INFECTIOUS MONONUCLEOSIS, EPSTEIN-BARR VIRUS INFECTIONS

Dennis E. Hughes, DO, FAAFP, FACEP

 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 (IM) (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 (antibody-positive)

Prevalence

Primary EBV infection

•  Military, college students, and others living in cloistered and crowded populations have highest infection rate.

•  Predominant age of primary infection is 10 to 19 years.

–  Primary clinical manifestation is 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 invisible to the immune system.

•  A subsequent coinfection increases risk for an EBV-associated condition (e.g., malignancy).

•  Either through B-cell stimulation or diminished EBV-specific immune modulation, the previously latent EBV-infected B cells replicate, allowing clinical expression of the EBV genome. The proteins produced may either modify host response to or contribute directly to subsequent malignancy (1,3).

•  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 symptomatic with EBV/IM.

•  Good hand washing and hygiene

•  General precautions with potential blood exposure (EBV can be transmitted via blood contamination, as well as hematopoietic cell and solid organ transplant)

•  EBV vaccines are undergoing study but have had limited efficacy in small studies.

COMMONLY ASSOCIATED CONDITIONS

•  IM: Symptomatic primary EBV infection is 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 co-factor)

•  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

 DIAGNOSIS

HISTORY

•  May begin abruptly or insidiously

•  Syndrome of fatigue, malaise, and sore throat

•  In adults, temperature may rise to 103°F (39.4°C) and gradually fall over a variable period of 7 to 10 days; in severe cases, temperature elevations of 104–105°F (40.0–40.6°C) may persist for 2 weeks.

•  Children typically have low-grade fever or are afebrile.

•  Rash

•  Chest pain (myocarditis and pericarditis)

PHYSICAL EXAM

•  Fever, lymphadenopathy, pharyngitis in >50%, with palatal petechiae and hepatosplenomegaly in ~10%

•  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

•  Tender lymphadenopathy (cervical nodes are most commonly enlarged)

•  Splenomegaly in 50%

•  Skin manifestations in 3–16%

–  Erythematous macular/maculopapular rash

–  Petechial and purpuric exanthems reported

–  Rash typically on 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/2nd week of illness and disappears in 4 to 6 weeks.

–  In general, agglutinin titer is higher in IM than other disorders; an unabsorbed heterophile titer >1:128 and ≥1:40 is significant.

•  Specific antibodies to EBV-associated antigens

–  Develop regularly in IM

–  Viral capsid-specific IgM and IgG are present early in illness.

–  Viral capsid-IgM disappears after several weeks; viral capsid-IgG persists for life.

•  Liver tests: hypertransaminasemia, hyperbilirubinemia are common; jaundice is rare.

•  Atypical lymphocytes are not specific for EBV infections and may be present in other clinical conditions, including rubella, infectious hepatitis, allergic rhinitis, asthma, and atypical pneumonia.

•  Abdominal ultrasound to monitor for splenic enlargement is not supported routinely.

•  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 IM 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.

 TREATMENT

•  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 β-hemolytic streptococci. Previously, ampicillin rash in presumed group B Streptococcus (GBS) was thought to be highly suggestive of IM. Incidence of rash is 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 may be used for 1 to 3 days.

  Also for patients with marked toxicity/major complications (e.g., hemolytic anemia, thrombocytopenic purpura, neurologic sequelae, myocarditis, pericarditis) (5)[B]

•  Antiviral medications (acyclovir) evaluated in small randomized controlled trials (RCTs) have been found to shorten recovery time and improve subjective symptoms in acute EBV infection.

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 eat food or drink fluids

•  Immune suppressed

•  Splenic rupture

 ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

ALERT

Rupture of the spleen may be fatal if not recognized; it requires blood transfusions, treatment for shock, and splenectomy. Occurrence is estimated at 0.1%.

Patient Monitoring

•  Avoid contact sports, heavy lifting, and excess exertion until spleen and liver have returned to normal size (ultrasound can verify).

•  Eliminate alcohol/exposure to other hepatotoxic drugs until LFTs return to normal.

•  Monitor patients closely during the first 2 to 3 weeks after the onset of symptoms as rates of complications 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 very important.

PROGNOSIS

•  Most recover in ~4 weeks.

•  Fatigue may persist for months.

COMPLICATIONS

•  Neurologic (rare)

–  Aseptic meningitis

–  Bell palsy

–  Meningoencephalitis

–  Guillain-Barré syndrome

–  Transverse myelitis

–  Cerebellar ataxia

–  Acute psychosis

•  Hematologic (rare)

–  Thrombocytopenia, slight to moderate, early in illness

–  Hemolytic anemia with marked neutropenia during early weeks

–  Aplastic anemia

–  Agammaglobulinemia

•  Pneumonitis

•  Splenic rupture

–  Rare, but most often occurs in first 21 days of illness

REFERENCES

1.  Grywalska E, Rolinski J. Epstein-Barr virus-associated lymphomas. Semin Oncol. 2015;42(2):291–303.

2.  Dowd JB, Palermo T, Brite J, et al. Seroprevalence of Epstein Barr virus infections in the 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 O, Hogquist K, Balfour H. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev. 2011;24(1):193–209.

ADDITIONAL READING

•  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

ICD10

•  B27.00 Gammaherpesviral mononucleosis without complication

•  B27.09 Gammaherpesviral mononucleosis with other complications

•  B27.01 Gammaherpesviral mononucleosis with polyneuropathy

CLINICAL PEARLS

•  In cases of acute symptomatic IM, 98% manifest 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 IM.