Hepatitis E: Spanish researchers discover the largest series of human cases of rat-borne virus

Researchers in Córdoba have discovered dozens of patients in Spain carrying a mysterious new disease, rat hepatitis E virus (RHEV), marking the largest series of cases described in the world of an ailment first identified in Hong Kong in 2018. Many questions regarding the infection, caused by Rocahepevirus ratti, remain unanswered. It is known that about one third of rats in Spanish cities carry the pathogen but there is no clear idea of how it is transmitted to humans. Nor is the current incidence rate known, although initial results indicate that more than 100 cases occur in Spain each year.

In the face of all this uncertainty there are two reassuring elements. The first is that there are no indications that the number of people affected will increase in the coming years, but rather that the cause of many hepatitis cases classified until now as “of unknown origin” is becoming clearer. The second is that finding out the real impact of the virus and clarifying the routes of transmission will be the first step in adopting measures that can reduce the number of infections.

“We are facing an unknown emerging disease. We have several lines of research open that provide us with data on its prevalence, true dimension as a public health problem, and the clinical ways in which it manifests itself. But we still have a lot of work ahead of us,” says Antonio Rivero Juárez, a researcher specializing in hepatitis at the Maimónides Biomedical Research Institute of Córdoba (Imibic) and the Center for Biomedical Research in Infectious Diseases Network (CIBERINFEC).

The bulk of the new findings were presented at the recent European Society of Clinical Microbiology and Infectious Diseases (ESCMID) congress held in Barcelona. The organization’s Viral Hepatitis Study Group has awarded a grant of €30,000 ($32,378) for a first study to be led by Imibic that will also involve hospitals and research centers in the United Kingdom, Sweden, Italy, Hungary, Romania, and Turkey with the aim of determining the incidence of RHEV in these countries.

Hepatitis is one of a group of viral infections that produce inflammation in the liver, categorized from A to E. The one carried by rats has so far been considered a type of E, although this could change. “Within hepatitis E virus (HEV), it was considered there are eight different genotypes and the rat virus was included in this common group. But phylogenetic analyses have shown that the differences are sufficiently large to consider it a different genus within the same family,” explains Federico García, head of the Microbiology Department at the San Cecilio Hospital in Granada and president of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). Currently, to distinguish between them, the two diseases are called hepatitis E and rat hepatitis E, respectively.

Hepatitis B, C, and D tend to evolve into chronic and more severe forms, with significant mortality (although effective treatment is available for C). Hepatitis A and E, on the other hand, are considered milder by experts. They can cause acute illnesses but these are usually self-limiting and the immune system is able to overcome them in a few weeks, except in immunosuppressed patients. Mortality is also much lower. In this sense, “as far as we know so far, infections by Rocahepevirus ratti (RHEV) are similar to those of hepatitis E,” notes García.

This virus was first discovered in Germany in 2010, although it was initially believed that it could not infect humans. This changed in 2018 when researchers in Hong Kong detected the first case in a patient who had received a liver transplant, which has been followed to date by up to 16 further diagnoses in the special administrative region of China.

“There is no data and we don’t know how prevalent it is”

“We conducted a first study in Spain in which we investigated patients with acute hepatitis of unknown origin and identified the first three cases of rat hepatitis in Seville, Córdoba, and Pamplona. One of them suffered from metastatic cancer and died of acute liver failure,” explains Rivero Juárez. These results were published in 2022 in the field’s specialist Journal of Hepatology.

The first problem that these investigations encountered was a lack of adequate diagnostic tests. “These cases were just the tip of the iceberg. We were not diagnosing more simply because we did not have the right tools to do so, so the first thing we had to do was to improve them,” says Antonio Rivero Román, head of the infectious diseases department at the city’s Reina Sofía Hospital and Antonio Rivero Juárez’s father. Both have led the research on the new disease.

Research presented at the ESCMID congress in Barcelona has expanded the number of cases detected in Spain to 40, although that figure continues to rise as studies progress. “The new patients are from various parts of Spain, such as Andalusia, Galicia, Navarre, and Catalonia. This suggests that the virus is present in a good part of the country. The 40 cases were discovered by analyzing samples from just over 250 patients with acute hepatitis of unknown origin from 10 hospitals, which indicates a prevalence of 14% in this group. They are immunocompromised patients and immunocompetent people,” explains Rivero Juárez.

The 10 hospitals studied treat slightly less than 15% of the Spanish population and the data correspond to a period of 18 months, so an initial estimate indicates that the annual number of cases in Spain is well over 100. Of the 40 cases detected, two patients have died from acute liver failure and a third from other complications apparently unrelated to the infection.

“The other line we have followed has been to investigate the presence of the virus in rats. We have analyzed samples from more than 1,000 animals from all over Spain, including the Canary Islands and the Balearic Islands, and we have seen that about 30% are carriers of the virus. We do not know much about the impact it has on them, although it is likely that it also causes hepatitis,” adds the researcher.

Having confirmed the presence of the virus in a large proportion of rodents and in a significant number of patients, the big question now facing researchers is how the pathogen is transmitted from rats to people. “We have two hypotheses. We know that the animals excrete the virus in their feces and, most probably, also in their urine, so the first possibility is that this route contaminates food and liquids, or surfaces and instruments that come into contact with them, which are then consumed by people,” Rivero Juárez explains.

The second possibility is that there is another species of animal that acts as an asymptomatic intermediate host. As with hepatitis E, the pig is the main candidate and infections would occur — although this has not been proven — by consuming products made from parts of the animal that have not been subjected to heat or other types of treatment with sufficient intensity to eliminate the virus. A study recently published in the journal Emerging Infectious Diseases investigated the presence of the virus on five Spanish pig farms and found it in 44 animals (11.4%). A total of 93.2% of the positives occurred on the same farm.

Rivero Román puts the focus on other clinical questions that also remain to be resolved. “We are investigating how these [types of] hepatitis manifest themselves, to see if they present some characteristics that make them different from the rest. We also want to define whether the virus causes other conditions, such as neurological processes and febrile syndromes,” he explains.

All the experts consulted agree that there is no reason to think that the presence of the virus and cases of rat hepatitis are less pronounced in other countries. If they have not been diagnosed until now, they point out, it is because they have not been investigated using precise diagnostic techniques. They recall that the virus was first detected in rats in Germany, the first case in humans was discovered in Hong Kong, and now Spain has made the most progress in research, so it is very likely that the disease is in fact as globally distributed as rodents are.

Clarifying this in Europe is the objective of the European study to be financed by ESCMID. The participating hospitals will send samples to Córdoba, where they will be analyzed. The first results are expected by the end of the year. “Our aim is to see if this specific type of hepatitis E virus, Rocahepevirus ratti, is present in Europe. There is no data and we don’t know how prevalent it is, so our aim is to see what the prevalence and incidence of this type of infection is,” says Gülşen Özkaya Şahin, a member of the ESCMID Viral Hepatitis Study Group and a senior consultant in clinical microbiology in Lund, Sweden.

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