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

Background

Epstein-Barr virus (EBV), also known as human herpes virus 4, is a widely disseminated double stranded DNA herpesvirus. It is the causative agent of infectious mononucleosis ("mono" or "glandular fever").^[1]

Since the 1800s, infectious mononucleosis has been recognized as a clinical syndrome consisting of fever, pharyngitis, and adenopathy. The term glandular fever was first used in 1889 by German physicians and was termed Drüsenfieber. Infectious mononucleosis was first described by Sprunt and Evans in the Bulletin of the Johns Hopkins Hospital in 1920.^[2]  They described the clinical characteristics of EBV infectious mononucleosis. At the time, their article was entitled "Mononuclear leukocytosis in reaction to acute infection (infectious mononucleosis)" because the causative organism, EBV, had yet to be described.

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Pathophysiology

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.

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Epidemiology

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]

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Prognosis

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.

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Patient Education

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.

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History

Epstein-Barr virus (EBV) infection is widespread, with approximately 90% of adults exhibiting serological evidence of prior exposure. While many infections are asymptomatic, when symptoms do occur, they typically manifest after an incubation period of 4 to 6 weeks. Common symptoms include fatigue, prolonged malaise, sore throat, and fever, which may reach up to 104°F but usually remain below 102°F. Less frequently, patients may experience arthralgias, myalgias, nausea, anorexia without vomiting, cough, ocular muscle pain, chest pain, and photophobia. Notably, in the absence of central nervous system involvement, cognitive functions remain unaffected.

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Causes

The primary risk factor for EBV infectious mononucleosis is close contact with an infected individual, as the virus can persist in oropharyngeal secretions for months following clinical resolution. Individuals with congenital immunodeficiencies are at increased risk for EBV-induced lymphoproliferative disorders and malignancies. Similarly, those with acquired immunodeficiencies, whether due to immunosuppressive therapies (eg, post-transplant patients) or infections like HIV, may be predisposed to conditions such as oral hairy leukoplakia or non-Hodgkin lymphoma.

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Physical Examination

Infectious mononucleosis, primarily caused by Epstein-Barr virus (EBV), presents with a spectrum of physical findings that vary in frequency and onset during the disease course.

Early signs

Fever

• Typically, low-grade but can reach up to 104°F.

Lymphadenopathy

Bilateral and symmetrical lymph node enlargement, particularly in the posterior cervical region.

• Highly suggestive of EBV infection. Lymphadenopathy is a hallmark of infectious mononucleosis, with bilateral posteriod cerviacl adenopathy being particularly indicative of EBV infection. A meta-analysis has highlighted the diagnostic significancne of posterior cerviacl lymphadenopathy, with a positive likelihodd ratio of 3.2 for predicting the disease. Although any lymph node chain may be involved, axillary and inguinal lymphadenopathy are also common and can aid in distinguishing infectious mononucleosis from other causes of pharyngitis. Generalized lymphadenopathy accompanied by prominent splenomegaly should heighten suspicion for infectious momonucleosis.^[19]

Pharyngitis

• May be exudative or non-exudative.
• Often accompanied by tonsillar enlargement, which can be severe ("kissing tonsils").

Rash

• Faint, evanescent, nonpruritic maculopapular rash may appear early and resolve rapidly.

Antibiotic-associated rash

• Administration of beta-lactam antibiotics (eg, amoxicillin) during EBV infection can induce a pruritic rash that is not a true drug allergy.
• Less than 5% of patients develop maculopapular, urticarial, or petechial rashes.

Periorbital edema

• Known as Hoagland's sign, presenting as transient, bilateral upper eyelid swelling.
• Typically occurs in the initial days of illness and is a specific indicator of EBV mononucleosis.

Relative bradycardia

Observed in some patients but not consistently present.

Later findings

Hepatomegaly and jaundice

Liver enlargement and jaundice occur in:

Up to 30% of older adults.

< 10% of young adults.

Splenomegaly

A common late finding associated with tenderness upon palpation.

Physical exam limitations:

• Sensitivity: 20%–70%.
• Specificity: 69%–100%.

