Zoonotic diseases remain under-recognized in Europe, despite increasing awareness, which can lead to delayed or missed diagnoses. We spoke with Yasemin Balaban, Professor of Gastroenterology, about the diagnostic challenges of HEV and why detection should extend beyond the liver.
Why are zoonotic diseases still under-recognized in Europe, despite growing awareness?
Screening tests for HEV, including HEV IgM and HEV IgG, are routinely available in most countries. However, HEV RNA testing is often performed using in-house assays and remains poorly standardized.
One barrier to diagnosis may be the perception that HEV is primarily associated with developing countries and poor sanitation, rather than industrialized nations. In Europe, zoonotic HEV is more common and often presents differently from waterborne HEV, making diagnosis more challenging.
As a result, HEV may not always be included in the differential diagnosis, particularly in patients with extrahepatic manifestations. For example, physicians may not routinely consider HEV in patients presenting with meningitis, encephalitis, or facial palsy.
HEV is typically seen as a liver disease. What extrahepatic manifestations should clinicians and pathologists be aware of?
HEV infection should be considered a systemic disease, although it most commonly presents with hepatitis. The virus can affect multiple organs either through direct infection or immune-related mechanisms.
Reported extrahepatic manifestations include:
● Neurological: Guillain–Barré syndrome, neuralgic amyotrophy, meningoencephalitis
● Renal: glomerulonephritis, IgA nephropathy
● Hematological: anemia, thrombocytopenia, lymphocytopenia, cryoglobulinemia, monoclonal gammopathy
● Gastrointestinal: acute pancreatitis
● Cardiovascular: myocarditis
● Endocrine: thyroiditis
● Muscular: myositis
These findings highlight the need to consider HEV beyond liver disease in diagnostic assessment.
Which patient groups are most at risk of missed or delayed diagnosis?
A major barrier to diagnosing HEV is that it is often not considered in the differential diagnosis, particularly in atypical presentations. As a result, cases may be missed or delayed.
HEV should be investigated in several clinical scenarios. These include patients with acute hepatitis of unknown cause, unexplained chronic liver disease, or persistent abnormalities in liver enzymes – especially in immunosuppressed individuals. Testing should also be considered in patients who develop abnormal liver function after blood transfusion. In addition, HEV may present outside the liver, so it should be included in the workup for unexplained neurological symptoms, hematological disorders, renal disease, autoimmune features, or acute pancreatitis.
HEV is detected three times more often in men than in women. The highest risk group is men over 60 who consume meat. In clinical practice, delayed diagnosis is most likely in immunocompetent patients presenting with extrahepatic symptoms, and in immunocompromised patients with chronic liver disease or ongoing liver enzyme abnormalities.
What are the main diagnostic challenges when testing for hepatitis E in routine laboratory practice?
The main diagnostic challenges in routine hepatitis E testing relate to the limitations of both serological and molecular assays, particularly in cases of zoonotic HEV infection.
Although the sensitivity and specificity of HEV IgG and IgM assays are generally high, the antibody response in zoonotic HEV infection differs from the typical pattern seen in other viral infections. HEV IgG and IgM often develop simultaneously and may not become detectable until 2 to 3 weeks after infection, limiting the usefulness of early serological testing. In addition, reinfection can be difficult to diagnose because these patients may not develop an IgM response. In such cases, diagnosis may rely on demonstrating rising IgG titers in convalescent serum together with detection of HEV RNA in blood samples.
Serological testing may also produce false-negative results in patients with primary immunodeficiency or impaired cellular immunity, as these patients may not mount detectable antibody responses. Conversely, false-positive results can occur in patients with autoimmune diseases because of cross-reactivity with other antigens.
HEV RNA testing offers high analytical sensitivity and may provide a more reliable diagnostic approach. However, several practical limitations affect its routine use. In zoonotic HEV infection, the period of viremia is relatively short compared with waterborne HEV infection, reducing the diagnostic window for PCR detection. Stool testing is also less useful because viral shedding in stool may be absent or minimal. Additional challenges include RNA instability in serum samples and the lack of fully standardized commercial HEV RNA assays.
Because of these limitations, simultaneous use of serological testing and PCR is recommended when hepatitis E infection is suspected.
What role can clinical laboratories play in improving detection and surveillance of zoonotic diseases in Europe?
Laboratories in Europe are generally well equipped to diagnose HEV infection. However, a major challenge remains limited clinician awareness of the risk factors and clinical presentations associated with zoonotic HEV infection. Improving clinician education may help increase recognition and testing for HEV, and the European Centre for Disease Prevention and Control (ECDC) could play an important role in supporting these efforts.
A practical approach would be to establish specialized teams and reference laboratories for zoonotic diseases, ideally with at least one center in each country. These centers should collaborate closely to share clinical expertise and research data.
They should also have the capacity to carry out HEV testing beyond human cases, including environmental surveillance of water, food, wildlife, and farm animals.
How important is a One Health approach in addressing these infections?
HEV is well suited to a One Health approach because transmission occurs through multiple human, animal, and environmental pathways. The virus spreads primarily through the fecal–oral route via contaminated water in waterborne hepatitis E and through contaminated meat products in zoonotic hepatitis E. Transmission can also occur through blood products and from mother to child.
As a result, effective control – and potentially eradication – of HEV requires a coordinated One Health strategy that integrates human, animal, and environmental health efforts. Key priorities include monitoring HEV in wildlife and livestock, maintaining safe water and food systems, and improving early outbreak detection and surveillance.
What are the most urgent research or diagnostic priorities in this field?
Current routine HEV tests generally demonstrate strong diagnostic performance. However, there is still a need for inexpensive, easy-to-use screening assays capable of detecting all HEV genotypes.
The recently identified rat hepatitis E virus (ratHEV/rHEV) presents an additional diagnostic challenge because it requires separate serological and molecular testing methods. At present, rHEV testing is typically limited to specialized reference centers. Because rHEV is not currently considered a major concern in Europe, routine screening is not yet recommended. However, rHEV PCR testing may be considered in patients with positive HEV IgG or IgM results but negative HEV RNA findings, particularly when there is a history of rodent exposure.
Prevention also remains an important priority. Development of vaccines that provide protection across multiple HEV genotypes, together with effective public health measures, may help reduce the global burden of disease. Hecolin, a vaccine developed in China using the genotype 1 capsid protein, has demonstrated efficacy greater than 95 percent. However, its effectiveness against genotype 3 infection remains unclear. The vaccine is currently used in China, Pakistan, and India, and the World Health Organization currently recommends it primarily for outbreak settings. Researchers in Norway are also developing a vaccine targeting HEV genotype 3.
What is the key takeaway from your ESCMID Global presentation for laboratory professionals?
A key priority is supporting the development of simple, affordable, and easy-to-use screening tests capable of reliably detecting active HEV infection across all genotypes, including rHEV.
In addition, hepatitis E should be considered in the differential diagnosis not only by hepatologists, but also by neurologists, nephrologists, hematologists, and rheumatologists because of the wide range of extrahepatic manifestations associated with the infection.
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