Overview

Epstein-Barr virus (EBV) is a double-stranded DNA virus that infects our immune cells, B lymphocytes. These viruses from the herpesvirus family were first discovered in 1964 and have since been linked to various disorders.

The virus spreads through saliva containing epithelial cells infected with it. About 95% of adults worldwide have acquired the infection, which is an established cause of infectious mononucleosis. Treatment usually is supportive care.¹

Prevalence of the Epstein-Barr virus

The International Agency for Research on Cancer (IARC) demonstrated, in the 1970s, that over 90% of the adult global population is infected with EBV by detecting the antibodies against it. Many other studies have documented that EBV is one of the most prevalent viruses worldwide, including in remote populations.

The global prevalence greatly varies because socio-economic factors like overcrowded living conditions and poor sanitation mainly determine EBV exposure. For example, over 80% of children in Uganda have developed antibodies against EBV by age one. However, the estimate is about 45% for rural United States of America.

Primary EBV infection in early childhood is usually asymptomatic or has non-specific respiratory symptoms. EBV infection in late childhood or adolescence, as is the case in developed countries, can result in infectious mononucleosis in approximately 25-75% of persons.²

Lifecycle of the virus

The lifecycle of EBV is complex and divided into two major stages: latency and lytic replication. It enables EBV to persist in its host for a lifetime, with intermittent reactivations causing a wide range of clinical manifestations. 

The latent stage of EBV infection establishes a long-term infection, mainly in B lymphocytes. The virus persists in an episome, a circular DNA form, within the nucleus of these cells. The virus evades the host's immune system during this stage. 

On the other hand, the lytic phase is a stage of active production of new viral particles. Various stimuli, including stress and immunosuppression, can induce virus reproduction through multiple stages.³

Transmission of the virus

The virus spreads from an infected person through:^1,4

• Shared food and utensils
• Kissing
• Blood transfusion
• Stem cell and organ transplantation

The main route of EBV transmission is oral. Viral transmission through blood transfusion can also occur.^1,4

In low and middle-income countries (LMICs), poor hygiene increases the chances of viral infection in infants. Practices such as pre-chewing food for infants can also increase the prevalence of EBV transmission.^1,4

In high-income countries (HICs), the transmission is more likely to happen in adolescence during physical intimacy, causing infectious mononucleosis.^1,4

EBV infection usually occurs in individuals of young age, with low socioeconomic status, from a bigger family size than average, or with poor hygienic standards. In such people, 80-100% become carriers of the infection by the third decade of life. About 50% of primary EBV infections during young adulthood result in clinical infectious mononucleosis. 

Liver functions

The liver is the largest solid organ in the body with a distinct role in immune regulation:⁵

• Induces immune tolerance
• Strengthens innate immunity
• Regulates adaptive immune response
• Avoids over-reactive autoimmunity

Thus, the liver is said to be an immunological organ.

Other functions of the liver include:⁵

• Metabolism and digestion in coordination with the endocrine and gastrointestinal systems
• Storage of fat-soluble vitamins
• Storage of iron and copper
• Regulation of cholesterol levels
• Participates in the synthesis of blood proteins and clotting factors
• Filters blood
• Processing of haem into bilirubin for excretion
• Metabolism of sex hormones to produce carrier proteins required in reproduction and development

The connection between viral infection and liver health

The liver is the major blood-filtering organ and, therefore, is inclined to blood-borne infections leading to infectious hepatitis. Viral infections have a special tendency to affect the liver. 

