Epstein–Barr virus (EBV), also called human herpesvirus 4 (HHV-4), is a member of the herpesvirus family. It is one of the most common viruses in humans, with about 90–95% of people worldwide becoming infected at some point in their lives. The virus spreads mainly through saliva, but it can also be transmitted through blood transfusions and organ transplants. EBV is best known for causing infectious mononucleosis, often called “mono” or the “kissing disease.”
In children, EBV infection usually causes no noticeable illness. In teenagers and young adults, however, it may lead to fever, sore throat, swollen lymph nodes, tiredness, and an enlarged spleen. Most people recover within two to four weeks, though fatigue can last longer. EBV has also been linked to certain cancers (such as Hodgkin lymphoma, Burkitt lymphoma, and nasopharyngeal carcinoma) and to autoimmune diseases such as multiple sclerosis.
Once a person is infected, EBV remains in the body for life in a “latent” (inactive) state within immune cells called B lymphocytes. The virus can occasionally reactivate, sometimes leading to illness, especially in people with weakened immune systems. There is currently no licensed vaccine to prevent EBV, though several are being studied.
Treatment focuses on relieving symptoms rather than curing the infection. This usually involves rest, drinking fluids, and taking pain relievers or fever reducers such as acetaminophen or ibuprofen. In severe cases, corticosteroids may be given to reduce inflammation or airway blockage. Antiviral drugs such as acyclovir, ganciclovir, and valganciclovir can lower EBV activity, but they have limited benefit in mild cases.
For serious EBV-related illnesses, especially in transplant patients, treatment may also include adjusting immune-suppressing medications or using drugs like rituximab, a monoclonal antibody that targets certain immune cells.
Virus Classification
Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is a member of the family Herpesviridae. Within this family, it belongs to the subfamily Gammaherpesvirinae and the genus Lymphocryptovirus. EBV is a double-stranded DNA virus and is classified as one of the nine herpesviruses known to infect humans.
The virus primarily targets two types of cells: B lymphocytes, a class of white blood cells involved in immune defense, and epithelial cells, which line surfaces such as the throat and nasal passages. EBV is most commonly recognized as the cause of infectious mononucleosis (“mono”), but it is also associated with several cancers, including Burkitt lymphoma, Hodgkin lymphoma, gastric carcinoma, and nasopharyngeal carcinoma.
Like other herpesviruses, EBV has the ability to establish latency, a state in which the virus remains dormant within host cells for long periods without producing new viral particles. Transmission occurs mainly through saliva, which is why it is sometimes called the “kissing disease.” Less commonly, EBV can spread through blood transfusions, organ transplants, and sexual contact.
Virology and Structure
EBV particles are roughly 120–180 nanometers in diameter and have a complex structure typical of herpesviruses. The virus consists of:
- Capsid: An icosahedral capsid (a 20-sided protein shell) that encloses the viral DNA.
- Envelope: A lipid membrane derived from the host cell, containing viral glycoproteins essential for infection.
- Tegument: A protein layer between the capsid and envelope that contains enzymes and regulatory proteins required for the early stages of infection.
Among the envelope glycoproteins, gp350/220 is the most abundant. It mediates attachment to CD21 (complement receptor 2) on the surface of B cells, allowing viral entry. Other glycoproteins, such as gp42, gH, and gL, play roles in fusing the viral envelope with host cell membranes.
This complex structure contributes to EBV’s ability to evade immune detection, persist in the host, and spread efficiently.
Genome Organization
The EBV genome is a linear double-stranded DNA molecule approximately 172 kilobase pairs (kbp) in length, encoding around 85 genes. The genome can be divided into two functional programs:
- Latent phase: During latency, EBV expresses only a limited set of genes that help maintain the virus in host cells without triggering immune elimination. These include Epstein–Barr nuclear antigens (EBNAs) and latent membrane proteins (LMPs), which alter host cell signaling and promote persistence.
- Lytic phase: In the lytic cycle, the virus activates a broader set of genes responsible for viral DNA replication, structural protein production, and release of new viral particles.
