Introduction
The hepatitis E virus (HEV) was first comprehensively identified in 1983 during an outbreak of non-A, non-B, non-C hepatitis among military personnel [1]. As a significant cause of acute viral hepatitis, HEV presents particular challenges and risks in pediatric populations. Although often associated with sporadic outbreaks and transmission through contaminated water in areas with inadequate sanitation, the virus’s full impact on children is often overlooked. Each year, HEV infects over 20 million people globally, with 3.4 million symptomatic cases reported [2]. However, this likely underestimates the virus’s true prevalence due to the limited availability of broad-based screening programs that could enhance surveillance. In industrialized countries, such as Poland, HEV infections are so rare that only 55 infections were detected in the Polish annual bulletin of infectious diseases in 2023, accounting for all infections with viruses other than HAV, HBV and HCV [3]. However, with the increasing number of people traveling to exotic destinations, the number of cases has been increasing in recent years. A recent study by Grabarczyk et al. reported that anti-HEV immunoglobulin (Ig) G seroprevalence among Polish blood donors ranged from 22.7% to 60.8% in groups aged 18 to 27 years and 48 to 57 years, respectively, indicating a high level of HEV endemicity throughout Poland compared with other countries [4]. Similar results were reported by Bura et al., where among the same population in Poland, anti-HEV IgG was detected in 60.9% of blood donors (p < 0.0001) [5]. Cytogenetic analysis of HEV strains has identified four main genotypes to infect humans: HEV-1, HEV-2, HEV-3, and HEV-4 (Table 1) [6]. Genotypes 1 and 2, which exclusively affect humans, are primarily found in developing regions and are highly endemic in parts of Asia, Africa, the Middle East, and Mexico. These genotypes are known for causing large-scale waterborne outbreaks linked to contamination of water supplies with human feces [7]. Among populations especially vulnerable to severe HEV-1 infection are pregnant women, who may experience a mortality rate as high as 30% in some cases [8]. In contrast, genotypes 3 and 4 are zoonotic and have been identified in several animal species. Cross-species transmission occurs through the consumption of contaminated food products or through direct contact with infected animals [2]. HEV is predominantly spread through the fecal-oral route, and outbreaks are common in regions with insufficient sanitation infrastructure. In endemic areas, children are frequently exposed to HEV early in life, typically showing mild symptoms or remaining asymptomatic. Although symptoms in children are generally mild, they can serve as potential reservoirs, indirectly facilitating community transmission. The incubation period for acute hepatitis E symptoms ranges from 2 to 6 weeks [9]. Primary symptoms include nausea, fever, vomiting, abdominal discomfort, appetite loss, itching, liver enlargement, jaundice, pale stools, and darkened urine. For most children, the acute phase of HEV infection leads to full recovery within a few weeks, without long-term effects. However, the infection may be more severe in children with coexisting health issues, particularly those with other liver diseases or immunocompromised conditions, such as organ transplant recipients or children undergoing chemotherapy [10]. In these cases, HEV infection can result in significant liver damage and, in severe instances, may lead to acute liver failure. Globally, the lack of widespread surveillance and underreporting makes it challenging to fully assess HEV prevalence and outcomes in pediatric populations. Due to the often mild or asymptomatic nature of HEV in children, many cases go undiagnosed, leaving the true burden of HEV in children largely unknown.
