Epidemiology
EBV infections occur worldwide, and, in most populations, 90% to 95% of adults have antibodies against EBV. Depending on geo graphic and socioeconomic factors, there is a wide variation in the age of primary EBV infections. Early, asymptomatic primary EBV infection occurs more often in individuals from lower socioeconomic groups, particularly those living in low- and middle-income countries. In higher socioeconomic groups in high-income countries, the age of primary infection is more often delayed until the second decade of life and clinically apparent IM is more prevalent.
Humans are the only source of EBV, which is present in the saliva of patients with IM. A majority of EBV-positive adults shed virus into their saliva, and this percentage is increased in immunocompromised patients such as SOT recipients. EBV is viable outside the body for 2 weeks at 4°C but is susceptible to drying; the virus has not been recovered from environmental sources, suggesting that close contact is needed for viral spread. The incubation period of EBV is estimated to be 30 to 50 days.
Clinical Manifestations
Primary EBV infection in infants and young children is either asymptomatic or accompanied by mild, nonspecific symptoms and signs such as fever, upper respiratory tract infection, pharyngitis with or without tonsillitis, and cervical lymphadenopathy. In contrast, approximately 30% to 50% of adolescents and young adults present with the clinical picture of IM. Frequently, a prodrome consisting of fatigue, malaise, and low-grade fever is present for 1 to 2 weeks. Prominent pharyngitis with exudative tonsillitis is often the cardinal sign of IM; other signs and symptoms are listed in Table 1. The adenopathy in IM most commonly affects the posterior cervical lymph nodes, although diffuse adenopathy can occur. The enlarged lymph nodes are not fixed, may be tender to palpation, and lack over lying skin erythema. Hepatomegaly is uncommon; however, splenomegaly develops in 15% to 65% of patients and is more prominent in the second to fourth week of the illness. Skin manifestations include a faint, morbilliform rash reminiscent of rubella and less commonly erythema multiforme and erythema nodosum. Most patients with primary EBV infection have symptoms for 2 to 4 weeks and recover without significant complications or sequelae.
Table1. Clinical Manifestations of Infectious Mononucleosis
Complications of Infectious Mononucleosis
Although the majority of patients with IM fully recover without severe complications, any organ system can be affected in this clinical syndrome of primary EBV infection.
Hematologic Complications
Patients with IM may present with a wide range of hematologic findings besides the atypical lymphocytosis (Fig. 1). These include anemia, neutropenia, thrombocytopenia, and rare cases of aplastic anemia.
Fig1. PERIPHERAL BLOOD SMEAR IN INFECTIOUS MONONUCLEOSIS. (A) Low power shows moderately high white blood cell count and high number of reactive, or “atypical” lymphocytes. (B–G) Higher power illustrates spectrum of lymphoid morphology, including small resting lymphocyte (B) for comparison, large granular lymphocyte (C), atypical forms (D–F), also referred to as “reactive” lymphs, and circulating plasma cell (G).
Anemia
Autoimmune hemolytic anemia occurs in approximately 3% of patients with IM. It presents in the first 2 weeks of the illness, and the majority of patients recover within 1 to 2 months. Patients usually have a positive direct Coombs test. Most common anti-I antibodies are present; however, anti-I, anti-N, and Donath-Landsteiner antibodies have also been reported. In addition to hemolysis, IM-associated anemia can be caused by transient erythroblastopenia.
Neutropenia
Mild, self-limiting neutropenia is a common finding during the first 4 weeks of the disease. However, severe neutropenia associated with fatal bacterial infections has been reported.
Thrombocytopenia
Mild thrombocytopenia (50,000 to 150,000/mm3) is a common finding in patients with IM. It usually occurs within the first 2 weeks of presentation and resolves within 2 months. Severe thrombocytopenia with overt bleeding is rare; however, death from intracranial hemorrhage has been described. The etiology of the thrombocytopenia is not completely understood, and a variety of explanations have been suggested. Because bone marrow examination shows normal or increased numbers of megakaryocytes, peripheral platelet consumption is most likely due to the presence of antiplatelet antibodies or platelet pooling and destruction within an enlarged spleen.
