Unexpected long-lasting anti-HEV IgM positivity: Is HEV antigen a better serological marker for hepatitis E infection diagnosis?

Hepatitis E virus (HEV) is the leading cause of acute hepatitis worldwide. The minimum criterion for diagnosis of acute infection is detection of anti-HEV antibodies, although there are scant data on IgM duration. Our aim was to assess the persistence of HEV markers after acute self-limited hepatitis E. HEV serological tests (IgM by Mikrogen and Wantai and HEV-Ag) and HEV RNA were carried out in two cohorts: (a) patients with prior acute hepatitis E (ALT >10 x ULN plus positive IgM ± HEV RNA) currently self-limited and (b) 50 blood donors with positive HEV RNA. Among 25 cases of prior acute hepatitis E, after a median follow-up of 34 months, all presented undetectable HEV RNA. However, anti-HEV IgM remained detectable in 14 (56%) by Mikrogen, 6 (24%) by Wantai and none for HEV-Ag. Anti-HEV IgM tested positive in 80%-100% within the second year and 17%-42% over 3 years later, by Wantai and Mikrogen, respectively. Among HEV RNA-positive donors, 12 (25%) tested positive for either IgM by Mikrogen or Wantai, 9 (18%) for both and 18 (36%) for HEV-Ag. HEV-Ag positivity was more likely as HEV RNA was higher (14% if <2.2 log IU/mL; 64% if RNA ≥ 3.7). Overall, HEV-Ag performed best, with a positive predictive value of 100% and diagnostic accuracy of 57%. Anti-HEV IgM exhibited unexpectedly long persistence after a self-limited acute hepatitis E. HEV-Ag had the best performance and could be especially useful in settings where HEV RNA is not available.