AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Infectious mononucleosis (IM) is a clinical syndrome. IM represents the immunopathologic expression that occurs under a specific set of circumstances and in response to infection with the Epstein-Barr virus (EBV).

These circumstances primarily relate to the age and immunocompetency of the patient when the infection is acquired.

IM was first described in 1920. In 1932, the association between the disease syndrome and a positive heterophile antibody test was recognized. It was not until 1968 that EBV was identified as the most likely causative agent of IM.

Pathophysiology

EBV is a member of the family Herpesviridae, which includes other human pathogens (eg, herpes simplex viruses, herpes varicella-zoster viruses, cytomegalovirus, human herpes viruses 6 and 7).

Herpes viruses contain double-stranded DNA, and they have an icosahedral capsid and a glycoprotein-containing envelope. They are relatively fragile and do not survive long outside the human host fluids.

EBV is ubiquitous. It is estimated that more than 90% of adult humans demonstrate serologic evidence of a prior infection with EBV. Most cases of IM are due to EBV, but the vast majority of EBV infections do not result in IM. In industrialized nations and among higher socioeconomic groups, infection with EBV tends to occur in adolescents and young adults. It is in this age group that the ensuing immunopathology gives rise to the characteristic clinical syndrome.

The most common mode of transmission of EBV is through exposure to infected saliva from asymptomatic individuals, often as a result of kissing.

Following exposure, EBV infects epithelial cells of the oropharynx and salivary glands. B lymphocytes may become infected through exposure to these cells or may be directly infected in the tonsillar crypts. B-cell infection allows viral entry into the bloodstream, which systemically spreads the infection.

In the immunocompetent patient, the proliferation of infected B cells results in massive activation and proliferation of cytotoxic T lymphocytes, leading to the characteristic lymphoid hyperplasia. Clinically, this is observed as tonsillitis, lymphadenopathy, and hepatosplenomegaly.

The T-cell response is largely responsible for the rise in the absolute lymphocyte count and for the finding of atypical lymphocytes. These atypical lymphocytes (ie, Downey cells) actually are CD8 cytotoxic T cells.

B-cell infection caused by EBV leads to the transformation of the B cells to immortal plasmacytoid cells, which secrete a wide variety of immunoglobulins (eg, heterophile antibodies). Antibodies against specific EBV antigens and a number of autoantibodies also are produced.

Other disease states that are associated with EBV include African Burkitt lymphoma and certain nasopharyngeal cancers.

Frequency

United States

The incidence of IM as a recognizable clinical syndrome due to EBV is estimated at 45 per 100,000 patients.

International

The worldwide incidence of IM is unknown, but in developing countries, 90% of children experience an asymptomatic EBV infection when younger than 5 years and are not susceptible to mononucleosis that is associated with EBV.

Mortality/Morbidity

• Fatalities secondary to IM are rare and most often are the result of splenic rupture. Other fatal occurrences have been attributed to secondary bacterial infection, hepatic failure, and myocarditis.
• Airway obstruction can occur due to massive edema of the Waldeyer ring.
• Serious nonfatal complications also are rare and may include involvement of the CNS or the hematologic system.
  • CNS complications can include meningitis, encephalitis, hemiplegia, psychosis, cranial nerve palsies, Guillain-Barré syndrome, transverse myelitis, and peripheral neuritis. Evidence also exists to suggest EBV infection as an adult is a risk factor for the development of multiple sclerosis.
  • Hematologic complications can include development of autoimmune hemolytic anemia, pancytopenia, red cell aplasia, severe thrombocytopenia, or agranulocytopenia.

Race

No known ethnic or racial predilections exist; however, in developed countries, it is more common in persons of a higher socioeconomic class.

Sex

• No predilection exists for either sex.
• The only sex-related factor is the complication of splenic rupture; more than 90% of these cases occur in males.

Age

The syndrome of IM most often is an immunopathologic response to an infection with EBV. The clinical expression of that response is influenced greatly by the age of the infected individual.