Imaging recommendation:

• Use ultrasonography for accurate detection.

Clinical course:

• The spleen typically returns to normal size within 3 weeks post-presentation.
• Rare Complication: Splenic rupture (1–2%) necessitates caution regarding physical activity during recovery up to 4 weeks.

Palatal petechiae

Small red spots on the soft palate.

• Helpful in distinguishing EBV mononucleosis from other causes of pharyngitis, though not exclusive to EBV infection.

Uvular edema:

• An uncommon but specific finding aiding differentiation from other pharyngitis etiologies.

Neurological manifestations: Although rare, EBV mononucleosis can lead to neurological complications such as encephalitis, aseptic meningitis, cranial nerve palsies (especially CN VII), transverse myelitis, and Guillain-Barré syndrome. These typically occur later in the disease course.

Age-related variations

Children and young adults: The classic triad of fever, pharyngitis, and lymphadenopathy is most observed.

Older adults: May present with fewer oropharyngeal symptoms and minimal adenopathy, often resembling anicteric viral hepatitis.

Additional considerations

• Exudative pharyngitis: Can be mistaken for group A streptococcal pharyngitis. Approximately 30% of patients with EBV mononucleosis may carry group A streptococci in the oropharynx, potentially leading to diagnostic confusion.
• Rash with antibiotics: Administration of antibiotics such as amoxicillin or ampicillin during EBV infection can result in a generalized, pruritic maculopapular rash. This reaction is not indicative of a true drug allergy, and patients can tolerate these antibiotics after recovery.
• HIV co-infection considerations: Patients with HIV infection can develop secondary conditions caused by EBV, including lymphadenopathy, atypical lymphoproliferation, and malignant transformations of lymphoid and epithelial cells

Recognizing these physical findings and their temporal progression is crucial for the accurate diagnosis and management of EBV infectious mononucleosis.

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Complications

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Other clinical manifestations

Malignancy

After the resolution of the acute viral syndrome, EBV persists in memory B cells, maintaining a latent infection. In certain cases, this latent infection can lead to uncontrolled B-lymphocyte proliferation, resulting in malignancies.^[20]  Associated cancers include nasopharyngeal carcinoma, gastric carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and leiomyosarcomas in immunocompromised children.^[21]  Selective immunodeficiency, such as that seen in X-linked lymphoproliferative syndrome, may result in severe or even fatal infectious mononucleosis.

1. Burkitt's lymphoma (BL):BL is an aggressive B-cell neoplasm associated with the translocation and deregulation of the MYC gene on chromosome 8. The disease manifests in three clinical forms: endemic, sporadic, and immunodeficiency associated. Endemic BL, predominantly seen in Africa and Papua New Guinea, typically affects the jaw. EBV is implicated in nearly all cases of endemic BL but is less commonly associated with sporadic or immunodeficiency-associated forms. Antibodies to EBV early antigens (EA-R) are often elevated in African BL, highlighting a link between chronic EBV infection and this malignancy.^{[22, 23]}
2. Hodgkin lymphoma (HL): HL is divided into classical HL (cHL) and nodular lymphocyte-predominant HL. EBV gene expression in cHL is thought to contribute to aberrant signaling, immune evasion, and suppression of apoptosis in tumor cells. EBV is less commonly associated with nodular lymphocyte-predominant HL. Its involvement highlights the virus's role in oncogenesis via immune modulation.^[20]
3. Nasopharyngeal carcinoma: EBV is universally associated with the undifferentiated subtype of nasopharyngeal carcinoma,^[24]  prevalent in southern China and other high-incidence areas. IgA antibodies to EBV antigens and EBV DNA in plasma are valuable diagnostic and prognostic markers. Recent meta-analyses have identified specific EBV variants linked to a higher risk of nasopharyngeal carcinoma, particularly in southern China.^[25]
4. Diffuse large B-cell lymphoma (DLBCL): EBV-positive DLBCL is recognized as a subtype in the WHO classification.^[26]  This lymphoma often affects extranodal sites in immunocompetent individuals, with higher prevalence in Asian populations. Patients with EBV-positive DLBCL generally have a poor prognosis, with median survival around 2 years.^[26]
5. Leiomyosarcoma: EBV-associated smooth muscle tumors primarily affect immunocompromised patients, such as those with HIV.^[27]  These tumors can appear in atypical locations, including the CNS, lungs, and spleen. High EBV DNA levels in tumor tissues link the virus to the pathogenesis of these aggressive malignancies.^{[28, 29]}
6. Non-Hodgkin’s lymphoma (NHL): Immunocompromised individuals, particularly those with HIV, have a higher risk of developing EBV-associated NHL due to cytotoxic lymphocyte dysfunction.

