Hepatitis E virus infections

Abstract

Hepatitis E virus (HEV) infection is now endemic worldwide. Most patients with acute infection recover uneventfully. Outbreaks and sporadic cases, particularly in high-risk individuals are emerging increasingly. The patients with risk factors like pregnancy and pre-existing chronic liver disease, present with or progress rapidly to severe disease. Immuno-suppression in post-transplant patients is an additional risk factor. Standardized FDA-approved diagnostic tests are the need of the hour. Further studies are needed to establish guideline-based treatment regimen and outbreak preparedness for HEV to decrease global morbidity, mortality, and healthcare burden. Policies for screening donors and transplant cases are required.

Key Words: Challenges, Chronic hepatitis E, Hepatitis E virus, Post-transplant hepatitis, Risk factors

Core Tip: In this editorial we have tried to throw light on various aspects of hepatitis E virus, that help in better understanding about the virus, disease process, various diagnostic approaches, treatment and prevention. We are sure that this will be helpful to plan proper surveillance and management protocols with improved outcomes.

INTRODUCTION

The Hepatitis E virus (HEV) was considered a shy little member of the Hepeviridae family, playing only in some endemic nations. Over the past three decades, it has picked up the pace to emerge as an equally concerning issue as with other hepatitis viruses. Multiple outbreaks and grave outcomes of HEV in immunocompromised patients may be a whistleblowing reflection on public sanitation and surveillance measures. Insufficient knowledge of clinico-pathological features, limited resources for diagnosis, lack of systematic surveillance, and poor sanitation appear to be major reasons for poor suspicion index, late diagnosis, and inadequate estimate of disease burden due to HEV.

THE VIRUS

Five genotypes (HEV-1 to 4 and 7) are associated with human disease. HEV-1 is the most prevalent[1,2]. HEV infections in developed nations and developing nations differ in genotype, mode of transmission, outbreak characteristics, and presentations[3]. Hepatitis due to HEV-1 and 2 (less commonly 4 and 7) are prevalent in low- and mid-income nations. Genotypes 3 and 4 are common in European and other developed nations[1]. They are responsible for autochthonous cases, zoonotic-related cases, and HEV in immunocompromised patients[1,4-7].

Poor food and water sanitation and poor sewage management are primarily responsible for the feco-oral spread of HEV[1,3,8]. Zoonotic transmission may also occur due to contaminated or undercooked animal products or seafood[3,5,8,9]. Transmission through blood and blood products is a recently observed route[3,10]. The seroprevalence of IgG antibodies is variable according to the endemic regions. The presence of IgM antibodies and HEV RNA in samples from blood banks and hemodialysis units is concerning[7,11].

Labeled as travel-associated diseases, Humanitarian aid workers, immigrants and refugees, immunocompromised travelers, and travelers to low- and middle-income countries, are the new categories of vectors for spread[1,8]. We believe that medical tourism, the war and its consequences, and the relief measures during war and natural calamities, have contributed to worldwide endemicity. Person-to-person transmission has not been reported[1,5].

THE ROUTINE

HEV enters through contaminated water or food (undercooked animal products in particular), reaches the liver by the entero-portal circulation, and targets hepatocytes using intracellular machinery to replicate. In many patients, humoral and cellular immunity restricts the viral replication. The host clears out the infection, self-limiting the illness[12]. This host response is but a double-edged sword. The hepatocellular damage is mainly immune-mediated. The lymphocytosis (CD8+ and natural killer cells) and increased levels of cytokines (Interferon-gamma and interleukin-10) limit and clear out the infection at the cost of intrinsic damage to hepatocytes and resultant hepatitis[2,13,14].

Most infected people remain asymptomatic. Some patients present with acute hepatitis with the prodromal phase followed by the icteric phase. Management is usually supportive. The phase lasts over a week or so with a very low mortality rate[9,15,16]. A literature search revealed that HEV-3-related acute disease is known to progress to chronicity in immunocompromised and a small number of immunocompetent hosts[3,7,8,16,17].