Splenic Rupture
Splenic rupture occurs predominately in males, with an incidence of 1/1000 to 1/3000. The incidence of rupture is highest in the second and third week of illness and can be the first sign of IM. Clinical symptoms include abdominal pain or pain referred to either shoulder. Because abdominal pain is an unusual symptom of uncomplicated IM, a splenic rupture should be strongly considered in IM cases when abdominal pain is reported. Although it is a life-threatening complication, with current management the mortality rate is very low.
Neurologic Complications
Neurologic complications develop usually during the first 2 weeks of IM and may be the only manifestation of IM. EBV infection can cause a wide spectrum of neurologic diseases, including encephalitis, meningitis, Guillain-Barré syndrome, acute transverse myelitis, and peripheral neuritis. Most patients with neurologic complications recover completely.
Other Organ Involvement
Although symptomatic heart disease with IM is uncommon, in one cohort of patients, nonspecific ST- and T-wave abnormalities were found in 6% of patients. Renal involvement manifested as microscopic hematuria, and proteinuria is seen in 10% to 15% of patients; however, significant renal dysfunction is rare. Airway compromise due to hypertrophy of the adenoids and tonsils or mucosal inflammation and edema is uncommon but potentially fatal.
Diagnosis
Atypical lymphocytosis is the cardinal hematologic finding in IM (see Fig. 1). It develops during the first week of the illness and peaks between the second and third week. Atypical lymphocytes represent 60% to 70% of the total white cell count, which usually ranges between 12,000/mm3 and 18,000/mm3. In general, the atypical lymphocytes are large and vary in size. Nuclei are large and eccentrically placed; the cytoplasm is basophilic, and vacuoles are often present. The variable morphologic pattern of atypical lymphocytes in IM distinguishes them from the monotonous appearance of immature leukemic blasts. Atypical lymphocytosis is not pathognomonic for IM and is associated with other diseases such as acute viral hepatitis, CMV infections, mumps, toxoplasmosis, rubella, roseola, and drug reactions.
The diagnosis of EBV infection depends on serologic testing. Tests for heterophile antibodies, including the monospot test and slide agglutination tests, are routinely available. The results of these tests are often negative in children younger than monopod 4 years of age, but they identify 90% of cases in older children and adults. Of the available EBV-specific serologic tests, VCA-IgM antibodies are most commonly determined to diagnose primary EBV infection in heterophile-negative IM cases; determining antibodies against EA may also be helpful (see Table 1). VCA-IgG antibodies are positive during acute infections as well as the convalescent period. The presence of anti-EBNA antibodies excludes an acute infection. Isolation of EBV from throat washings is feasible; however, it is of little diagnostic value because 10% to 20% of healthy adult EBV carriers may shed the virus.
Table2. Frequently Determined Epstein-Barr Virus–Specific 55.1 Antibodies
Differential Diagnosis
In the majority of cases, the diagnosis of IM is straightforward. The differential diagnosis includes streptococcal and nonstreptococcal pharyngitis, acute infections with CMV, HHV-6, hepatitis viruses, and toxoplasma. Depending on the presentation, other diseases may be considered such as HIV, rubella, and leukemia or lymphoma.
Treatment
Supportive therapy should include rest and analgesia in the acute stage of IM. Contact sports should be avoided until the patient has fully recovered and the spleen is no longer palpable. The use of corticosteroids is not indicated for uncomplicated IM; however, a trial of corticosteroids may be warranted in patients with marked tonsil lar inflammation and hypertrophy resulting in impending airway obstruction. Although acyclovir reduces EBV shedding into oral secretions, treatment of IM with acyclovir has resulted in no clinical benefit.