Multiple sclerosis (MS)

Multiple sclerosis (MS), a chronic inflammatory demyelinating disorder of the central nervous system (CNS) and EBV association has been heavily discussed. While the exact cause of MS remains unknown, mounting evidence suggests a strong association between Epstein-Barr virus (EBV) infection and the development of MS. This hypothesis was tested in a landmark study involving a cohort of more than 10 million young adults on active duty in the US military who were monitored over a 20-year period. The study revealed a striking 32-fold increased risk of developing MS following EBV infection, a risk not observed with other viruses, such as Cytomegalovirus, which is similarly transmitted.^[30]

The mechanism underlying this association is thought to involve molecular mimicry between EBV proteins and host proteins, particularly GlialCAM, which is in the insulating sheath of nerves.^[31] This mimicry may trigger an autoimmune response, leading to the demyelination characteristic of MS. Vaccines that might prevent EBV infection are an area of active research. If effective, the impact of these vaccines on MS incidence will be of interest.^[32]

Meningoencephalitis

Meningoencephalitis is a rare manifestation of Epstein-Barr virus (EBV) infectious mononucleosis. Patients presenting with unusual neurologic symptoms, such as scalp tenderness or optic neuritis, often exhibit other features of EBV infectious mononucleosis, aiding in the identification of the underlying cause. Isolated neurologic manifestations without accompanying symptoms are uncommon. The diagnosis of EBV infectious mononucleosis is typically syndromic, relying on the presence of fever, pharyngitis, lymphadenopathy, and characteristic hematologic abnormalities. Recent studies have highlighted that EBV can directly invade the central nervous system (CNS), leading to conditions like encephalitis and meningitis.^[32]

Chronic Active EBV (CAEBV)

Chronic Active Epstein-Barr virus disease (CAEBV) is a significant contributor to EBV-related morbidity. The revised World Health Organization (WHO) classification defines CAEBV as an EBV-positive T- and NK-cell lymphoid proliferation, emphasizing its distinct pathophysiology.^{[33, 34]} This condition is considered a disease of exclusion, requiring careful differential diagnosis to rule out other EBV-associated disorders and chronic inflammatory conditions.

CAEBV is characterized by persistent inflammatory symptoms lasting for more than three months, including fever, lymphadenopathy, liver dysfunction, and mononucleosis-like symptoms. Diagnostic criteria include an EBV DNA load exceeding 10,000 IU/mL in whole blood as detected by PCR testing.^[35] Dermatologic manifestations such as hydroa vacciniforme, lymphoproliferative disorders, and severe mosquito bite allergies are common in CAEBV. Additionally, cardiovascular complications, including aneurysms and valvular disorders, have been reported, underscoring the systemic nature of this disease.^[35] Hematologic complications are particularly severe and may include hemophagocytic lymphohistiocytosis (HLH), T/NK lymphoma, and leukemia.

Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for CAEBV. Early identification and timely intervention are critical, as the disease can progress to life-threatening complications such as HLH and lymphoma.^[35]

Post transplantation Lymphoproliferative Disorders (PTLDs)

Post-transplantation lymphoproliferative disorder (PTLD) is a serious complication that occurs after solid organ and hematopoietic stem cell transplantation. The majority of PTLD cases are associated with Epstein-Barr virus (EBV), with EBV-negative recipients who receive grafts from EBV-positive donors at particularly high risk.^{[36] .} PTLD encompasses a wide spectrum of diseases categorized histopathologically into four main groups: Non-destructive PTLD, Polymorphic PTLD, Monomorphic PTLD, and Classic Hodgkin Lymphoma.^{[37] .}