Table 1
Characteristics of hepatitis E virus (HEV) genotypes
Epidemiology
Hepatitis E virus infection is a widespread contributor to global morbidity and mortality. Initially, it was believed to be endemic only in developing countries, where incidence rates are highest due to poor sanitation conditions. However, in the past decade, sporadic, locally acquired cases have also been observed in high-income countries, making it challenging to accurately trace sources of infection in these areas [11]. HEV is now recognized in populations worldwide, although genotypes vary by region [10]. In endemic areas, including South Asia, sub-Saharan Africa, and parts of Central America, genotypes 1 and 2 are more common and are frequently linked to waterborne outbreaks, contributing to higher rates of pediatric cases. A study by Raya et al. found that HEV was present in about 15% of wastewater samples in Vietnam and up to 24% in Japan [12]. Similarly, in the Middle East, Younes et al. examined 2,670 manual laborers in Qatar and found that 27.3% (729/2670; 95% CI: 25.6-29.0) tested positive for HEV IgG antibodies [13], suggesting that HEV prevalence may be significantly underestimated. In non-endemic areas, HEV genotypes 3 and 4 are more prevalent and are commonly linked to zoonotic transmission. Historically, these infections were mostly associated with travelers returning from endemic regions. However, over the past decade, there has been a marked rise in autochthonous cases of genotype 3 and 4 infections in developed regions, with increasing evidence pointing to animal reservoirs and zoonotic transmission routes [14]. A study conducted in the Netherlands indicated that locally acquired cases of hepatitis E in both children and adults outnumbered those associated with travel (52/81, 64%) [15]. Data on pediatric HEV prevalence in developed countries are sparse, with, to our knowledge, only a few studies available from Japan [16], Germany [17], Spain [18], and reporting anti-HEV antibody rates ranging from 1% to 7.5%. The most extensive pediatric study in Europe, which involved 1,646 children (ages 0-17), revealed an increase in HEV antibody prevalence with age, from 0.4% in infants under 2 years to 1.5% among 15- to 17-year-olds [17]. Due to the limited amount of research available, further studies are necessary to accurately determine HEV infection rates in pediatric populations.
Transmission routes
Hepatitis E virus is primarily transmitted through the fecal-oral and zoonotic routes, typically via water or food. In developing countries, drinking of water contaminated with HEV-1 or HEV-2 is responsible for most sporadic cases and outbreaks. In contrast, in developed regions, most autochthonous hepatitis E cases are associated with genotype 3 and are linked to the ingestion of undercooked pork [19]. While person-to-person transmission of HEV is uncommon, maintaining strict hygiene practices in endemic areas is crucial to prevent the spread of the virus within households and healthcare settings [19]. Less frequent transmission routes also contribute to HEV infections. Blood transfusions and vertical transmission from mother to child are thought to be an emerging concern [20]. Vertical transmission, most often linked to HEV-1 and HEV-2, can result in severe liver damage during pregnancy, with mortality rates reaching up to 25% in affected mothers [20]. While HEV-3 and HEV-4 infections have been observed in pregnant women, the associated mortality rates are significantly lower [21]. Bloodborne transmission has also been documented in case reports, with several studies describing HEV infections transmitted via transfusions [22]. The most extensive investigation to date, conducted by Hewitt et al., analyzed samples from 225,000 blood donors [23]. HEV RNA was detected in 1 out of 2,848 donations, with most donors testing seronegative at the time of donation. The findings highlighted a higher-than-anticipated detection rate of HEV RNA and raised concerns about persistent viremia in immunosuppressed recipients. The accompanying editorial recommended implementing universal HEV RNA testing in blood donation screening to address this risk effectively.
Pathophysiology and immune response in pediatric patients
The developing immune system in children significantly influences the progression and clinical expression of HEV infections. In most immunocompetent pediatric patients, HEV infection is self-limiting and asymptomatic, as the immune system typically mounts an adequate response to clear the virus [24]. However, the immune system of younger children may elicit a differential response, which in most instances features increased regulatory T (Treg) cell activation and plays an important role in immune tolerance and viral clearance [25]. The increased Treg responses may be accompanied by an undeveloped cytokine network, thereby providing one possible explanation for the high asymptomatic or mildly symptomatic infection rates recorded among children [26]. The immune response in children is reported to affect the virus’s clearance, with variable outcomes influenced by nutritional and environmental factors common in developing countries. Tripathy et al. reported that high levels of Treg cell responses are a hallmark of pediatric HEV infection [26], and increased circulating Treg cells expressing forkhead box P3 protein (FOXP3) promote immune regulation through the secretion of anti-inflammatory cytokines such as interleukin (IL)-10 and transforming growth factor β (TGF-β) [25]. This immunomodulation could also be an explanation for the higher rate of asymptomatic HEV infections among children compared with adults [26]. Cytokine profiles in children have distinct immune activity at different acute and recovery phases of the HEV infection [27]. High levels of IL-1α and soluble IL-2 receptor α in acute infection are associated with active inflammation [27]. The shift toward anti-inflammatory cytokines helps the process of recovery [27]. Despite this, a protective and balanced immunity that minimizes excessive inflammation has still emerged as a critical determinant for the outcomes [26].