THE SPECIALS

Chronic HEV and immunocompromised

In a histological study, Lenggenhager observed that HEV can have different presentations regarding clinical and histological findings and outcomes, depending on immune status and preexisting liver disease[6]. Differences due to geographical pattern and genotype have also been noted[6,14]. Patients with pre-existing liver disease are at increased risk for severe HEV infection, liver failure, and grave outcomes[5,16-18]. Despite ribavirin treatment, some of these patients may progress and need a liver transplant[5].

Chronic HEV infection predominantly occurs in immunocompromised hosts, solid organ transplant patients, HIV patients (low CD4 < 200), and chemotherapy patients. HEV-3 and less commonly HEV-4, result in this manifestation[7,9,19]. Chronic hepatitis is defined as having a carrier state in a post-transplant patient for six months or more and persistent HEV replication, three months after the acute phase[20]. Chronic HEV in post-transplant patients runs an unpredictable course and outcome[18]. Seroprevalence has been reported in both adults and pediatric recipients of liver transplants in developed nations and is increasing[19]. Chronic HEV in liver recipients may have an accelerated progression to liver cirrhosis and failure[18].

Drugs like Janus kinase inhibitors, therapies for rheumatoid or autoimmune diseases, and CD20-directed therapy for haematologic disorders, affect B-cell immunity and modulate HEV replication and subsequent hepatitis[6,10,21]. A substantial number of these patients progress to chronicity[10]. HEV hepatitis in patients with hematological malignancies needs dose adjustments of chemotherapeutic drugs and even it can delay the definitive management of underlying malignancy[10,22].

HEV and pregnancy

HEV genotype-1 is associated with fulminant hepatitis of pregnancy[1,16]. Poor host response, as evident by low counts of CD4 and CD8, high interferon, and higher viral load, contributes to higher prevalence in endemic areas. Pregnant patients are more susceptible to HEV-induced acute liver failure, increasing the odds of mortality by seven times[23]. Reported mortality in pregnant patients is 5% to 31% along with a significantly high risk for fetal loss, prematurity, and vertical transmission[2,8,23,24]. Deterioration and resultant outcome are unpredictable and may not be affected by pregnancy status[25-28]. Survivors of vertical transmission have a self-restricting infection without delayed/prolonged effects[29].

Extrahepatic manifestations

Literature review shows many extrahepatic manifestations but pathophysiology is unclear. Both altered host-immune response and direct cytotoxicity by the virus are hypothesized for these complications. Reported disorders include neurological disorders like Guillain-Barre syndrome, Bell’s palsy, polyradiculopathy, neuralgic amyotrophy, acute transverse myelitis, acute meningoencephalitis, glomerulonephritis, pancreatitis, biliary disorders, hematological complications like aplastic anemia, thrombocytopenia and Monoclonal gammopathy of unknown significance. HEV-associated pancreatitis and pancreatitis in existing HEV hepatitis are poorly understood phenomena[2,5,15,30,31]. Genotypes 1 and 3 are associated with renal and neurological pathologies[1,15,16]. Immunocompetent patients are more likely to have neurological complications for unknown reasons whereas renal complications (glomerulonephritis) do not have such predilections for immune status[15].

THE CHALLENGES

Diagnosis and surveillance

The non-standardization, cost, and limited availability restrict the usage of diagnostic assays in surveillance. Serological tests are now widely available, with anti-HEV IgM antibodies common for all genotypes[7]. The Anti-HEV- IgM antibodies are detectable in 1-4 wk of infection but closely followed or overlapped by IgG. Thus, single serology cannot definitely conclude acute infection as in other viral illnesses[2,3,32]. IgG may remain serologically detectable over many years[3,32,33]. Overall specificity of various IgM tests is > 99% with sensitivity in the range of 85%-87.5% for immunocompromised patients[32].

