Basics
Description
A double-stranded DNA virus implicated as a causative agent for infectious mononucleosis by an infected laboratory worker in 1968 �
General Prevention
- No vaccine is clinically available.
- Standard precautions should be used in the hospitalized patient.
- Restriction of intimate contact with immunosuppressed individuals may be advisable.
- Patients with recent Epstein-Barr virus (EBV) infection, either proven or suspected, should not donate blood or solid organs.
Epidemiology
- Worldwide distribution
- Humans are the only known reservoir.
- Transmission occurs through saliva and, occasionally, via blood transfusions and solid organ transplant (SOT).
- Incubation period is 4-7 weeks.
- Antibodies to EBV are almost universally present in adult populations.
- Areas with a high population density or low socioeconomic status usually become primarily infected within the first 3 years of life.
Incidence
In developed countries, acquisition of EBV is biphasic. �
- Initial peak in incidence occurs before the age of 5 years.
- Second peak occurs during adolescence, coinciding with an increased frequency of intimate oral contacts.
Prevalence
90-95% of adults have demonstrable EBV titers. �
Pathophysiology
- Replicates initially in the oropharyngeal epithelium
- Selective infection of B lymphocytes occurs.
- The clinical syndrome of infectious mononucleosis results from proliferation of cells in the tonsils, lymph nodes, and spleen.
- Nonspecific humoral immune responses include the formation of heterophile antibodies and autoantibodies.
- Specific antibodies to EBV antigens are produced.
- Despite humoral responses, cellular immunity is responsible for controlling EBV infection.
- Latent, lifelong infection of B lymphocytes occurs.
- Latent virus may be reactivated during periods of immunosuppression.
Commonly Associated Conditions
- Subclinical infection
- Most EBV infections in children, and even in adolescents, are clinically inapparent.
- Mild, nonspecific symptoms may include coryza, diarrhea, and/or fever.
- Immunologic seroconversion does occur.
- Infectious mononucleosis ("glandular fever"�): most commonly observed with late primary acquisition of EBV. The classically defined illness is characterized by the following:
- Fatigue
- Malaise
- Fever
- Tonsillopharyngitis (often exudative)
- Lymphadenopathy
- Splenomegaly
- Usually associated with increased atypical lymphocytes in the peripheral blood
- Rare illnesses of the nervous system have been reported, including the following:
- Guillain-Barr � syndrome
- Bell palsy
- Aseptic meningitis
- Meningoencephalitis
- Peripheral and/or optic neuritis
- Hematologic complications have been reported in association with EBV.
- Aplastic anemia
- Hemolytic anemia
- Agranulocytosis
- Hemophagocytic syndrome
- Other illnesses associated with EBV in case reports include the following:
- Hemolytic uremic syndrome
- Hepatitis
- Pancreatitis
- Myocarditis
- Mesenteric adenitis
- Orchitis
- Genital ulcerative disease
- Lymphoproliferative disorders
- Burkitt lymphoma
- Nasopharyngeal carcinoma
- Lymphoma and non-Hodgkin lymphoma (in immunocompromised children)
- Lymphomatoid granulomatosis
- Posttransplant lymphoproliferative disorders (PTLD)
- X-linked lymphoproliferative disease (Duncan disease)
Diagnosis
History
- A prodrome may occur.
- Most often, lasts 3-5 days
- Malaise, fatigue, with or without fever
- In the acute phase, the following features are common:
- Fever: begins abruptly, lasts 1-2 weeks
- Fatigue
- Malaise
- Anorexia
- Sore throat
- "Swollen glands"�
- Rash; more common with ampicillin administration
- Young children are more likely to have rash or abdominal pain.
Physical Exam
- Tonsillopharyngitis
- May be exudative and mimic streptococcal pharyngitis
- Often accompanied by palatal petechiae
- Lymphadenopathy
- Occurs in 90%
- Most prominent in cervical chains
- May be diffuse
- Usually nontender, nonerythematous, and discrete
- Hepatosplenomegaly
- Splenomegaly occurs in more than half the cases.
- Even if not palpable, splenomegaly may be demonstrated on ultrasound.
- Most prominent in 2nd-4th week of illness
- Hepatomegaly is less common.
Diagnostic Tests & Interpretation
Lab
- Complete blood count with differential
- Leukocyte count up to 20,000/mm3
- Lymphocytosis
- Atypical lymphocytes often constitute >10% of total leukocyte count.
- Thrombocytopenia may occur.
- False positives: Atypical lymphocyte counts >10% of the total leukocyte count also occur with cytomegalovirus and toxoplasmosis infections.
- Liver enzymes
- Mild hepatitis is often found.
- Jaundice is rare.
- "Monospot"� (mononucleosis rapid slide agglutination test for heterophile antibodies)
- Detects heterophile antibodies (nonspecific IgM antibodies to unrelated antigens)
- Appears in first 2 weeks of illness, usually slow decline over 6 months
- Detects 85% of cases in adolescents/adults
- False positives: infrequent; heterophile antibodies are also produced in serum sickness and neoplastic processes; heterophile antibodies may persist for months after acute infection and be indicative of past illness.
- EBV serology
- Usually reserved for heterophile-negative patients or children <4 years of age when strong clinical suspicion persists
- Antibodies are detected by indirect immunofluorescence or enzyme-linked immunosorbent assay techniques.
- Acute or past infection can usually be detected and differentiated.