A notable feature of the EBV genome is the presence of terminal repeats, which allow the DNA to circularize once inside the host nucleus. This circular form is stable and necessary for latency.
In addition to protein-coding genes, EBV produces several non-coding RNAs that influence infection. These include:
- EBERs (Epstein–Barr virus–encoded small RNAs): Abundant non-coding RNAs that help the virus avoid immune detection.
- miRNAs (microRNAs): Small regulatory RNAs that can alter host and viral gene expression.
Through these mechanisms, EBV maintains a long-term presence in the host and can periodically reactivate.
Transmission and Epidemiology
Epstein-Barr Virus spreads through specific routes and affects a broad population worldwide. Various factors influence the risk and rate of infection depending on geographic and social conditions.
Routes of Transmission
The primary mode of Epstein–Barr virus (EBV) transmission is through saliva, which contains high concentrations of infectious viral particles. Close personal contact, including activities such as kissing, sharing drinks, eating utensils, or toothbrushes, facilitates the exchange of saliva between individuals. Because of this, EBV is sometimes referred to as the “kissing disease.”
Although less common, several other medically significant transmission routes exist. EBV can be spread through blood transfusion, particularly when infected blood is given to immunocompromised individuals. Organ transplantation is another route of infection, as the virus may be carried into the recipient through donor tissue, occasionally leading to serious outcomes such as post-transplant lymphoproliferative disorder (PTLD). Maternal–child transmission can also occur when infants are exposed to infected saliva through close contact with caregivers, though transmission before birth (in utero) is considered rare.
Unlike respiratory viruses such as influenza or SARS-CoV-2, EBV is not transmitted by casual contact, coughing, or sneezing. Instead, infection typically requires relatively close or intimate interaction.
Global Prevalence
EBV infection is nearly universal in human populations. Serological studies consistently show that more than 90% of adults worldwide carry antibodies indicating past infection.
Patterns of infection differ across regions. In developing countries, EBV is most often acquired in early childhood, when the infection usually produces few or no noticeable symptoms. In contrast, in developed countries, infection is often delayed until adolescence or early adulthood. At this later stage, the likelihood of developing infectious mononucleosis is much higher, with symptoms including fever, sore throat, swollen lymph nodes, and fatigue.
The age at primary infection plays an important role in how the disease presents. Early childhood infections are usually mild or unnoticed, while delayed infections are more likely to be symptomatic.
Risk Factors
A variety of factors influence the risk of EBV transmission and the severity of infection. Age is a key determinant. Young children in regions where the virus is widespread are more likely to be infected early in life, while adolescents and young adults in higher-income countries face an increased risk of symptomatic illness if they acquire the virus later.
Immune status also plays an important role. Individuals with weakened immune systems such as those living with HIV/AIDS or patients receiving immunosuppressive therapy after organ transplantation are more vulnerable to complications from EBV, including certain cancers and lymphoproliferative disorders.
Living conditions contribute significantly to transmission patterns. Overcrowding, poor sanitation, and lower socioeconomic status increase the likelihood of early infection. In contrast, in higher-income settings where childhood exposure is less common, infection is postponed to adolescence or adulthood, when it is more likely to cause disease.
Occupational and social environments may also elevate exposure risk. People who work in healthcare, childcare, or caregiving frequently encounter saliva or bodily fluids and may therefore face a greater likelihood of EBV exposure.
Clinical Manifestations of EBV Infection
Epstein-Barr Virus (EBV) infection presents in diverse ways depending on the host’s age and immune status. Symptoms range from mild or absent to severe and life-threatening.
Infectious Mononucleosis
Infectious mononucleosis (IM) is the most recognized clinical syndrome caused by EBV, especially in adolescents and young adults. It typically manifests after a 4-6 week incubation period.
Patients usually experience fever, pharyngitis, and lymphadenopathy, often with marked fatigue lasting weeks to months. Other common signs include splenomegaly, hepatomegaly, and a maculopapular rash.
Laboratory findings often show lymphocytosis with atypical lymphocytes. Elevated liver enzymes are common but usually mild and transient. The disease is generally self-limited but can cause complications requiring medical attention.
