E; organ transplantation; seroepidemiologic studies; transplant recipients.

FIGURE 1

(A) Comparison of HEV IgG seroprevalence among SOT recipients and non-transplant controls by age using the chi-square test. (B) Comparison of HEV IgG concentration among SOT recipients and non-transplant controls using the Mann–Whitney U test. (C) Comparison of rHEV IgG optical density (OD) values between SOT recipients and non-transplant comparisons using the Mann–Whitney U test. Bars represent the median and interquartile range. ***p<0.05. Only significant comparisons are presented. Abbreviations: EIA, enzyme immunoassay; OD, optical density; SOT, solid organ transplant.

FIGURE 2

Phylogenetic analysis of Rocahepevirus ratti (rHEV) isolates from patients in this study. Complete genomes were combined with partial ORF2 sequences from rHEV_patient_1 and rHEV_patient_2 before a multiple sequence alignment was generated using MAFFT (--genafpair --maxiterate 1000; v7.526). A maximum likelihood phylogenetic tree was inferred using IQ-TREE, with the best-fit substitution model determined by ModelFinder. Branch support was assessed using UFBoot with 10,000 bootstrap replicates. The final phylogenetic tree was visualized and annotated using TreeViewer. Abbreviations: ORF, open reading frame; rHEV, rat hepatitis E virus—Rocahepevirus ratti.

FIGURE 3

Treatment response of a bHEV (A) and a rHEV (B) patient given oral RBV (box). Abbreviations: bHEV, bat hepatitis E virus; rHEV, rat hepatitis E virus; RBV, ribavirin.

FIGURE 4

(A) IgG avidity testing of 19 transplant recipients seroconverting in the Wantai HEV IgG assay. Viremic patients (n=4) are immunocompetent individuals with acute hepatitis E. Early convalescence refers to individuals (n=4) within 3 months of recovery from hepatitis E. Late convalescence refers to individuals who have recovered from hepatitis E for >1 year (n=6). (B) Comparison of IgG levels in transplant recipients seropositive at both times. Individuals with doubling IgG levels are highlighted in red.

FIGURE 5

Proposed conceptual model of hepatitis E epidemiology in solid organ transplant recipients.