Immunocompromised children, such as those undergoing chemotherapy or receiving post-transplantation immunosuppressive therapy, face heightened susceptibility to chronic HEV infections [28]. In these patients, HEV infection can transition from acute to chronic, with prolonged viremia and increased risk of liver fibrosis and cirrhosis [28]. Case studies document persistent HEV genotype 4 infections in pediatric leukemia patients undergoing intensive chemotherapy, emphasizing the role of compromised immunity in viral persistence [28]. The evolution of HEV infection to a chronic form appears to be related, at least in part, to the intensity of the immunosuppressive therapy used. Due to the small number of studies on this topic in the pediatric population, further research with larger populations is needed. Combination of the developing immune system, Treg cell activity, and cytokine profiles defines the clinical course of HEV infections in pediatric patients [25, 26]. While most children exhibit mild or asymptomatic infections, immunocompromised populations face significant risks of chronic disease progression [28]. Early diagnosis, targeted antiviral therapies, and careful monitoring of immunocompromised children are crucial in improving outcomes and reducing morbidity associated with HEV.
Clinical manifestations and outcomes in pediatric HEV cases
Hepatitis E virus infection is primarily a self-limiting condition, often asymptomatic or presenting with mild, subclinical manifestations [29]. Its largely asymptomatic nature contributes to an underestimated number of diagnoses, leaving many cases undetected [29]. However, HEV can exhibit diverse clinical manifestations. When symptoms do appear, they often mimic those of viral hepatitis A, such as nausea, vomiting, malaise, fever, and body aches during the initial week of infection [10]. As the condition progresses, symptoms may evolve over two weeks to include myalgia, anorexia, pale stools, and dark urine [29]. Several factors can trigger a symptomatic or worsening course of the disease, including immunosuppression, hematological malignancies, post-transplant conditions, malnutrition, and geographical disparities [30]. Additionally, studies have documented mother-to-child transmission rates of HEV ranging from 23.3% to 50% [29]. While guidelines on the connection between HEV infection and pre-existing pediatric liver disease remain unclear, evidence suggests that the interaction between chronic liver disease (CLD) and acute hepatitis E (AHE) significantly exacerbates clinical presentations and outcomes, increasing the risk of severe complications and mortality [29]. Studies indicate that genotypes 1 and 2 are primarily responsible for AHE [10]. While elderly individuals are at a significantly higher risk, aforementioned factors can also predispose children to AHE due to a weakened immune system [29]. AHE typically presents with elevated levels of alanine aminotransferase (ALT), γ-glutamyl transferase (GGT), and total bilirubin [29]. Clinical symptoms may include jaundice, icteric hepatitis, and pruritus, despite the disease being predominantly asymptomatic in most cases [29]. In rare instances (0.5-4%), AHE progresses to acute liver failure (ALF) [10]. Research suggests that significantly lower interferon γ (IFN-γ) and higher IL-4 levels in HEV-ALF patients compared to those with AHE may indicate a potential association between IFN-γ levels and the prognosis of HEV-ALF [29]. Notably, the development of ALF is driven by the host’s immune response rather than the virus itself, similar to hepatitis A and B [29]. Chronic hepatitis E (CHE) is defined by HEV replication persisting for over three months [10]. The exact mechanisms underlying the chronicity of CHE remain unclear [29]. However, studies have linked the development of CHE primarily to HEV genotype 3 infection [29]. The condition is often associated with elevated transaminase levels, although in rare cases, patients may consistently test negative for anti-HEV IgM and IgG, which highlights the critical role of HEV RNA in ensuring accurate diagnosis [29]. CHE can lead to rapid and progressive liver fibrosis, culminating in cirrhosis within 2-3 years – or even sooner in severely immunosuppressed individuals [10], who are at heightened risk of developing CHE [29]. Interestingly, a few studies have reported that a small percentage of pediatric patients who underwent liver or combined liver-kidney transplants tested positive for HEV IgG, though none were diagnosed with CHE [10]. Furthermore, emerging evidence suggests the possibility of CHE in patients with SARS-CoV-2 (COVID-19), although more research is needed to clarify this association [29]. A potential correlation between COVID-19 infection and a predisposition to AHE is currently under investigation, though further research is needed to establish a definitive link [31]. HEV infection, while primarily associated with hepatic manifestations, is also linked to a wide range of extrahepatic complications. Neurological complications are among the most common extrahepatic outcomes of HEV, with Guillain-Barré Syndrome being the most frequently reported [10]. Interestingly, these complications occur more often in younger patients without jaundice and with normal immune function [29]. HEV genotype 3 accounts for approximately 90% of these cases, followed by genotype 1 [29]. Although the pathogenesis is not fully understood, it is believed to involve both direct viral damage and immune-mediated mechanisms [29]. Pancreatic complications frequently occur in association with HEV, particularly in endemic regions or among travelers [10]. HEV-related pancreatic conditions can progress to severe complications, such as necrotizing pancreatitis, pseudocysts, and multi-organ failure [10]. Hematological complications, though rare, can be severe. These include various forms of anemia, as well as thrombocytopenia. The latter is often associated with reduced thrombopoietin production, hypersplenism, and bone marrow suppression, with genotypes 1 and 3 being the most commonly implicated [10]. Renal disorders linked to HEV include membranoproliferative glomerulonephritis, cryoglobulinemia, and IgA nephropathy [10]. HEV infection has also been linked to other systemic manifestations such as myocarditis, polyarthritis, or subacute thyroiditis [10].
