> Table of Contents > Infectious Mononucleosis, Epstein-Barr Virus Infections
Infectious Mononucleosis, Epstein-Barr Virus Infections
Dennis E. Hughes, DO, FACEP
image BASICS
DESCRIPTION
  • Epstein-Barr virus (EBV) is a member of the herpes virus family.
    • Two subtypes: ST1 predominates in Western Hemisphere, Southeast Asia; ST1 and ST2 equally prevalent in Africa
  • Primary infection typically occurs in childhood; responsible for infectious mononucleosis (most common disease association) and numerous cancers.
  • WHO classified EBV as “tumor virus” in 1997 due to association with cancer induction (1).
EPIDEMIOLOGY
Incidence
Worldwide, infects >90% of people (antibodypositive)
Prevalence
Primary EBV infection
  • Military, college students, and others living in cloistered and crowded populations have the highest infection rate.
  • Predominant age of primary infection is 10 to 19 years.
    • Primary clinical manifestation is infectious mononucleosis (IM).
    • Early childhood infections are usually asymptomatic.
  • By ˜20 years of age, 60-90% of persons have a persistent (lifelong) anti-EBV antibody.
  • Seroconversion occurs later in childhood in developed countries; there is suggestion of race/ethnicity disparity in the United States with higher seroprevalence in non-Hispanic black, Asian, and Hispanic populations (2).
ETIOLOGY AND PATHOPHYSIOLOGY
  • After inoculation, the virus replicates in the nasopharyngeal epithelium with resulting cell lysis, virion spread and viremia. The reticuloendothelial system is affected, resulting in a host response and the appearance of atypical lymphocytes in the peripheral blood.
  • A polyclonal B-cell proliferative response follows. Relatively few circulating lymphocytes are infected by EBV (<0.1% of circulating mononuclear cells in the acute illness).
  • A persistent (asymptomatic) state ensues with the EBV genome sequestered.
  • A subsequent coinfection increases risk of developing an EBV-associated condition (e.g., malignancy).
  • Either by B-cell stimulation or diminished EBV-specific immune modulation, the previously latent EBV-infected B cells replicate, allowing clinical manifestation of the EBV genome. The proteins produced may either modify host response to or contribute directly to the subsequent malignancy (3,4).
  • Immunosuppression (organ transplant/acquired immune deficiency) can result in transformation and lymphoproliferative disorders.
RISK FACTORS
  • Age
  • Sociohygienic level
  • Geographic location
  • Close, intimate contact
  • Immunosuppression
GENERAL PREVENTION
  • Avoid close physical contact with persons known to be currently symptomatic with EBV/IM
  • Hand washing and personal hygiene
  • General precautions with potential blood exposure (EBV can be transmitted via blood contamination, and marrow/organ transplant)
  • EBV vaccines are currently undergoing study.
COMMONLY ASSOCIATED CONDITIONS
  • Infectious mononucleosis: Symptomatic primary EBV infection common in otherwise healthy older children, adolescents, and young adults.
    • Clinical features vary in severity and duration: In children age <10 years, generally mild; in adolescents and adults, symptoms can be more severe and protracted.
    • Incubation period is 30 to 50 days.
  • X-linked lymphoproliferative syndrome (XLP-rare inherited extreme vulnerability to EBV infection)
  • Lymphoproliferative syndromes due to EBV infections in transplant recipients
  • Lymphomas (B-cell lymphoblastic, T-cell)
  • Lymphocytic interstitial pneumonitis
  • Hairy leukoplakia of the tongue, leiomyosarcoma, and CNS lymphomas in patients with AIDS
  • Burkitt lymphoma (most common childhood tumor in Africa and Papua New Guinea where malaria is also endemic and may be a cofactor)
  • Nasopharyngeal carcinoma (particularly in Southeast China)
  • Parotid carcinoma
  • Hodgkin lymphoma (most common EBV-associated malignancy in United States, European Union)
  • Postulated to be associated with multiple sclerosis (2 to 3 times incidence in EBV-positive individuals)
  • Chronic active Epstein-Barr Virus (CAEBV) due to loss of host control of viral replication
image DIAGNOSIS
PHYSICAL EXAM
  • Fever, lymphadenopathy, pharyngitis in >50%, with palatal petechiae and hepatosplenomegaly in ˜10%
  • Tender lymphadenopathy (cervical nodes are most commonly enlarged)
  • Splenomegaly in 50%
  • Diffuse hyperemia and hyperplasia of oropharyngeal lymphoid tissue
  • Gelatinous, grayish-white exudative tonsillitis persists for 7 to 10 days in 50%.