PTLD arises due to unchecked activation and continuous proliferation of EBV-infected B cells, which occurs when post-transplant immunosuppression compromises immune surveillance.^{[38] .}Restoration of cellular immunity by reducing immunosuppression remains the cornerstone of PTLD management. However, caution must be taken to balance the risk of organ rejection against reducing immunosuppression.^{[38, 37]}

Rituximab, an anti-CD20 monoclonal antibody, is the standard of care for patients who do not adequately respond to reduced immunosuppression. Recent studies have shown that Rituximab as part of the induction regimen significantly reduces the risk of developing PTLD, while antiviral prophylaxis has not demonstrated efficacy in preventing EBV-associated PTLD.^[38]  The introduction of rituximab has markedly improved the overall prognosis of PTLD.^[39]

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Approach Considerations

Epstein-Barr virus (EBV) should be suspected in adolescents or young adults presenting with sore throat, fever, and malaise, accompanied by lymphadenopathy and pharyngitis on physical examination. The diagnosis is supported by the presence of lymphocytosis and increased circulating atypical lymphocytes; however, confirmation should be obtained through a heterophile antibody test or EBV-specific antibody testing as noted below or heterophile antibody if above tests are not readily available. Confirmatory testing is particularly useful to inform patients about potential risks associated with infectious mononucleosis, such as splenic rupture or airway obstruction. The timing of test ordering is crucial, as it can impact diagnostic accuracy.

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Laboratory Studies

When IM is clinically suspected testing with WBC with differential and further confirmatory test for EBV is suggested.

EBV-Specific Serology

Viral Capsid Antigen (VCA)

• Anti-VCA IgM: Appears early in infection and typically disappears within 4 to 6 weeks.
• Anti-VCA IgG: Emerges during the acute phase, peaks at 2 to 4 weeks, and persists for life^[40]

Early Antigen (EA)

• Anti-EA IgG: Appears in the acute phase and generally falls to undetectable levels after 3 to 6 months. However, about 20% of healthy individuals may have antibodies against EA for years^[40]

EBV Nuclear Antigen (EBNA)

• Anti-EBNA IgG: Not present in the acute phase; appears 2 to 4 months after onset and persists for life. Its presence early in the disease course excludes acute EBV infection.
• Heterophile Antibody Tests:

The Monospot test, which detects heterophile antibodies, is no longer recommended first line for general use due to its limited sensitivity and specificity. False-negative results are common, especially in children under 4 years old, and false positives can occur in conditions like leukemia, lymphoma, and autoimmune diseases.

Molecular testing

EBV DNA Quantification by PCR: Quantitative PCR assays measure EBV DNA load and are particularly useful in immunocompromised patients, such as transplant recipients, to monitor for EBV-associated complications. Elevated EBV DNA levels can indicate active infection or risk of lymphoproliferative disorders.^[41]

Accurate diagnosis requires correlating serological and molecular test results with clinical presentation. For instance, the presence of anti-VCA IgM and absence of anti-EBNA IgG suggest a primary EBV infection. Conversely, the presence of anti-EBNA IgG indicates past infection.

Alternative Diagnoses:

• Heterophile-Negative Mononucleosis: If heterophile antibody tests are negative and EBV-specific antibodies are not indicative of acute infection, consider other causes of mononucleosis-like symptoms, such as cytomegalovirus (CMV), toxoplasmosis, or human herpesvirus 6 (HHV-6).

Table 2. EBV Serologic Responses in EBV-Associated Diseases

View Table

See Table

Additional General Laboratory Studies

Complete blood cell count (CBC):The complete blood cell (CBC) count is more valuable for ruling out alternative diagnoses that mimic infectious mononucleosis than for providing specific diagnostic information. While leukocytosis is typical in infectious mononucleosis, a normal or decreased white blood cell (WBC) count suggests an alternative diagnosis. Lymphocytosis often accompanies infectious mononucleosis, peaks during the first few weeks of illness, and gradually returns to normal. Similarly, atypical lymphocytes follow the same timeline as lymphocytosis. A relative atypical lymphocyte counts of ≥20% in patients with fever, pharyngitis, and lymphadenopathy strongly suggests Epstein-Barr virus (EBV) infectious mononucleosis.

