SAN FRANCISCO – Hepatitis E is an uncommon but often serious infection in immunosuppressed heart transplant recipients that warrants routine screening, according to investigators at Erasmus University Medical Center in Rotterdam, the Netherlands.

In a study of 263 recipients, 3% were found to have become infected with hepatitis E, most with symptomatic chronic disease. The infections ranged in severity from mild, transient viremia to severe and possibly progressive hepatitis with marked steatosis on liver biopsy.

"Chronic hepatitis E virus infection can have serious consequences in this group of patients," Dr. Annemiek A. van der Eijk said in presenting the findings at the annual meeting of the American Association for the Study of Liver Diseases (AASLD). "We advise systematic hepatitis E virus RNA screening in solid organ transplant recipients. In cases in which liver enzymes are increased, additional hepatitis E virus screening should be implemented."

"Chronic hepatitis E virus infection ... is a treatable disease," she added. Some patients were able to clear the virus when their immunosuppressants were tapered, but doing so also sometimes triggered rejection, which necessitated a resumption of therapy. "In our center, we are now treating patients with ribavirin (Copegus, Rebetol), but there are no large, randomized, controlled trials about the dose and duration of therapy."

"We advise systematic hepatitis E virus RNA screening in solid organ transplant recipients."

Importantly, she stressed, physicians should include hepatitis E infection in the differential diagnosis when transplant recipients have signs and symptoms of liver dysfunction, as it could be mistaken for a variety of other conditions having distinctly different treatments.

Chronicity "is not something we often associate with hepatitis E; it really doesn’t cause chronic infection like hepatitis B or C. But in this kind of immunosuppressed situation, it could," commented Dr. T. Jake Liang, president of the AASLD and chief of the Liver Diseases Branch at the National Institute of Diabetes and Digestive and Kidney Diseases.

"This [study] makes us aware of another cause of chronic liver disease, especially in people who are immunosuppressed, or receiving chemotherapy, or undergoing transplantation with lifelong immunosuppression," he said in a press conference.

Hepatitis E is transmitted mainly by the fecal-oral route (especially through contaminated water) but it can also be acquired by consuming raw or undercooked meat, through parenteral and vertical transmission, and – rarely – by person-to-person contact.

Swine are known to carry the virus. "In the Netherlands, more than 50% of the pig population is infected with hepatitis E virus, and 7% of the livers sold in supermarkets are hepatitis E virus RNA positive," Dr. van der Eijk noted.

Infection is especially worrisome in immunocompromised patients, as they can develop persistent elevation of liver enzymes and chronic hepatitis, with some reports also suggesting the possibility of rapid progression to cirrhosis.

In a cross-sectional study, the investigators tested serum samples from orthotopic heart transplant recipients at the center who were alive in 2010 and 2011 and had banked serum. The patients were receiving tacrolimus (Prograf)- and prednisolone-based immunosuppression.

Samples were tested by both polymerase chain reaction (PCR) for viral RNA – which was used to define infection – and serologic assays for antibodies to the virus. "We decided to screen all of our patients with PCR because we know serology outcomes differ greatly between the different tests used," Dr. van der Eijk explained.

Overall, 7 of the 263 patients studied were found to be infected with hepatitis E virus, for a point prevalence of 3%, and six of them had chronic infection (defined as PCR positivity for more than 6 months). The six men and one woman had a median age of 53 years. Retrospective serum testing showed that the time between transplantation and infection was a median of 8 years, but it ranged widely, from 1 to 20 years.

Viral genotyping showed that all of the patients were infected with genotype 3, which is associated with sporadic cases of hepatitis E in Western countries unrelated to travel and is likely of swine origin. Phylogenetic testing showed no evidence that the infections shared a common source or were acquired nosocomially.

Only two patients had virus-specific IgM antibodies at the time of initial PCR-detected infection and, on average, the PCR became positive 143 days before IgM antibodies were detectable. Thus, "PCR is superior [to serology] to detect infection in immunocompromised patients," Dr. van der Eijk commented.

The patients with chronic infection had elevations to varying extents of alanine aminotransferase levels, gamma-glutamyl transferase levels, or both. On liver biopsy, their Histologic Activity Index scores also ranged considerably, but three patients had scores of 10, indicating moderate disease, with features such as hepatocyte degeneration and fibrosis.

Although all of the patients with chronic hepatitis E had fecal shedding of the virus, none of their spouses was found to be infected on either serologic or PCR testing.

Dr. van der Eijk and Dr. Liang reported that they had no relevant conflicts of interest.

Hepatitis E Screening Advised for Transplant Recipients