  • Petechiae develop at border of hard and soft palates in 60%.
  • Axillary, epitrochlear, popliteal, inguinal, mediastinal, and mesenteric lymphadenopathy (95% of patients)
  • Lymph node enlargement subsides over days/weeks
  • Skin manifestations in 3-16%
    • Erythematous macular/maculopapular rash
    • Petechial and purpuric exanthems have been reported.
    • Rash location: trunk and upper arms; occasionally, the face and forearms are involved.
DIFFERENTIAL DIAGNOSIS
  • Streptococcal pharyngitis and tonsillitis
  • Diphtheria
  • Blood dyscrasias
  • Rubella, measles
  • Viral hepatitis
  • Cytomegalovirus, toxoplasmosis
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • CBC with differential
  • Lymphocytes and atypical lymphocytes
    • Increased numbers of lymphocytes (especially atypical lymphocytes; may be up to 70% of leukocytes) in peripheral blood
    • In 1st week after onset, WBC count is normal/moderately decreased.
      • By the 2nd week, lymphocytosis develops with >10% atypical lymphocytes.
    • During early illness, atypical lymphocytes are B cells transformed by the EBV; later, atypical cells are primarily T cells.
  • Antibodies
    • Heterophile antibodies in 80-90% of adults
    • Heterophile antibody is an IgM response, which appears during the 1st and 2nd week of illness and disappears in 4 to 6 weeks.
    • In general, agglutinin titer is higher in infectious mononucleosis than in other disorders; an unabsorbed heterophile titer >1:128 and ≥1:40 after absorption is significant.
  • Specific antibodies to EBV-associated antigens
    • Viral capsid-specific IgM and IgG are present early
    • Viral capsid-IgM disappears after several weeks, viral capsid-IgG persists for life.
  • Liver tests: hypertransaminasemia, hyperbilirubinemia are common; jaundice is rare.
  • P.555

  • Atypical lymphocytes are not specific for EBV infections and may be present in other clinical conditions, including rubella, infectious hepatitis, allergic rhinitis, asthma, and primary atypical pneumonia.
  • Abdominal ultrasound to monitor for splenic enlargement is not routinely indicated. Consider ultrasound for those wishing to return to strenuous activity/contact sports at day 21 of illness to ensure resolution of splenomegaly.
Follow-Up Tests & Special Considerations
  • Abnormal hepatic enzymes persist in 80% of patients for several weeks; hepatomegaly in 15-20%
  • In transplant recipients, quantitative polymerase chain reaction (PCR) used to monitor EBV loads
Diagnostic Procedures/Other
Chest x-ray
  • Hilar adenopathy may be observed in infectious mononucleosis with extensive lymphoid hyperplasia.
Test Interpretation
  • Mononuclear infiltrations involve lymph nodes, tonsils, spleen, lungs, liver, heart, kidneys, adrenal glands, skin, and CNS.
  • Bone marrow hyperplasia with small granulomas formation may be present; these findings are nonspecific and have no prognostic significance.
image TREATMENT
GENERAL MEASURES
  • Treatment is mostly supportive.
  • NSAIDs or acetaminophen
  • During acute stage, limit activity for 4 weeks to reduce potential complications (e.g., splenic rupture).
  • Transplant recipients who develop EBV infection may require reduction in immunosuppression as well as administration of monoclonal anti-CD20 (rituximab).