Asymptomatic Infections
Many EBV infections, especially in children, are asymptomatic or produce nonspecific mild symptoms. These cases often go undiagnosed because symptoms do not prompt medical evaluation.
The virus establishes a lifelong latent infection within B cells after the initial exposure, allowing for possible future reactivation. Asymptomatic carriers may still transmit the virus through saliva.
Serological studies reveal high EBV antibody prevalence in adults worldwide, reflecting extensive asymptomatic infections during childhood or adolescence that do not advance to overt disease.
Complications and Severe Manifestations
While most Epstein–Barr virus (EBV) infections resolve without major consequences, a subset of cases can progress to serious or life-threatening complications. These outcomes are more likely in individuals with weakened immune systems, though rare events may also occur in otherwise healthy patients.
One significant complication is airway obstruction, which can develop in infectious mononucleosis due to severe tonsillar and pharyngeal enlargement. In such cases, breathing difficulties may require hospitalization and treatment with corticosteroids or, in extreme situations, airway management. Another acute complication is splenic rupture, a medical emergency characterized by sudden abdominal pain, low blood pressure, and internal bleeding. Because the spleen is commonly enlarged during infection, patients are often advised to avoid strenuous physical activity for several weeks to reduce the risk of rupture.
In immunocompromised individuals, EBV carries additional risks. The virus has been strongly linked to lymphoproliferative disorders, a group of conditions marked by abnormal and uncontrolled proliferation of lymphocytes. A notable example is post-transplant lymphoproliferative disorder (PTLD), which arises in organ transplant recipients receiving long-term immunosuppressive therapy. Furthermore, EBV is associated with several cancers, including Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma, with geographic variation in incidence.
Rare but recognized neurological complications may also result from EBV infection. These include Guillain–Barré syndrome, an autoimmune condition that leads to muscle weakness and paralysis; encephalitis, an inflammation of the brain that can cause seizures or altered mental status; and meningitis, an infection of the membranes surrounding the brain and spinal cord. Although uncommon, such complications can be severe and require early recognition and specialized care to prevent long-term disability or death.
Associated Diseases and Conditions
Epstein-Barr Virus (EBV) is linked to several serious medical conditions, ranging from cancers to autoimmune disorders. These diseases vary in severity but share EBV as a common contributing factor.
EBV-Related Lymphomas
EBV is linked to several malignant lymphoproliferative disorders. The virus infects B cells by binding to the CD21 receptor, leading to latent infection and dysregulation of normal cellular proliferation. In some instances, this promotes uncontrolled growth and tumor formation.
- Burkitt Lymphoma (BL): This highly aggressive non-Hodgkin lymphoma is strongly associated with EBV, particularly in endemic regions of equatorial Africa and Papua New Guinea. In these areas, more than 90% of BL cases are EBV-positive, often in conjunction with chronic Plasmodium falciparum malaria infection, which is thought to impair immune surveillance. The disease is characterized by rapidly proliferating tumors of the jaw or abdomen. Outside endemic regions, EBV is present in a smaller proportion of cases.
- Hodgkin Lymphoma (HL): EBV is detected in the Reed–Sternberg cells of approximately 40–60% of Hodgkin lymphoma cases worldwide. The prevalence varies geographically, being higher in developing countries and among younger or immunocompromised patients. EBV contributes by driving the expression of viral oncogenes such as latent membrane protein 1 (LMP1), which mimics constitutive CD40 signaling and promotes cell survival.
- Other Non-Hodgkin Lymphomas: EBV is implicated in extranodal NK/T-cell lymphoma, nasal type, which is prevalent in East Asia and Latin America. The virus is also associated with post-transplant lymphoproliferative disorders (PTLD), where immunosuppression reduces the ability to control latent EBV infection, leading to unchecked B-cell proliferation.
Treatment of EBV-associated lymphomas typically involves chemotherapy, radiotherapy, and increasingly immunotherapy, such as monoclonal antibodies (e.g., rituximab) and checkpoint inhibitors.
Nasopharyngeal Carcinoma
Nasopharyngeal carcinoma (NPC) is a cancer arising from the epithelial cells of the nasopharynx. EBV is detected in nearly all cases of undifferentiated NPC, linking the virus strongly to this malignancy.