- EBV IgM is consistent with acute infection, whereas EBV nuclear antibody (EBNA) is indicative of past infection.
- Other technology
- Tissue culture of EBV is difficult and, therefore, not clinically useful.
- Polymerase chain reaction (PCR) may detect EBV genetic material.
- Real-time PCR may quantify the amount of EBV genome present, which is useful in patients with PTLD.
Alert
- Heterophile antibodies may not appear early in the illness.
- Up to 10% of patients with acute EBV infection may have no heterophile response 3 weeks into the illness.
- The heterophile response is less common in infants and children and should not be used in children <4 years of age.
Differential Diagnosis
- Infectious
- Group A Streptococcus
- Adenovirus
- Cytomegalovirus
- Toxoplasma gondii
- Human herpesvirus-6
- Mycoplasma pneumoniae
- Human immunodeficiency virus
- Rubella
- Diphtheria
- Viral hepatitis (A, B, C)
- Noninfectious
Treatment
Medication
- Acetaminophen or ibuprofen reduces fever and provides analgesia.
- Corticosteroids (prednisone 1 mg/kg/24 h PO, maximum of 20 mg/24 h) may reduce swelling of lymphoid tissues (see "FAQ"�)
- Indicated for patients with impending airway obstruction
- May be considered for patients with severe tonsillopharyngitis requiring IV hydration
- May be considered for patients with rare, life-threatening manifestations of EBV infection, such as hepatitis, aplastic anemia, and central nervous system dysfunction
- 7-day treatment followed by tapering
- Acyclovir has not been shown to provide clinical benefit; sometimes, used in cases of active replicating EBV in posttransplant situations
- Patients with PTLD should have immunosuppression reduced.
- Advise avoidance of contact sports until resolution of symptoms and no further splenomegaly.
Inpatient Considerations
Admission Criteria
- Respiratory distress secondary to airway obstruction
- Dehydration secondary to severe pharyngitis and poor oral intake
Discharge Criteria
- Resolved airway obstruction
- Good oral intake
Issues for Referral
- PTLD
- EBV in immunocompromised host
- EBV-associated lymphoproliferative disorders
- Considering steroid use as treatment
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Immunocompetent individuals usually recover uneventfully in 1-4 weeks.
- Recovery is often biphasic, with a worsening of symptoms after a period of improvement.
- Splenomegaly may persist for weeks after primary infection (see "FAQ"�).
- Fatigue may persist months after recovery.
Prognosis
- Most patients with primary EBV infection will recover uneventfully in 1-4 weeks.
- Long-lasting immunity generally ensues.
- Prognosis of patients with unusual manifestations of EBV infection depends on the severity of the illness and the organ system involved.
- Patients with inherited or acquired immunodeficiency are at higher risk of complications and neoplasms.
Complications
- Dehydration
- Severe pharyngitis often limits fluid intake.
- Most common problem requiring hospitalization
- Antibiotic-induced rash
- Morbilliform in appearance
- Most common after administration of ampicillin or amoxicillin
- Rare association with penicillin
- Usually benign; resolves with discontinuation of the aminopenicillin
- Splenic rupture
- Incidence of ~1 in 1,000 patients
- More common in males
- 50% of the cases of splenic rupture are spontaneous; 50% follow blunt trauma.
- Airway obstruction: may result from massive lymphoid hyperplasia and mucosal edema
Additional Reading
- Bravender �T. Epstein-Barr virus, cytomegalovirus, and infectious mononucleosis. Adolesc Med State Art Rev. 2010;21(2):251-264. �[View Abstract]
- Hurt �C, Tammaro �D. Diagnostic evaluation of mononucleosis-like illness. Am J Med. 2007;20(10):911. e1-911. e8. �[View Abstract]
- Macsween �KF, Crawford �DH. Epstein-Barr virus-recent advances. Lancet Infect Dis. 2003;3(3):131-140. �[View Abstract]
- Okano �M. Overview and problematic standpoints of severe chronic active Epstein-Barr virus infection syndrome. Crit Rev Oncol Hematol. 2002;44(3):273-282. �[View Abstract]
- Putukian �M, O'Connor �FG, Stricker �P, et al. Mononucleosis and athletic participation: an evidence-based subject review. Clin J Sport Med. 2008;18(4):309-315. �[View Abstract]
Codes
ICD09
- 075 Infectious mononucleosis
ICD10
- B27.90 Infectious mononucleosis, unspecified without complication
- B27.99 Infectious mononucleosis, unsp with other complication
- B27.91 Infectious mononucleosis, unspecified with polyneuropathy
- B27.92 Infectious mononucleosis, unspecified with meningitis
SNOMED
- 402121009 Epstein-Barr virus infection (disorder)
- 271558008 Infectious mononucleosis (disorder)
FAQ
- Q: Should all patients with infectious mononucleosis be given corticosteroids?
- A: No. Symptomatic EBV infection is most often self-limited. EBV has been linked to certain lymphoproliferative disorders, and theoretic risks to modulating the host immune response with corticosteroids have been proposed.
- Q: How long after infectious mononucleosis may a patient return to athletic activity?
- A: More than half of patients with "mono"� will have a boggy, enlarged spleen, which is prone to rupture even if it is not palpable. Athletic activity should be restricted until no evidence exists for a clinically enlarged spleen. Return to contact sports is not advised until 4-6 weeks after resolution of illness. Some experts recommend ultrasound of the spleen before a return to heavy contact sports such as rugby, football, lacrosse, and hockey.