Hepatitis E virus (HEV) infection is a worldwide disease. An improved understanding of the natural history of HEV infection has been achieved within the last decade. Several reservoirs and transmission modes have been identified. Hepatitis E is an underdiagnosed disease, in part due to the use of serological assays with low sensitivity. However, diagnostic tools, including nucleic acid-based tests, have been improved. The epidemiology and clinical features of hepatitis E differ between developing and developed countries. HEV infection is usually an acute self-limiting disease, but in developed countries it causes chronic infection with rapidly progressive cirrhosis in organ transplant recipients, patients with hematological malignancy requiring chemotherapy, and individuals with HIV. HEV also causes extrahepatic manifestations, including a number of neurological syndromes and renal injury. Acute infection usually requires no treatment, but chronic infection should be treated by reducing immunosuppression in transplant patients and/or the use of antiviral therapy. In this comprehensive review, we summarize the current knowledge about the virus itself, as well as the epidemiology, diagnostics, natural history, and management of HEV infection in developing and developed countries.

Hepatitis E Virus Infection

Hepatitis E virus (HEV) infection can lead to acute and chronic hepatitis as well as to extrahepatic manifestations such as neurological and renal disease; it is the most common cause of acute viral hepatitis worldwide. Four genotypes are responsible for most infection in humans, of which HEV genotypes 1 and 2 are obligate human pathogens and HEV genotypes 3 and 4 are mostly zoonotic. Until quite recently, HEV was considered to be mainly responsible for epidemics of acute hepatitis in developing regions owing to contamination of drinking water supplies with human faeces. However, HEV is increasingly being recognized as endemic in some developed regions. In this setting, infections occur through zoonotic transmission or contaminated blood products and can cause chronic hepatitis in immunocompromised individuals. HEV infections can be diagnosed by measuring anti-HEV antibodies, HEV RNA or viral capsid antigen in blood or stool. Although an effective HEV vaccine exists, it is only licensed for use in China. Acute hepatitis E is usually self-limiting and does not require specific treatment. Management of immunocompromised individuals involves lowering the dose of immunosuppressive drugs and/or treatment with the antiviral agent ribavirin.

Hepatitis E virus infection.

to the editor—The coronavirus disease 2019 (COVID-19) pandemic has brought not only far too many losses of human lives but an economic crisis as well. Thus, effective treatments and vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Eyal et al have discussed challenge studies [1] to accelerate the assessment of vaccine effectiveness. In a challenge study, all participants are vaccinated with placebo or with the test vaccine and are then intentionally exposed to doses of SARS-CoV-2. There is already a worldwide initiative to register volunteers for such studies [2]. As all participants have been exposed, the effectiveness of a vaccine can be assessed with smaller sample sizes and possibly more quickly compared to the conventional trial with community participants; however, challenge studies are accompanied by serious ethical issues [3]. First, the characteristics of a distinct group of volunteers without risks for fatal progression or serious late complications of COVID-19 need to be reliably known. Second, a highly effective and safe treatment should be available for patients with COVID-19, so that fatalities and persistent adverse consequences can be avoided. Both these problems are not yet solved. Third, the consent of the volunteer must be with their full understanding of comprehensive information, including appreciation of potential long-term consequences. It may be questioned, however, whether someone at age 20 years or so can imagine the consequences of a scarred lung occurring many years later. Finally, it cannot be taken for granted that a vaccine that works in a challenge study with young, healthy volunteers will work in elderly patients with possible comorbid conditions [4]. Thus, even the social value of challenge trials can be questioned. Fortunately, there is an ethically more acceptable alternative for an accelerated evaluation of SARS-CoV-2 vaccines. The large, simple, randomized trial (LSRT), as proposed by Yusuf et al in 1984, is a reliable, methodologically and ethically sound alternative [5]. Characteristics of this design include: wide, simple eligibility criteria; central randomization; recording of only few baseline data; simple and short-term treatment; reduced or no follow-up visits; and outcome assessments of hard endpoints, preferably by registries. Using this design, truly large randomized trials with sample sizes beyond 40 000 patients have been carried out and answered important questions [6]. Probably due to the increasing bureaucratization of clinical research activities, including very costly monitoring, in the last 20 years there has been an almost complete disappearance of this trial design. At the current stage of evaluation of the effectiveness of SARS-CoV-2 vaccines, this design should be revived as it is ideally suited for this task. There would be wide eligibility criteria with very few exclusion criteria as the vaccine should become available for almost everybody. The investigational vaccine is a 1 or 2-time treatment only and no follow-up visits are needed. The outcomes, COVID-19 or death, can be collected either by registries available in many countries (eg, in the United States, United Kingdom, or Scandinavia) or by patient reporting. Vaccine safety information can be collected by established systems like the Vaccine Safety Datalink in the United States [7], prescription event monitoring programs (eg, the Drug Surveillance Research Unit in the United Kingdom [8]), or by direct patient safety reporting on websites, including those accessible with smartphones [9], which can be specifically designed for vaccine trials. Among the advantages of using the LSRT design are that it allows central randomization of large numbers of volunteers within a short time and rapid collection of the relevant outcomes at a low cost compared to the conventional phase 3 trials with many follow-up visits and extensive monitoring. Adaptive design features (eg, modification of the eligibility criteria considering the accruing safety information) are feasible as well. Given the wide entry criteria, the results provide external validity for large parts of the population compared to any challenge trial, which would need to focus on participants with extremely low risks for developing serious COVID-19. As there will be very many people who would like to participate in such a vaccination trial, the sample sizes needed should be achieved within a very short time. When the LSRT double-blind design is used, the validity of the results is assured and it does not generate the serious ethical issues inherent in challenge trials. Regarding the Salk vaccine, large randomized trials with sample sizes of more than 70 000 were done in the early 1950s [10] and such LSRTs should be feasible in 2020. Thus, the sponsors of vaccine trials and the drug regulatory agencies should start the preparatory work now to be ready once an investigational vaccine is ready to be administered on a large scale.

