This disorder is seen most commonly in adolescents and young adults and is characterized by a prodromal period of chills, sweats, anorexia, or malaise followed by the clinical triad of symptoms to include sore throat, fever and lymphadenopathy, usually of the cervical chains. Hepatosplenomegaly is a common finding on physical examination. Oropharyngeal examination often reveals a thick pharyngeal exudate and palatal petechiae. Cutaneous symptoms are noted in approximately 5% of affected patients, and when affected patients are given ampicillin, 90% will develop a pruritic maculopapular rash. The mechanism for this ampicillin-induced skin reaction is unknown; however, it does not represent an allergic reaction to penicillin antibiotics. Other associated symptoms include dysphagia, anorexia, nausea, cough, myalgia, ocular muscle pain, and chest pain. Most symptoms resolve within 2 weeks; however, malaise, fatigue and anorexia are often more persistent and last for approximately 1 month.

The Epstein-Barr virus (EBV) is the etiologic agent in the majority of cases followed by cytomegalovirus (CMV). EBV only causes disease in persons who are EBV-antibody negative. The virus is usually transmitted by contact with the saliva of infected individuals, and the virus can be isolated from the throat washings of patients months after the illness. Less commonly, the virus may be transmitted in contaminated blood during transfusion therapy. CMV usually causes mononucleosis in young adults. Tonsillopharyngitis, splenomegaly and lymphadenopathy are uncommon manifestations when infection with CMV is the underlying etiology.

The majority of patients experience an uneventful recovery. Complications may include splenic rupture, encephalitis, meningitis, Guillain-Barré syndrome, hemolytic anemia, tonsillar hypertrophy with resultant respiratory obstruction, pericarditis, and myocarditis. Splenic rupture is associated with abdominal pain and is more common during the second or third week of illness. Rupture of the spleen is usually associated with trauma, and it is for this reason that patients should be cautioned not to participate in contact sports, physical activities, or allow vigorous palpation of the spleen during the first few weeks of their illness. Associated lab abnormalities include lymphocytosis with the presence of atypical lymphocytes (10% or more), the aforementioned Coombs-positive hemolytic anemia, thrombocytopenia that is usually asymptomatic, and hepatitis characterized by mild elevations of serum transaminases (AST and ALT).

There are two tests to aid in the diagnosis of EBV mononucleosis. The monospot test will be positive (show agglutination when serum and horse red cells are mixed with guinea pig kidney cells but not with beef red cell stroma). False-positive monospot tests may be seen with serum sickness, Forssman antibodies, leukemia, Burkitts lymphoma, rheumatoid arthritis, viral hepatitis, and other infections caused by EBV or CMV. When the monospot test is positive, the diagnosis is confirmed. Intitially, the monospot test may remain negative for the first three weeks; therefore, serial weekly monospot testing may be needed to make the diagnosis.  If the diagnosis remains in doubt then testing for IgM anti-EBV viral capsid antigen (VCA) will aid in making the diagnosis.

As the disease is usually self-limited, no therapy is required. The pharyngitis is usually not associated with bacterial superinfection, and because therapy with penicillin antibiotics may induce a skin rash, antibiotics should not be administered. Patients should be counseled not to engage in potentially traumatic physical activities until several weeks after the onset of the illness to avoid the possibility of splenic rupture. Also, patients should be counseled of the highly contagious nature of their infection, and they should be instructed to maintain precautions to prevent the spread of infection.