Atypical lymphocytes should be distinguished from abnormal lymphocytes:

• Atypical Llmphocytes: Associated with viral infections, noninfectious diseases, or drug reactions. They display diverse morphology on a peripheral smear.
• Abnormal lymphocytes: Linked to lymphoreticular malignancies and appear morphologically similar, allowing for clear differentiation on a peripheral smear.

Leukopenia, rather than leukocytosis, is commonly seen in infectious mononucleosis caused by cytomegalovirus (CMV), rubella, human herpesvirus 6 (HHV-6), acute HIV, and anicteric hepatitis.

• Thrombocytopenia: Mild transient thrombocytopenia is common in EBV infectious mononucleosis. However, severe or persistent thrombocytopenia should prompt consideration of alternative diagnoses, such as acute HIV or other viral infections.
• Thrombocytosis: Not a feature of EBV infectious mononucleosis; its presence may suggest malignancy (e.g., lymphoma) in adults or Kawasaki disease in children.

Erythrocyte sedimentation rate (ESR):The erythrocyte sedimentation rate (ESR) can help differentiate group A streptococcal pharyngitis from EBV infectious mononucleosis. While ESR is elevated in most patients with EBV infectious mononucleosis, it typically remains normal in group A streptococcal pharyngitis. However, an elevated ESR cannot distinguish EBV from other heterophile-negative causes of mononucleosis-like illness.

Liver function tests (LFTs):Abnormal liver function tests (LFTs) are observed in more than 90% of EBV infectious mononucleosis cases:

• Aminotransferases (ALT, AST): Mildly elevated levels are common.
• Alkaline phosphatase and gamma-glutamyl transpeptidase (GGTP): These are typically not elevated.
• Bilirubin: Elevated in approximately 40% of cases.Markedly elevated transaminases should raise suspicion for viral hepatitis rather than EBV infection. Persistent mild-to-moderate transaminase elevations in a mononucleosis-like illness may indicate CMV rather than EBV as the cause.

Group A Streptococcal co-testing:Throat cultures for group A streptococci are not recommended in patients with suspected infectious mononucleosis due to a high carriage rate (~30%) in this population. Rapid streptococcal antigen tests cannot differentiate colonization from true infection. Testing with cultures should be driven by clinical syndrome.^[42]

Gram Stain Differentiation

• Patients with EBV infectious mononucleosis or other viral pharyngitis and group A streptococcal colonization show little or no white cell response on Gram stain.
• In contrast, patients with acute group A streptococcal pharyngitis exhibit an intense polymorphonuclear response with cellular debris and fibrinous fragments, indicating acute infection.

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Imaging Studies

Patients with presumed CNS involvement with EBV infectious mononucleosis should undergo a CT scan and/or MRI to rule out other causes of encephalitis.

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Other Tests

Patients with presumed CNS involvement with EBV infectious mononucleosis should also undergo an EEG to rule out other causes of encephalitis.

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Procedures

Rarely, if ever, is a bone marrow biopsy or lymph node biopsy needed in patients with EBV infectious mononucleosis. In the diagnosis of EBV infectious mononucleosis, the assessment of lymph node enlargement can be made confidently based on specific EBV antibody testing, and surgery is almost never necessary.

Patients with presumed CNS involvement with EBV infectious mononucleosis should also undergo a lumbar puncture to rule out other causes of encephalitis.

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Histologic Findings

Oropharyngeal epithelium demonstrates an intense lymphoproliferative response in the cells of the oropharynx. The lymph node and spleen show lymphocytic infiltration primarily in the periphery of a lymph node.

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Medical Care

Closely monitor patients with extreme tonsillar enlargement for airway obstruction. Steroids are indicated for impending or established airway obstruction in individuals with Epstein-Barr virus (EBV) infectious mononucleosis.

