Published by Chia-Yu Chiu and Supavit Chesdachai
Diagnosis of hepatitis E virus (HEV) infection can be challenging and requires a careful clinical evaluation. In populations with normal immune function, HEV infection, associated with foodborne transmission, is typically self-limiting. Diagnostic workups are often not pursued as supportive care remains the cornerstone of management. However, this does not always apply to immunocompromised populations as they often cannot clear HEV infections. The European Association for the Study of the Liver (EASL) published the first, and still the only, comprehensive HEV practice guideline in 2018 [1]. This guideline emphasizes that in immunocompromised populations, HEV RNA testing is crucial to avoid missing cases of chronic HEV infection, defined as persistent HEV viremia for more than three months.
In the United States, only a few research or reference laboratories can perform HEV RNA testing, which is associated with long turnaround times and prohibitive costs. Consequently, HEV serological testing (IgG and IgM) remains the most ordered diagnostic test for suspected HEV infection in the United States. A two-step HEV IgM testing protocol has been employed at Mayo Clinic Laboratories, one of the largest reference laboratories worldwide, since 2013 [2]. If the result of the recomWell HEV IgM ELISA (first step) (Mikrogen, Neuried, Germany) is negative, no further testing will be performed. However, if the first step yields a positive or equivocal result, the recomLine HEV IgM Strip (second step) (Mikrogen, Neuried, Germany) test is conducted. A “true-positive” HEV IgM result requires reactivity in both the first and second steps, while a “false-positive” HEV IgM result is defined as a reactive first step but a nonreactive second step. The rationale for this two-step approach stems from the low prevalence of HEV in the United States and the risk of false-positive HEV IgM results.
A recent study from Mayo Clinic led by Dr. Chia-Yu Chiu and Dr. Supavit Chesdachai described the clinical characteristics of 1,640 patients tested HEV using HEV IgM, HEV RNA, or both over the past 10 years [2]. They found that only 18 patients were diagnosed with acute HEV, and 2 had chronic HEV. As expected, the two patients with chronic HEV were solid organ transplant recipients. Notably, they failed to exhibit ture-positive HEV IgM results under the two-step HEV IgM testing protocol. Conversely, the two-step HEV IgM testing successfully identified 17 false-positive HEV IgM cases, each with an alternative diagnosis that explained their abnormal liver enzyme. HEV RNA testing is also considered for patients with extrahepatic manifestations of HEV infection. While these patients may not meet the criteria for chronic HEV infection, early treatment with ribavirin could potentially prevent long-term complications associated with HEV.
The most cost-effective diagnostic strategy for HEV infection in low-prevalence settings remains to be determined. One area warranting further exploration is the utility of reflex testing protocols that incorporate HEV RNA testing for immunocompromised patients. This approach could parallel established practices in hepatitis B (reflex HBV DNA testing for HBsAg-positive individuals) and hepatitis C (reflex HCV RNA testing for HCV antibody-positive individuals).
Read the full article published in Hepatol Commun. 2024 Dec 11;9(1):e0611. https://journals.lww.com/hepcomm/fulltext/2025/01010/clinical_utility_of_two_step_hepatitis_e_virus_igm.13.aspx?context=latestarticles
References
- EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol 2018; 68(6): 1256-71.
- Chiu CY, Razonable RR, Yao JD, Watt KD, Chesdachai S. Clinical utility of two-step hepatitis E virus IgM antibody testing in a low-prevalence setting: A 10-year retrospective multicenter study. Hepatol Commun 2025; 9(1).