Infections caused by viruses other than the hepatitis viruses can be broadly categorised into three major groups.⁶

• Liver disease in patients with fever returning from tropical and subtropical areas, which is often caused by exotic agents
• Severe liver damage in patients with immunodeficiency as a result of infections or worsening by common agents such as herpes viruses or adenoviruses
• Liver involvement in patients with respiratory and systemic infections is often linked to immunologic mechanisms

EBV-associated hepatitis

The most common medical manifestations include the triad of fever, generalised lymphadenopathy (swollen lymph nodes), and pharyngitis (sore throat), constructing the image of infectious mononucleosis.⁷

Affected individuals may present with complaints of:

• Profound tiredness
• Nausea
• Vomiting
• Anorexia

The symptoms, possibly a result of mild hepatitis, are present in approximately 90% of infected patients. Though hepatic involvement in individuals with mononucleosis is reported, with 80 to 90% of cases showing a moderate and temporary rise of liver enzymes, clinical features of hepatitis are uncommon.⁷

The levels of serum aspartate aminotransferases (AST) are described as mildly increased, consistent with liver tissue damage. Cholestatic liver disease presented by elevated serum alkaline phosphatase (ALP) and bilirubin levels due to EBV infection is rare.⁷

Furthermore, chronic hepatitis associated with EBV infection has occasionally been reported. Also, half of the fatal infectious mononucleosis cases have been reported from liver failure.⁷

Diagnosis

The diagnosis is most commonly based on clinical presentation (symptoms and signs) combined with laboratory findings (blood tests):⁴

• Lymphocytosis with numerous lymphocytes 
• Elevated liver enzymes are most often seen
• EBV-specific antibodies (in combination with liver enzyme elevation) are observed 

EBV-specific antibodies can be detected through heterophile antibody tests. Though inexpensive and fast, the test could produce false negatives in children as they do not produce detectable heterophile antibodies.⁴

Management

The EBV infection can be treated with:^4,8

• Medications to lower fever and relieve pain
• Antiviral medications can reduce viral shedding from the mouth
• Corticosteroids are not therapeutic but can provide relief in patients with respiratory or autoimmune complications after EBV infection^. 

Prevention

The basic preventive measures for EBV infection emphasise:

• Avoid transmission by not sharing personal utensils, drinking glasses, water bottles, toothbrushes, etc.
• Good hygiene with frequent handwashing, especially after salivary contact
• Avoiding events that involve close contact, like oral contact, with active EBV infection
• Educate the children not to share anything that may have saliva on it
• Educating the public, particularly young adults and parents, regarding modes of transmission, symptoms, and potential complications of EBV infection and increasing awareness about the role of EBV in liver health
• Public health strategies are based on surveillance of EBV infection-related conditions, including hepatitis and other complications of the liver, monitoring trends in the incidence of EBV infection and its sequelae and studies on vaccine and therapeutic interventions. Several candidates for an EBV vaccine are in development, and some are already in early clinical testing. In 2022, the NIH initiated a trial of a vaccine for EBV
• Improved diagnosis and reporting of cases of hepatitis caused by EBV
• Developing guidelines to manage EBV infection and associated liver diseases
• There is a need for more studies regarding the long-term effects of EBV infection on the liver
• There is a need for active research on developing an effective vaccine that might help cut down the number of EBV infections and their related diseases, such as infectious mononucleosis, cancers, and autoimmune diseases 

Summary

Epstein-Barr virus (EBV) is a double-stranded DNA virus that infects our immune cells, B lymphocytes. The virus spreads predominantly through saliva, and poor hygiene increases the chances of an infection. The liver is the major blood-filtering organ and, therefore, is inclined to EBV infections that cause infectious hepatitis. The most common medical manifestations of EBV include the triad of fever, swollen lymph nodes, and sore throat, constructing the image of infectious mononucleosis.

Blood tests include monitoring lymphocyte numbers, liver enzyme levels, and EBV-specific antibodies to diagnose EBV infection. Medications are usually prescribed to treat the symptoms of EBV infection. Good hygiene and education of the public, particularly young adults and parents, are required to prevent EBV infection from affecting liver function.

Prevention is based on hygiene practices and education about modes of EBV transmission. Currently, there is no approved vaccine, but studies are ongoing. Improvement in diagnostic tools, effective antiviral therapies, vaccine research, and molecular mechanisms underlying EBV-induced liver injury are some areas that need to be taken up in the near future.