Infectious mononucleosis (IM) is a symptomatic infection most commonly caused by Epstein-Barr virus (EBV) and characterized by a classic triad of fever, tonsillar pharyngitis, and lymphadenopathy (predominantly cervical).¹ Fatigue is also a very common finding. IM was first coined in 1920 to describe a syndrome characterized as an acute infectious process accompanied by atypical large peripheral blood lymphocytes.

Mononucleosis

EBV

Kissing disease

• Following an incubation period of 4 to 7 wk, there are two common presentations.^1-3 The first presentation represents the prodromal period with gradual onset of fever, chills, malaise, and anorexia for several days. This is followed by the second presentation of the classic triad of pharyngitis, fever, and lymphadenopathy. These patients often report the worst sore throat of their life. Pharyngitis (Fig. E1) is typically the most severe symptom and is characterized by white tonsillar exudates that may spread to the tongue. Up to half of patients may have palatal petechiae.
• Lymphadenopathy (nonnecrotic) can be diffuse, but most commonly occurs in both the anterior and posterior triangles of the neck.
• Splenomegaly may be palpable, most commonly during the second week of illness. Most patients have some degree of splenomegaly on ultrasound assessment. Hepatomegaly with some degree of hepatitis is also common. In 75% of cases there is some increase in alanine aminotransferase (ALT).³
• Rash (Fig. E2) is uncommon but will occur in nearly all patients who receive ampicillin or amoxicillin due to a transient penicillin hypersensitivity.
• IM is usually a self-limited illness (2 to 4 wk), but symptoms of malaise and fatigue may last months before resolving.¹
• At times, IM can present as fever and adenopathy without pharyngitis.
• Although acute complications may be severe, they are uncommon and tend to resolve completely. Reported complications include cholestatic liver disease, chronic hepatitis, or even liver failure; hemolytic anemia; splenic rupture; or airway compromise.^3,4
• Splenic rupture is rare, with an incidence rate <1%, but it is the most feared.⁴ It should be suspected in anyone with confirmed or suspected IM who presents with acute abdominal or chest pain. Most cases occur in the first 3 wk of symptoms.
• Airway compromise, as evidenced by stridor, cyanosis, and/or tachypnea, is reported in 1% to 3% of cases and is an indication for hospitalization.
• Systemic corticosteroids are indicated for treating those at risk or with impending airway obstruction, and usually lead to improvement in 12 to 36 hr. Acute tonsillectomy may be pursued if steroids are not sufficient to mitigate the risk for obstruction.⁵
• Late complications may include lymphoproliferative cancers (Burkitt lymphoma and Hodgkin lymphoma), multiple sclerosis, rheumatoid arthritis, and chronic active EBV infection (CAEBV).³
• EBV may also cause hemophagocytic disease, alternatively referred to as EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), characterized by fever, splenomegaly, and cytopenias with high ferritin and soluble CD25.
• Box 1 and Table 1 summarize the features of IM in immunocompetent patients.

The most common cause of IM (90%) is primary infection with EBV.¹ Cytomegalovirus (CMV) is the most common cause of the other 10% of IM, but CMV infection often occurs in infancy or early childhood and is minimally symptomatic. Other causes include human herpes virus-6, herpes simplex virus-1, and HIV. Primary EBV infection during childhood also often causes few or no symptoms; persistent fatigue and recurrent/persistent fevers are the most common reasons parents bring symptomatic children to medical care.

EBV infects epithelial cells and resting B cells of the oropharynx. It is then found in saliva, making it transmittable through coughing, sharing drink/food, and kissing; thus the pseudonym “kissing disease.” IM is more prevalent during adolescence when these types of close contact increase. How it is transmitted in younger children is less clear.

EBV levels peak during the active phase of infection but can persist in the oropharynx for up to 18 mo. Transmission may also occur sexually because EBV can be isolated in cervical epithelial cells and male seminal fluid. It has also been shown to be transmitted by blood transfusion, solid organ transplantation, or hematopoietic cell transplantation.

• Heterophile-negative IM caused by CMV
• Bacterial and viral causes of pharyngitis
• Toxoplasmosis
• Acute retroviral syndrome of HIV, lymphoma

Initial testing consists of heterophile antibody (monospot) and CBC with differential. Fig. 3 illustrates the serologic evaluation of patients with clinical symptoms of acute IM and atypical lymphocytosis.

• About 85% of patients with EBV-related IM will have a positive heterophile antibody test, making it the best initial test for diagnosis of EBV infection (sensitivity of 71% to 90% for diagnosing IM). However, the test has a 25% false-negative rate in the first week of illness because the amount of heterophile antibody may not be above the limit for detection early in the disease. A negative test should be repeated if clinical suspicion is high; negative results are common in patients symptomatic for <2 wk and children <4 yr. False-positive heterophile antibody tests have been reported in other acute infections, autoimmune diseases, and cancer.
• About 10% of patients will have a persistently negative heterophile antibody test. In this event, further testing may be pursued with EBV viral capsid antigen (VCA) IgG and IgM antibody testing, as well as EBV nuclear antigen (EBNA) antibodies for staging of infection. Early diagnosis in monospot-negative cases may be made by isolating IgM to the VCA, which is usually positive during the acute illness and disappears after 4 to 6 wk. If the monospot test remains negative (without evidence of acute infection with antibody testing) for 8 wk, alternative diagnoses should be considered. The monospot usually remains positive for 3 to 6 mo but can last >1 yr.
• Increased white blood count (WBC) is common, with a relative lymphocytosis and neutropenia. Atypical lymphocytes (Fig. E4) are the hallmark of IM but are not pathognomonic. Mild thrombocytopenia is common. A falling hematocrit may signal splenic rupture or severe immune-mediated hemolytic anemia. Elevated hepatocellular enzymes and cryoglobulins occur in many cases.

Chest x-ray may rarely show infiltrates. An elevated left hemidiaphragm may occur in cases of splenic rupture.

• No specific treatment exists; focus is on supportive care and symptomatic relief with analgesics, antipyretics, and hydration. Supportive rest is advocated by some, but the effect on outcome is not clear. Prolonged rest may result in deconditioning, which may contribute to further fatigue.
• Splenectomy if rupture occurs; transfusions for severe anemia or thrombocytopenia.

• There is no role for antiviral agents such as acyclovir in the management of IM.

CAEBV is treated with hematopoietic cell transplantation.

Eventual resolution of all symptoms is the rule.

• Contact sports should be avoided during the first month of illness because splenic rupture can occur during this time, even in the absence of clinically detectable splenomegaly.³
• Between 30% and 75% of college freshmen are seronegative for EBV. Each year nearly 20% of susceptible persons become infected, and up to 50% of these persons develop IM.
• Pharmacologic therapy, including corticosteroids, is not indicated in mild illness or for symptomatic relief. Use of corticosteroids is controversial because they may impair clearance of the viral load.
• The use of steroids, however (Fig. 5), should be considered in patients who have severe acute complications, such as thrombocytopenia, hemolytic anemia, or impending airway obstruction.

Mononucleosis (Patient Information)

Epstein-Barr Virus Infection (Related Key Topic)