Infection due to the Epstein-Barr virus (EBV), also known as human herpesvirus 4, causes a variety of clinical syndromes including infectious mononucleosis. Many people are exposed to EBV in childhood, and primary infection results commonly in an undifferentiated febrile illness. The virus then establishes latent infection in B lymphocytes.

Patients with infectious mononucleosis typically present with fever, lymphadenopathy, and pharyngitis. Physical exam should include evaluation for splenomegaly, which may or may not be present with infectious mononucleosis. If present, this warrants limitations on physical activity given the risk of splenic rupture. A peripheral blood smear will show atypical lymphocytes. Transaminases may also be elevated. Many patients who are treated with ampicillin or amoxicillin for presumed bacterial infection before the diagnosis of mononucleosis is made will develop a pruritic maculopapular rash. Rare complications can include splenic rupture.

Acute infection due to the human immunodeficiency virus (HIV primary infection) may present with similar symptoms and should always be considered in the appropriate clinical context.

Symptoms are usually self-limited. Patients usually develop nonspecific heterophile antibodies. Serologies may be positive for IgM antibodies to viral capsid antigen. Viral DNA may also be identified by nucleic acid amplification.

EBV reactivation can lead to oral hairy leukoplakia in immunosuppressed patients (including patients with AIDS). EBV has also been associated with hemophagocytic lymphohistiocytosis.

Chronic active EBV infection is a very rare condition. Patients with this condition have histologic evidence of major organ dysfunction with presence of EBV nucleic acid or proteins in the affected organs.

EBV has been associated with many malignant diseases. In immunocompromised patients, infection can facilitate the development of various lymphoproliferative disorders, including Burkitt lymphoma, Hodgkin lymphoma, oral hairy leukoplakia, primary central nervous system lymphoma, nasopharyngeal carcinoma, and, in transplant patients, post-transplant lymphoproliferative disease. EBV-positive mucocutaneous ulcers are seen in immunocompromised individuals.