HEV diagnosis and detection in pediatric populations
Current methods include serological testing for anti-HEV IgM and IgG antibodies, as well as polymerase chain reaction (PCR) analysis [32]. Clinically, blood tests remain a standard diagnostic tool for HEV infection [33]. However, emerging evidence highlights the complexity of detecting HEV due to atypical infection mechanisms. In at-risk populations, such as transplant patients, the diagnostic process is even more critical, as symptoms of HEV infection can mimic graft rejection, and the condition carries a high mortality rate. This underscores the importance of effective, widespread diagnostic approaches, with HEV IgM/IgG and PCR playing essential roles [32, 33]. However, due to sampling techniques being invasive, they pose challenges in pediatric populations. Non-invasive alternatives are being explored, including the use of oral fluid immunoassays to detect pathogen-specific antibodies. Such tests have the potential to replace traditional blood-based protocols. Pisanic et al. reported that oral fluid immunoassays demonstrated high sensitivity and specificity for HEV-IgG antibodies (98.7% and 98.4%, respectively) and for HEV-IgA antibodies (89.5% and 98.3%, respectively), showing strong concordance with invasive testing methods [33]. However, due to the small sample size of the population (n = 141) studied, further research into this method is needed. Despite these advancements, serological cross-reactions remain a significant concern. In a retrospective study, Hyams et al. reported that as many as 33.3% and 24.2% of HEV IgM positive samples were also positive for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) IgM, respectively, but only 13.3% of HEV IgM-positive samples were positive for HEV RNA [34]. This cross-reactivity is most likely due to the stimulation of polyclonal B cells [35]. Given that acute hepatitis can present similarly in these conditions, traditional serological tests may lack diagnostic precision. PCR technology, although more costly and time-intensive, currently remains the most reliable diagnostic tool for HEV detection [34].
Management and treatment approaches
Currently, there is no established treatment protocol for HEV infection in pediatric patients. For immunocompetent children, symptomatic management such as rest, proper nutrition, and medications to reduce liver inflammation and bile stasis is typically recommended [10, 29], and most pediatric AHE cases do not require antiviral therapy, with supportive care being sufficient [29]. For immunocompromised persons, ribavirin (RBV) has shown promise in reducing the need for liver transplantation. In such cases, reducing immunosuppressive medication is advised, and if the virus persists beyond three months, RBV therapy (15 mg/kg/day for at least three months) is recommended [10]. However, RBV can cause hemolytic anemia, particularly in patients with chronic kidney or liver disease [36]. Gorris et al. reported that 67% of pediatric patients treated with RBV achieved a sustained virological response (SVR), but the same percentage required intervention for anemia [36]. However, due to the small sample size of the study population, further research is necessary. RBV is also teratogenic, making its use risky in pregnancy and potentially contraindicated in pregnant patients [37, 38]. In human immunodeficiency virus (HIV)-infected patients, HEV pathogenesis may differ due to immunosuppression, altering the immune response to the virus. Rivero-Juarez et al. emphasized the importance of heightened prevention efforts in such cases, and that appropriate recommendations for the treatment of HEV in HIV-infected patients are needed [39]. HEV poses particular risks for pregnant women, with meta-analyses showing a 26% mortality rate in acute infections and complications such as preterm labor (50%), pre-labor rupture of membranes (10%), postpartum hemorrhage, and stillbirths, particularly in third-trimester infections [40]. Vertical transmission occurs in 46% of HEV IgM-positive mothers, potentially causing neonatal complications such as jaundice, hepatosplenomegaly, respiratory distress, or sepsis. Current treatment for pregnant patients remains supportive, as use of RBV is limited due to its teratogenic effects [40].