Journal of infectious diseases

Objective: The aim of the study was to determine whether Guillain-Barre syndrome (GBS) is associated with preceding hepatitis E virus infection. Methods: The frequency of hepatitis E virus (HEV) infections was determined by anti-HEV serology in a cohort of 201 patients with GBS and 201 healthy controls with a similar distribution in age, sex, and year of sampling. Blood samples from patients with GBS were obtained in the acute phase before treatment. In a subgroup of patients with GBS, blood, stool, and CSF samples were tested for HEV RNA. Results: An increased ratio of anti-HEV immunoglobulin (Ig) M antibodies was found in 10 patients with GBS (5.0%) compared with 1 healthy control (0.5%, odds ratio 10.5, 95% confidence interval 1.3–82.6, p = 0.026). HEV RNA was detected in blood from 3 of these patients and additionally in feces from 1 patient. Seventy percent of anti-HEV IgM-positive patients had mildly increased liver function tests. All CSF samples tested negative for HEV RNA. The presence of anti-HEV IgM in patients with GBS was not related to age, sex, disease severity, or clinical outcome after 6 months. Conclusions: In the Netherlands, 5% of patients with GBS have an associated acute hepatitis E virus infection. Further research is required to determine whether HEV infections also precede GBS in other geographical areas.

Guillain-Barré syndrome associated with preceding hepatitis E virus infection.

A nationwide survey of hepatitis E viral infection in French blood donors.

Hepatitis E virus (HEV) seroprevalences of 0.3%-53% were reported from industrialized countries. Because these estimates may be influenced by detection assays, this study compares 3 frequently used tests for HEV detection: the MP Diagnostics HEV immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), the Axiom Diagnostics HEV IgG enzyme immunoassay (EIA), and the Mikrogen recomLine HEV IgG assay. Sera from 200 healthy healthcare workers and 30 individuals with acute HEV infection were analyzed. Among the healthy individuals, HEV IgG was found in 4.5% by the MP Diagnostics assay, in 29.5% by the Axiom Diagnostics assay, and in 18% by the Mikrogen assay. Among individuals with acute HEV infection, positive results were obtained for 83.3%, 100%, and 96.7%, respectively. Thus, the 3 assays show clear differences in diagnostic sensitivity.

Julia Preiss

Papers

Test Performance Characteristics of Anti-HEV IgG Assays Strongly Influence Hepatitis E Seroprevalence Estimates