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Surgical Care

Surgery is necessary for spontaneous splenic rupture, which occurs in rare patients with EBV infectious mononucleosis and may be the initial manifestation of the condition.

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Consultations

Consult an infectious disease specialist in all but the most straightforward cases of EBV infectious mononucleosis.

Consulting a hematologist may be necessary if unusual hematologic manifestations of EBV infectious mononucleosis are present (eg, in anemia to determine the cause of the patient's anemia).

Consulting a neurologist is advised for patients with potential CNS involvement.

Consultation with a cardiologist is advised for the rare patients with EBV infectious mononucleosis who have presumed myocarditis.

Consult a gastroenterologist for patients with EBV-induced acalculous cholecystitis or if anicteric hepatitis is in the differential diagnoses.

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Diet

Normal diet is appropriate.

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Activity

Patients with acute EBV mononucleosis should be advised to refrain from active physical activity for 3-4 weeks.

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Prevention

Vaccine for EBV

Although, EBV was the first virus described to cause cancer in humans, there is still no vaccine approved against it. However, there are recent advancements regarding EBV vaccination with currently undergoing early phase clinical trials. One is an mRNA based multi-epitope vaccine which affirmed to elicit a proper immune response during immune simulations.^[43] Another one is an EBV gp350-Ferritin nanoparticle vaccine which works by inhibiting EBV cellular entry.^[44] Several clinical trials of virus vector vaccines for EBV associated malignancies are undergoing as well .^[45] Advances in the development of vaccines provide hope for the success of therapeutic vaccines for EBV.

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Medication Summary

No effective antiviral therapy is available for Epstein-Barr virus (EBV) infectious mononucleosis in immunocompetent persons. Acyclovir and ganciclovir may reduce EBV shedding, but are ineffective clinically.

Treatment of immunocompromised patients with EBV lymphoproliferative disease is controversial. Acyclovir has not been proven to be beneficial.

Short courses of corticosteroids are indicated for EBV infectious mononucleosis with hemolytic anemia, thrombocytopenia, CNS involvement, or extreme tonsillar enlargement, but are not indicated for uncomplicated EBV infectious mononucleosis. Corticosteroids should be considered in those with impending airway obstruction.

Patients with EBV infectious mononucleosis who have positive throat cultures for group A streptococci should not be treated because this represents colonization rather than infection.

Treatment of group A streptococcal oropharyngeal colonization in patients with EBV infectious mononucleosis may result in a maculopapular rash.

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Further Outpatient Care

Monitor patients to be sure that the infection is improving over time. Serial CBC counts should document the increase in lymphocytes as well as atypical lymphocytes, and this may be monitored on a weekly basis until these values normalize.

Patients with positive heterophile tests should not be monitored with serial testing because the heterophile test may remain positive for as much as 1 year after infection.

Serial specific Epstein-Barr virus (EBV) antibody testing is usually not necessary in patients with acute infection. Caution patients that increased IgG, VCA, and EBNA levels persist for life. Also, inform patients that titers vary and that IgG titers have no relationship to disease activity or to how the patient feels.

Patients should be advised that fatigue may take some time to resolve, and some patients may develop a state of chronic fatigue that is induced, but not caused by, EBV infectious mononucleosis.

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Further Inpatient Care

Patients with extreme tonsillar enlargement may require extended care if intubation is required.

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Deterrence/Prevention

Avoid close contact with body fluid secretions, particularly saliva.

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Complications

Extreme enlargement of the tonsils may result in airway obstruction.

Encephalitis and myocarditis are rare complications.

Splenic rupture is a rare, but potentially lethal, complication of EBV infectious mononucleosis.

Rare patients with EBV infectious mononucleosis develop lymphoma.

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Prognosis

If splenic rupture is recognized and expeditiously treated surgically, the prognosis is good.

Patients with EBV infectious mononucleosis who become asplenic as the result of splenic rupture and/or surgical removal should be treated as other patients with asplenia.

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Patient Education

Counsel patients to refrain from strenuous physical activity for the first 3 weeks of illness.

Patients should avoid exposing other people to their body secretions because EBV remains viable in patients with EBV infectious mononucleosis for months after the initial infection.

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