Prevention strategies for pediatric HEV
Vaccination plays a critical role in preventing HEV infection. In 2012, the Hecolin vaccine was approved in China and demonstrated efficacy against HEV genotypes 1 and 4. However, its protection against genotypes 3 and 7 and HEVC1 needs to be evaluated. The vaccine is indicated for healthy individuals aged 16 and older, particularly those traveling to endemic regions, military personnel, students, and women of childbearing age [41]. In endemic regions, contamination of drinking water by sewage is a significant issue, contributing to widespread HEV-1 and HEV-2 infections and associated mortality [10]. Preventing transmission involves a range of strategies tailored to specific genotypes. For HEV-3 and HEV-4, avoiding raw or undercooked products from pigs, wild boars, deer, and contaminated shellfish is essential. This is particularly crucial for individuals with weakened immune systems or chronic liver conditions [42, 43]. For HEV-1 and HEV-2, preventive measures include handwashing, ensuring public water quality, and washing fruits and vegetables, especially in highly endemic countries [42, 43]. Pregnant women represent a high-priority group for HEV prevention due to the severe complications associated with maternal-fetal transmission. Infections during pregnancy are linked to stillbirths, preterm deliveries, intrauterine fetal demise, and low birth weights [43]. Notably, breastfeeding does not increase HEV transmission risk [10]. Vaccination offers hope for pregnant women and their babies, although more extensive studies are required to confirm the Hecolin vaccine’s safety and efficacy in this population. Unfortunately, no data currently exist on the use of HEV vaccines in children.
Future directions and research gaps
Despite growing recognition of HEV as a significant cause of morbidity in children, considerable gaps persist in understanding its pediatric implications. Most existing research focuses on immunocompromised adults, such as transplant recipients or chemotherapy patients, with limited data on children in these vulnerable groups. Moreover, studies on HEV vaccine effectiveness, safety, and scalability for children are urgently needed. To date, the only studies involving HEV vaccines have been conducted exclusively on the adult population, even though the problem of infection in children continues to grow [10]. Global health organizations, including the World Health Organization (WHO) and UNICEF, could play a critical role in integrating HEV vaccination into existing programs for children in endemic regions to reduce the disease burden significantly. A related concern is HEV co-infection in children with HIV. According to UN AIDS data up to 2024, approximately 1.7 million children under 14 are living with HIV [44]. Although studies suggest no direct link between HIV viral load and increased HEV infection risk [39], HIV-infected children may exhibit unique immunological and clinical features that influence HEV pathogenesis and outcomes, including chronic hepatitis E [45]. HEV transmission in children remains closely linked to environmental and socioeconomic conditions [46]. Public health policies in low- and middle-income countries should prioritize access to clean water, improved sanitation, and educational initiatives to reduce fecal-oral transmission. In high-income nations, mitigating zoonotic risks by monitoring food safety and animal reservoirs is crucial. Additionally, implementing HEV RNA screening for blood donors in these regions could help protect immunocompromised children from transfusion-related infections [17]. Filling these research gaps and enhancing global efforts will be vital to reducing the impact of HEV on children worldwide.
Summary and conclusions
Hepatitis E virus remains an underrecognized yet significant cause of hepatitis in pediatric populations, with a wide spectrum of clinical manifestations ranging from asymptomatic infection to severe outcomes in immunocompromised children. Genotypes 1 and 2 are predominantly responsible for waterborne outbreaks in endemic regions, whereas genotypes 3 and 4 pose risks in developed countries through zoonotic transmission. Beyond hepatic involvement, HEV has been linked to extrahepatic manifestations, including neurological, renal, hematological, and pancreatic complications, which add to its clinical complexity. Diagnosis in children is often challenging due to the asymptomatic nature of infections and the limitations of serological testing, necessitating PCR-based detection for accuracy. Although vaccination offers promising preventive potential, its availability for pediatric populations remains limited. Addressing research gaps, improving diagnostic capabilities, and implementing effective prevention and treatment strategies are critical for mitigating HEV-related morbidity and advancing pediatric care globally.
