Epstein-Barr Virus (EBV) Infectious Mononucleosis (Mono)

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that causes lifelong infections in humans. ^[1] It is primarily spread through intimate contact with oropharyngeal secretions, though it can also be transmitted via genital secretions, blood transfusions, and organ transplants. Upon initial infection, EBV specifically targets B lymphocytes in the oropharyngeal epithelium. Following this acute phase, the virus can persist in oropharyngeal secretions for up to 32 weeks ^[3] and remain in the body for decades.

Once EBV infects B lymphocytes, atypical lymphocytes develop, primarily from CD8+ T cells that respond to the viral infection. After the primary infection, EBV remains dormant in the host, mainly within B lymphocytes, and undergoes intermittent asymptomatic shedding from the oropharynx. In healthy adults who are EBV-seropositive, the virus can be detected in the oropharyngeal secretions of 10-20% of individuals. This shedding is more frequent and at higher levels in immunocompromised patients, such as organ transplant recipients and individuals living with HIV.

Importantly, EBV has not been isolated from environmental sources and is not considered highly contagious, making its transmission primarily reliant on close personal contact.

Infection and immune response

Upon infecting B lymphocytes, EBV elicits both humoral and cellular immune responses:

• Humoral response: Generates antibodies against EBV structural proteins, which serve as the basis for diagnostic tests.
• Cellular response: Predominantly involves CD8+ cytotoxic T cells and natural killer (NK) cells, which control the proliferation of EBV-infected B cells. An ineffective T-cell response may lead to uncontrolled B-cell proliferation, potentially resulting in malignancies such as B-cell lymphomas.

The immune response to EBV infection often results in fever (due to cytokine release), lymphocytosis (caused by EBV-infected B-cell proliferation in the reticuloendothelial system), and pharyngitis (from lymphatic tissue proliferation in the oropharynx). ^[4]

Viral lifecycle and latency

EBV exhibits a biphasic lifecycle, alternating between latent and lytic phases. During latency, EBV maintains its genome as an episome within B lymphocytes, particularly memory B cells, allowing it to persist while evading immune detection by suppressing viral gene expression. Reactivation from latency into the lytic phase can occur under conditions such as immunosuppression or psychological stress, leading to viral replication and potential disease manifestations.

• Reactivation potential:  Factors such as psychological stress weaken immune responses, facilitating EBV reactivation. Reactivation has been implicated in various conditions, including chronic fatigue syndrome/ myalgic encephalomyelitis . ^[5]
• Increased viral loads in immunocompromised individuals, contributing to lymphoproliferative disorders. ^[4]
• Secondary complications such as oral hairy leukoplakia in HIV patients. ^[6]   

Genomic diversity and integration

Studies have highlighted the intra-host genomic diversity of EBV and its potential integration into the host genome. While EBV typically persists episomally, instances of viral integration have been observed, particularly in malignancies like mantle cell lymphoma. For example:

• Integration events: Involving the EBV LMP-1 gene and chromosome 17, likely facilitated by microhomology-mediated end joining, disrupt normal cellular functions and contribute to tumorigenesis.
• Dynamic behavior:  Patients with active EBV-related diseases often exhibit high viral loads and increased genetic diversity, emphasizing the virus's role in disease progression. ^[7]

EBV types and disease association

EBV is classified into two major types, EBV type 1 and type 2, distinguished by variations in their EBNA-3 genes:

• Type 1:  More efficient in transforming B cells and predominantly associated with malignancies such as Burkitt lymphoma, nasopharyngeal carcinoma, and Hodgkin lymphoma. ^[8]  
• Type 2: Less efficient but more prevalent in regions like Africa, potentially due to evolutionary adaptations.

The genetic differences between EBV types also influence reactivation potential, with implications for disease manifestations and geographic variability.

Implications for disease and therapy

EBV's ability to evade immune surveillance, transform host cells, and potentially integrate into the genome underpins its association with various malignancies, autoimmune conditions, and chronic diseases like chronic fatigue syndrome. Insights into its genomic diversity, lifecycle, and host interactions provide critical opportunities for therapeutic interventions, including vaccines and targeted antiviral therapies.

Epstein-Barr Virus (EBV) is among the most prevalent human viruses in the world. ^[9]  An estimated 90% of the global population is seropositive for EBV, ^[10]  with developed countries bearing a comparatively lower burden of EBV seroprevalence. ^[11]  Residents of developed countries also experience primary EBV infection at a later age. ^[12]  In the United States, the EBV seroprevalence for children and adolescents between ages 6-19 years is about 66.5%, with female, African-American, and Hispanic populations experiencing significantly higher rates of seropositivity. ^[11]  Significant seroprevalence differences exist by family income, with children in the lowest income quartile having 81.0% seroprevalence compared with 53.9% in the highest income quartile. ^[11]  In US institutions characterized by the presence of many young adults, such as universities and the armed forces, the annual incidence for infectious mononucleosis ranges from 11 to 48 cases per 1000 persons. ^[13]

Mortality/Morbidity

Various complications related to Epstein-Barr virus (EBV), either directly or secondary to unregulated immune response, are described in the literature. Important conditions include the following:

• Airway obstruction - Obstruction of the upper airway due to massive lymphoid hyperplasia and mucosal edema is an uncommon but potentially fatal complication of infectious mononucelosis.
• Splenic rupture - Splenomegaly is a common presentation among those with infectious mononucleosis, and although splenic rupture is rare, it can be life-threatening. Most spleen ruptures occur after even mild abdominal trauma and are more likely to occur between day 4 and 21 of the illness. Rest and restriction from weight-lifting and contact sports should be implemented at least for the first 4 weeks on onset of symptoms. These patients can present with non-specific abdominal pain, left upper quadrant pain that radiates to the left shoulder, acute drop in Hematocrit, or shock. ^{[14, 15]}  Some will require splenectomy and others will require supportive care which is the preferred treatment. ^[16]  
• Renal complications - Epstein-Barr virus is connected to a variety of renal syndromes, including interstitial nephritis, myositis-associated acute kidney injury, hemolytic uremic syndrome, and jaundice-associated nephropathy. ^[17]  Although rare, there are documented cases of fatalities resulting from the aforementioned diseases.
• Nervous system disorders- Central nervous system (CNS) mononucleosis is also responsible for increased morbidity in infectious mononucleosis.
• Malignancy
• Chronic Active EBV (CAEBV)
• Lymphoproliferative disorders 
• Posttransplantation lymphoproliferative disorders (PTLD)
• Fatigue - Patients with EBV infection who present clinically with infectious mononucleosis invariably experience accompanying fatigue. Fatigue may be profound initially but usually resolves gradually in 3 months. Some patients experience prolonged fatigue and, after initial recovery, enter a state of prolonged fatigue without the features of infectious mononucleosis.

A further source of morbidity in the context of this disease is research that points to a link between EBV and the development of multiple sclerosis (MS). The seroprevalence of EBV is higher among people with MS, symptomatic EBV infection (IM) is more prevalent among people with MS, and higher anti-EBV antibody titers are associated with an increased risk for MS. ^[18]  Epstein-Barr virus infection appears to be a necessary but not sufficient requirement for developing MS. Multiple sclerosis is overwhelmingly likely to be the result of multiple environmental risk modifiers.

Understanding Epstein-Barr virus (EBV) and infectious mononucleosis

What is Epstein-Barr virus (EBV)?

EBV is one of the most common human viruses, also known as human herpesvirus 4. Most people get infected with EBV at some point in their lives, often in childhood. Many infections are mild or go unnoticed, but in teens and adults, EBV can cause infectious mononucleosis (mono), a contagious illness.

How does EBV spread?

EBV spreads through saliva by:

• Kissing (hence the nickname "kissing disease").
• Sharing drinks, utensils, or personal items.
• Coughs or sneezes.Rarely, it spreads through blood transfusions or organ transplants.

What are the symptoms of mono?

Symptoms usually appear 4-6 weeks after exposure and may include:

• Fatigue
• Fever
• Sore throat
• Swollen lymph nodes (especially in the neck and armpits), Enlarged spleen or liver, Loss of appetite, Rash

Children often have mild or no symptoms, whereas teens and adults may experience more severe illness.

How is mono diagnosed?

Your healthcare provider may do the following:

• Perform a physical exam to check for swollen lymph nodes, tonsils, liver, or spleen.
• Order blood test, such as antibody tests, to confirm the diagnosis.

Can mono be prevented?

Although no vaccine exists, the risk can be lowered by doing the following:

• Avoiding sharing food, drinks, or personal items
• Practicing good hand hygiene

Treatment and recovery

There is no cure for mono; the virus resolves on its own. To manage symptoms, the following are recommended:

• Rest and hydrate.
• Use saltwater gargles or lozenges for sore throat relief.
• Take acetaminophen or ibuprofen for fever and pain.

Avoid physical activities or contact sports for at least 3-4 weeks or until cleared by your doctor. This helps prevent a rare but serious complication: a ruptured spleen.

Seek medical care if you notice any of the following:

• Sharp upper left abdominal pain.
• Persistent high fever.
• Breathing difficulties or severe fatigue.
• Jaundice (yellowing of the skin or eyes).

Living with mono

Most people recover within 2-4 weeks, but fatigue may persist longer. In rare cases, complications like anemia, liver inflammation, or nervous system problems may occur. EBV stays dormant in your body after infection and can reactivate without causing symptoms.

For more information, visit the Centers for Disease Control and Prevention (CDC)  website at www.cdc.gov/epstein-barr.

For parents: What you need to know about mono

• Young children infected with EBV usually have mild or no symptoms.
• Teens often experience fatigue, fever, sore throat, swollen lymph nodes, and enlarged tonsils with white patches. Mono can mimic strep throat or the flu.

Cautions for parents 

• Teach children not to share personal items like utensils or cups, even with seemingly healthy individuals, as many carriers are asymptomatic.
• Ensure frequent handwashing to reduce the risk of spreading the virus.
• Be vigilant about symptoms of an enlarged spleen (eg, sharp pain in the upper left abdomen, feeling lightheaded, or fainting), as a ruptured spleen can be life-threatening and requires emergency care.
• Restrict children from contact sports, rough play, and heavy lifting for at least a month after symptoms resolve. Consult your doctor before resuming activities.

Treatment tips

• In addition to above mentioned, avoid aspirin in children due to the risk for Reye syndrome. Antibiotics are not effective unless there is a bacterial co-infection.
• Symptoms typically resolve in 2-4 weeks, but fatigue may persist for months in some teens.