Immuno-compromised patients may have delayed or undetectable seroconversion. Nucleic acid amplification testing (NAAT) is useful for detecting HEV RNA from stool, serum, or liver biopsy[2,32]. Though a gold standard, NAAT has some pitfalls. RNA is detectable in the serum up to 3-4 wk after onset of illness and up to six weeks in the stool[5]. Patients with chronic HEV infection will show the presence of HEV RNA in serum/shed for a longer duration. Viral capsid antigen can be detected in blood before clinical presentation. This low-cost and easy-to-perform test may be valuable in blood screening[32]. Polymerase chain reaction and its advancements are also available[3]. Molecular assays to detect the open read frame (ORF)/conserved regions on the viral genome can contribute to better genotyping according to prevalent areas[34].

Treatment

Though no definitive approved options are available, Ribavirin is effective and widely used in the treatment of cases of HEV-associated fulminant hepatitis or chronic liver failure and other HEV complications[10,32,35,36]. Ribavirin clears the HEV virus by depleting guanosine triphosphate pools, thus inhibiting HEV-RNA replication[37]. The risk for hemolytic anemia is collateral damage, requiring monitoring.

Chronic HEV in solid-organ transplant recipients need dose adjustments of immunosuppressive agents that target T-lymphocytes. This step alone can lead to HEV clearance of patients[5,10,38]. In addition to dose reduction, treatment may include Ribavirin and Pegylated interferon-alpha[7,36,39]. Ribavirin is the safe and preferred agent to be consumed for three months or as per the response. The prophylactic role of Ribavirin has not been reported. Teratogenicity is under evaluation. Many researchers are evaluating the combinations of other direct-acting antiviral agents and ribavirin.

Being a virus, HEV requires host cell machinery for replication. Amidino-rocaglates are translation initiation inhibitors and are under research. In-vitro results of three Amidino-rocaglates (CMLD012073, CMLD012118, and CMLD012612) appear promising[40].

Standardized guidelines for the treatment of neurological and other extrahepatic complications are not available but ribavirin is effective in management and HEV clearance[2,5,35].

Prevention

Improved standards of sanitation and vigilance during traveling regarding food and water, remain the mainstay of prevention. The Chinese Center for Disease Control and Prevention has approved Hecolin vaccine after studies[3,9]. A safe and effective vaccine with long-lasting effects is still in its primary stage of development. WHO had advocated the use of Hecolin during the recent outbreak of 2022 in Sudan with the acceptability of the vaccine in about one-sixth of the concerned population[41]. Safe and effective vaccine with long-lasting effect is still in its primary stage of development. Vaccines, wherever available, should be considered in at-risk patients like pregnant ladies in endemic regions, solid organ transplant recipients, and chronic liver disease patients[3].

Artificial intelligence and HEV

With support of artificial intelligence (AI), researchers have integrated external/environmental factors and disease trends for issuing an alert/early warning about important infectious diseases like malaria, dengue, influenza, etc. Role of AI in hepatology (surveillance, diagnosis and treatment response prediction) is still in its primary stage with a majority of the work done with respect to Hepatitis B and associated disorders[42,43]. Fieulaine et al[44] had used AI tool known as AlphaFold2 for understanding the pORF1, which has a key role in viral replication. Time series prediction models like recurrent neural networks and Support Vector Machines are being used for disease and case-load prediction[45]. Peng et al[46] proposed an ensemble-based learning model that can correlate data on past HEV epidemics and various environmental factors, to give a better prediction analysis. Researchers are studying other models like long- and short-term memory networks, and other deep learning models to correlate environmental and meteorological data for better prediction over traditional models[47,48].

These advances can help the health care system to plan ahead of a HEV epidemic. Available literature is limited to analysis in certain provinces only. Global applicability and cost-effectiveness are the new targets for research.

CONCLUSION

Scientific knowledge and awareness about HEV among the medical fraternity and general population help to prevent a neglected approach during outbreaks and future consequences. Given its clinical significance and little-known mechanisms, we consider it is high time to act by vigilant research on HEV.