MEDICATION
  • In primary infections:
    • Antimicrobial agents (usually penicillin) only if throat culture is positive for group A &bgr;-hemolytic streptococci. Previously, ampicillin rash in presumed group B Streptococcus (GBS) was thought to be highly suggestive of infectious mononucleosis. Incidence of rash much lower than historically thought (4)[B].
    • Warm saline gargles for oropharyngeal pain
    • Corticosteroids
      • May provide some symptomatic relief but no improvement in resolution of illness
      • Consider in severe pharyngotonsillitis with oropharyngeal edema and airway encroachment. Dexamethasone 0.3 mg/kg/day for 1 to 3 days.
      • Consider steroids for patients with marked toxicity or major complications (e.g., hemolytic anemia, thrombocytopenic purpura, neurologic sequelae, myocarditis, pericarditis) (5)[B].
  • Antiviral medications (acyclovir) have been evaluated in small randomized controlled trials (RCTs) and found to shorten recovery time and improve subjective symptoms in acute EBV infection. They are not routinely used.
ISSUES FOR REFERRAL
Most cases can be managed as an outpatient without the need for specialty referral. Consider referral for complications such as oropharyngeal edema with airway compromise needing intubation or ventilator support.
SURGERY/OTHER PROCEDURES
  • With profound thrombocytopenia, refractory to corticosteroid therapy, splenectomy may be necessary.
  • Only current effective treatment for XLP is hematopoietic stem cell transplantation.
  • Inability to tolerate oral intake (solid or liquid)
  • Immunosuppression
  • Splenic rupture
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Avoid contact sports, heavy lifting, and excess exertion until spleen and liver have returned to normal size (ultrasound can verify in athletic populations).
  • Eliminate alcohol and exposure to other hepatotoxic drugs or herbal supplements until LFTs normalize.
  • Closely monitor patients during the first 2 to 3 weeks after the onset of symptoms since complication rates are highest during this period.
  • Alert patients that symptoms (malaise, fatigue, intermittent sore throat, lymphadenopathy) may persist for months.
DIET
No restrictions. Hydration during acute phase is important.
PROGNOSIS
  • Most recover in ˜4 weeks.
  • Fatigue may persist for months.
REFERENCES
1. Grywalska E, Rolinski J. Epstein-Barr virusassociated lymphomas. Semin Oncol. 2015;42(2):291-303.
2. Dowd JB, Palermo T, Brite J, et al. Seroprevalence of Epstein-Barr virus infections in U.S. children ages 6-19, 2003-2010. PLoS One. 2013;8(5):e64921.
3. Thorley-Lawson DA, Hawkins JB, Tracy SI, et al. The pathogenesis of Epstein-Barr virus persistent infection. Curr Opin Virol. 2013;3(3):227-232.
4. Chovel-Sella A, Ben Tov A, Lahav E, et al. Incidence of rash after amoxicillin treatment in children with infectious mononucleosis. Pediatrics. 2013;131(5):e1424-e1427.
5. Odumade OA, Hogquist KA, Balfour HH Jr. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev. 2011;24(1):193-209.
Additional Reading
&NA;
  • Almohmeed YH, Avenell A, Aucott L, et al. Systematic review and meta-analysis of the sero-epidemiological association between Epstein Barr virus and multiple sclerosis. PLoS One. 2013;8(4):e61110.
  • Klein G, Klein E, Kashuba E. Interaction of Epstein-Barr virus (EBV) with human B-lymphocytes. Biochem Biophys Res Commun. 2010;396(1):67-73.
Codes
&NA;
ICD10
  • B27.00 Gammaherpesviral mononucleosis without complication
  • B27.09 Gammaherpesviral mononucleosis with other complications
  • B27.01 Gammaherpesviral mononucleosis with polyneuropathy
Clinical Pearls
&NA;
  • In cases of acute symptomatic infectious mononucleosis, 98% present with fever, sore throat, cervical node enlargement, and tonsillar hypertrophy.
  • False-negative monospot (heterophile antibody) common in the first 10 to 14 days of illness. 90% will have heterophile antibodies by week 3 of illness.
  • Lymphocytosis (not monocytosis) is common in infectious mononucleosis.