This cancer is prevalent in Southeast Asia and parts of North Africa. EBV contributes to carcinogenesis by altering cell proliferation and inhibiting apoptosis. Diagnosis often involves biopsy and EBV DNA testing, while treatment includes radiotherapy and chemotherapy.
Autoimmune Disorders
EBV has been increasingly recognized as a possible environmental trigger for several autoimmune conditions. Its role is hypothesized to involve molecular mimicry, bystander activation, and persistent immune stimulation.
- Multiple Sclerosis (MS): Epidemiological studies consistently show that EBV infection precedes MS onset. Individuals who develop infectious mononucleosis, a symptomatic primary EBV infection, are at significantly increased risk of developing MS later in life. EBV may contribute to demyelination by producing viral antigens that resemble myelin proteins, thus provoking autoreactive immune responses.
- Systemic Lupus Erythematosus (SLE): EBV is thought to contribute to SLE pathogenesis by promoting the production of autoantibodies. Latent EBV infection may stimulate autoreactive B cells, leading to the generation of anti-dsDNA and other pathogenic antibodies. Studies have demonstrated higher EBV viral loads and altered immune responses to EBV antigens in SLE patients compared with healthy controls.
Other autoimmune conditions, including rheumatoid arthritis, Sjögren’s syndrome, and type 1 diabetes, have also been linked to EBV, though the strength of evidence varies.
EBV Diagnosis
Diagnosis of Epstein-Barr Virus involves identifying specific antibodies and detecting viral DNA. Accurate testing helps distinguish between active infection, past exposure, and other similar illnesses.
Serological Testing
Serological testing for EBV primarily detects antibodies against viral antigens. These include the viral capsid antigen (VCA), early antigen (EA), and Epstein-Barr nuclear antigen (EBNA).
The presence of VCA IgM indicates a recent or acute infection. VCA IgG appears during infection and persists for life, showing past or current infection. EBNA IgG typically emerges 2-4 months post-infection and usually signals past exposure.
Tests like the heterophile antibody test (Monospot) can detect antibodies produced during infectious mononucleosis caused by EBV but have limited sensitivity, especially in children under 4 years old.
Serology is essential for differentiating stages of EBV infection.
Molecular Diagnostic Methods
Molecular diagnostics involve detecting EBV DNA using polymerase chain reaction (PCR) techniques. PCR can quantify viral load in blood or tissue samples, providing insight into active viral replication.
This method is particularly useful in immunocompromised patients, where serological responses may be atypical or absent. It also helps in diagnosing EBV-associated malignancies and monitoring disease progression.
PCR is highly sensitive and specific but may not distinguish latent from active infection without correlation to clinical symptoms and antibody testing.
Differential Diagnosis
EBV infection symptoms overlap with other viral illnesses, requiring careful differentiation. Infectious mononucleosis mimics include cytomegalovirus (CMV), toxoplasmosis, and HIV.
Serological tests for these agents are necessary to exclude alternatives. For example, CMV infection shows different antibody patterns, and toxoplasmosis presents with distinct IgM and IgG profiles.
Clinical presentation coupled with comprehensive laboratory testing ensures correct diagnosis, preventing mismanagement of EBV or related conditions.
Treatment and Management of EBV
Treatment of Epstein-Barr Virus (EBV) primarily focuses on relieving symptoms and preventing complications. Specific antiviral medication use is limited, while managing systemic effects and potential issues requires targeted intervention.
Supportive Care Strategies
Supportive care forms the cornerstone of EBV management. Rest is particularly important, as the immune system requires adequate energy to combat viral infection and resolve inflammation. Patients are encouraged to balance physical rest with light activity as tolerated, but strenuous exercise should be avoided to prevent complications, particularly splenic rupture. Hydration is equally critical, as adequate fluid intake helps regulate body temperature, prevent dehydration from fever, and soothe sore throat discomfort.
