Epidemiology

EBV is a DNA virus in the family Herpesviridae that infects >90% of persons by adulthood.

• Infectious mononucleosis (IM) is a disease of young adults and is more common in areas with higher standards of hygiene; infection occurs at a younger age in areas with deficient standards of hygiene.
• EBV is spread by contact with oral secretions (e.g., by transfer of saliva during kissing) and is shed in oropharyngeal secretions by >90% of asymptomatic seropositive individuals.

Pathogenesis

EBV infects the epithelium of the oropharynx and salivary glands as well as B cells in tonsillar crypts prior to a period of viremia.

• B cells undergo polyclonal activation, and memory B cells form the reservoir for EBV. Reactive T cells proliferate, with up to 40% of CD8+ T cells directed against EBV antigens during acute infection.
• Cellular immunity is more important than humoral immunity in controlling infection. If T cell immunity is compromised, EBV-infected B cells may proliferate-a step toward neoplastic transformation.

Clinical Manifestations

The nature of EBV disease depends on the pt's age and immune status: young children typically develop asymptomatic infections or mild pharyngitis, adolescents and adults develop an IM syndrome, and immunocompromised pts can develop lymphoproliferative disease.

• In IM, a prodrome of fatigue, malaise, and myalgia may last for 1-2 weeks before the onset of fever, exudative pharyngitis, and lymphadenopathy with tender, symmetric, and movable nodes; splenomegaly is more prominent in the second or third week.
  • The incubation period is ∼4-6 weeks.
  • Earlier studies reported that most pts treated with penicillin derivatives develop a macular rash; these rashes do not represent a true penicillin allergy, nor do they occur more frequently in pts exposed to penicillin derivatives rather than other drugs.
  • Illness lasts for 2-4 weeks, but ∼10% of pts have fatigue that persists for ≥6 months. EBV is not, however, a cause of chronic fatigue syndrome.
  • Lymphocytosis occurs in the second or third week, with >10% atypical lymphocytes (enlarged cells with abundant cytoplasm and vacuoles); abnormal liver function is common.
  • Complications include CNS disease (e.g., meningitis, encephalitis), Coombs-positive autoimmune hemolytic anemia, splenic rupture, and upper airway obstruction due to hypertrophy of lymphoid tissue.
• Lymphoproliferative disease-i.e., infiltration of lymph nodes and multiple organs by proliferating EBV-infected B cells-occurs in pts with deficient cellular immunity (e.g., pts with AIDS, those with severe combined immunodeficiency, and those receiving immunosuppressive medications). Pts develop fever and lymphadenopathy or GI symptoms.
• Oral hairy leukoplakia-raised, white, corrugated, EBV DNA-containing lesions on the tongue-is an early manifestation of infection with HIV in adults.
• EBV-associated malignancies include Burkitt's lymphoma (∼90% of cases in Africa and ∼15% of cases in the United States), anaplastic nasopharyngeal carcinoma in southern China, gastric cancer (with ∼9% of these tumors positive for EBV), Hodgkin's disease (especially the mixed-cellularity type), and CNS lymphoma (especially HIV-related).

Diagnosis

Serologic testing is the mainstay of diagnostic assessment. PCR analysis can be useful in monitoring EBV DNA levels in blood from pts with lymphoproliferative disease.

• Heterophile antibodies (Figure 102-1. Pattern of Epstein-Barr Virus (EBV) Serology During Acute Infection) form the basis of most rapid testing, which assesses the ability of serum to agglutinate sheep, horse, or cow erythrocytes after adsorption with guinea pig kidney.
  • The antibodies can persist for up to 1 year after infection.
  • The monospot test for heterophile antibodies is somewhat more sensitive than the classic heterophile test; it is ∼75% sensitive and ∼90% specific in comparison with EBV-specific serologies.
  • Pts <5 years old and elderly pts usually do not develop heterophile antibodies.
• EBV-specific antibody testing can be used in heterophile-negative pts and in pts with atypical disease. Antibodies to viral capsid antigen occur in >90% of cases, with elevated IgM titers present only during the first 2-3 months of disease.
• Antibodies to Epstein-Barr nuclear antigen are not detected until 3-6 weeks after symptom onset and then persist for life.