Symptom control is achieved through the use of analgesics and antipyretics. Over-the-counter medications such as acetaminophen and ibuprofen are commonly recommended for fever, headaches, and myalgia. In more severe presentations, corticosteroids such as prednisone may be prescribed to reduce significant tonsillar hypertrophy, laryngeal edema, or impending airway obstruction. Nutritional support also plays a role, as patients with painful swallowing often benefit from a soft or liquid diet that minimizes irritation to inflamed mucosa. Careful monitoring for signs of worsening symptoms, dehydration, or airway compromise is recommended, especially in pediatric cases.
Antiviral Therapies
The use of antiviral therapy in EBV management remains limited and controversial. Standard antiviral drugs, including acyclovir, ganciclovir, and valganciclovir, target viral DNA polymerase and can reduce EBV replication during lytic phases of infection. However, because EBV predominantly persists in a latent state within B lymphocytes, these drugs are generally ineffective at clearing the infection or altering the course of infectious mononucleosis. Clinical trials have shown that antivirals may reduce viral shedding in saliva but have little effect on the duration or severity of symptoms.
For this reason, antivirals are not routinely recommended for uncomplicated EBV infections. They are sometimes considered in severe, life-threatening, or immunocompromised cases, such as post-transplant patients or those with EBV-related lymphoproliferative disorders. In these contexts, antivirals may be combined with immunosuppressive modulation or monoclonal antibody therapies to control viral proliferation.
Management of Complications
Complications from EBV infections are uncommon but require specialized and often urgent intervention when they arise. Airway obstruction due to severe tonsillar hypertrophy or pharyngeal swelling may necessitate corticosteroid therapy or, in rare cases, surgical airway management. Splenic rupture remains a critical concern, particularly in adolescents and young adults. Because the spleen may remain enlarged for weeks after infection, patients are strongly advised to avoid contact sports and vigorous activity for at least four weeks, or longer if splenomegaly persists on clinical examination. Splenic rupture presents as sudden abdominal pain and hypotension and is a medical emergency requiring immediate surgical evaluation.
Hematological complications such as hemolytic anemia, thrombocytopenia, and neutropenia may occur and typically require referral to a hematologist. Severe neurological manifestations, including encephalitis, Guillain-Barré syndrome, or transverse myelitis, demand prompt evaluation and may necessitate antiviral therapy, corticosteroids, or intravenous immunoglobulin depending on the underlying pathology.
Secondary bacterial infections, particularly streptococcal pharyngitis, can complicate EBV infection and should be treated with appropriate antibiotics. Routine use of antibiotics in uncomplicated EBV cases is discouraged, as drugs such as ampicillin and amoxicillin frequently trigger a characteristic rash in patients with infectious mononucleosis. Regular follow-up is recommended for patients with severe, prolonged, or atypical symptoms to ensure resolution and to monitor for late complications such as chronic active EBV infection.
Prevention and Infection Control
Since EBV is primarily transmitted through saliva, minimizing direct contact with saliva is the most effective method of prevention. Individuals are advised not to share eating utensils, drinking glasses, bottles, or toothbrushes, as these items can carry viral particles. Avoiding intimate contact, such as kissing, with someone experiencing active EBV symptoms including fever, sore throat, and swollen lymph nodes can also lower the risk of transmission.
Hand hygiene represents another cornerstone of personal prevention. Frequent handwashing with soap and water, particularly after contact with others or shared surfaces, helps reduce the possibility of viral spread. In settings where handwashing is not feasible, alcohol-based hand sanitizers provide a practical alternative.
Maintaining general cleanliness in household and communal environments also supports infection control. Regular cleaning of shared objects and surfaces, especially in schools, dormitories, and childcare centers, can reduce opportunities for indirect transmission..
Individuals with weakened immune systems including transplant recipients, patients undergoing chemotherapy, and those with advanced HIV/AIDS are at heightened risk of severe EBV-related disease. For these groups, preventive strategies extend beyond standard hygiene practices.
Avoidance of crowded places during active outbreaks of communicable diseases, consumption of a balanced diet to support immune resilience, and close medical monitoring are recommended. In clinical settings, screening of blood products and organs reduces the risk of EBV transmission through transfusion or transplantation.