• The highest occurrence rate is in those aged 15-25 years. It is estimated that 1-3% of college students are affected annually.
• In children younger than 4 years, the infection is most often asymptomatic, but they may present with atypical symptoms (eg, irritability, failure to thrive, abdominal pain due to mesenteric adenopathy or splenomegaly, upper respiratory infection [URI] symptoms).
• Elderly patients with EBV infection usually present with nonspecific complaints (eg, fever, fatigue, malaise, myalgias).

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• IM may have a varied clinical presentation, but the symptoms usually consist of fever, pharyngitis, and lymphadenopathy.
• The incubation period of IM is 4-6 weeks. Patients usually do not recall a history of possible exposure.
• Prodromal symptoms consisting of 1-2 weeks of fatigue, malaise, and myalgia are common.
• • Patients may present during the prodrome, which makes specific diagnosis difficult, or they may present with clinical IM and admit a history of antecedent prodromal symptoms.
  • Abrupt onset of IM symptoms with no prodrome may occur.
• Low-grade fever usually is present and lasts 1-2 weeks, but it may persist for 4-5 weeks.
• Pharyngitis is one of the cardinal symptoms of IM, and it may be severe and/or exudative, particularly during the first week of symptoms, with gradual improvement thereafter.
• Tonsillitis may be present.
• Lymphadenopathy is almost universal, and it lasts for 1-2 weeks.
• Posterior cervical nodes commonly are affected, but generalized adenopathy also may occur.
• Patients often complain of headache.
• A morbilliform or papular erythematous eruption of the upper extremities or trunk accompanies IM in approximately 5% of cases.
• A macular erythematous rash may occur in IM patients who are treated with ampicillin. This usually occurs after 5-9 days of antibiotic treatment, and typically this rash is tan or brownish in color. Since the color is quite different than the typical very red allergic-type rash, this should not be misinterpreted as a penicillin allergy. However, because the shape and distribution of the rash of IM plus antibiotics are similar to an allergic-type rash, they are often confused by patients and clinicians.
• Erythema nodosum and erythema multiforme also have been associated with IM, but these complications are not common.
• Petechiae may occur.
• Jaundice may occur.
• Severe abdominal pain is uncommon in patients with IM, and it should prompt immediate attention to a possible splenic rupture.
• In older adults, nonspecific symptoms (eg, fever, fatigue, myalgia, malaise) predominate, making it difficult to establish a specific diagnosis.

Physical

• Fever usually does not exceed 102°F, but it may be as high as 104°F.
• Pharyngitis often is the most prominent physical finding.
• Tonsillar edema and erythema with a grayish or greenish exudate are common and are clinically indistinguishable from streptococcal pharyngitis.
• Affected lymph nodes usually are symmetrically enlarged, firm, mobile, and tender. The nodes usually do not demonstrate warmth or overlying erythema.
• Splenomegaly is present in most cases of IM, but it may not be appreciated on physical examination.
• Hepatomegaly is found in 10-30% of cases.
• Periorbital edema occurs in 15-35% of patients with IM.
• Petechiae of the palate, occurring at the junction of the hard and soft palate, may occur in up to one third of cases. Petechiae are not pathognomonic, but evidence of them is highly suggestive of IM.
• Jaundice may occur.

Causes

Numerous etiologies exist.

• In more than 90% of cases, IM is secondary to EBV infection.
• Other infectious causes include the following:
• • Adenovirus
  • Cytomegalovirus (CMV)
  • Group A beta-hemolytic streptococci
  • Hepatitis A
  • Human herpes virus
  • Human immunodeficiency virus (HIV)
  • Rubella
  • Toxoplasma gondii
• Noninfectious causes of heterophile negative IM-like syndrome include medications (eg, phenytoin, sulfas) and malignancy (eg, lymphomas, leukemias).
• Risk factors include the following:
• • Being a college or high school student
  • Kissing
  • Blood transfusion

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Cytomegalovirus (CMV)
Rubella
Adenovirus
Drug adverse effects
Streptococcal pharyngitis
Viral tonsillitis
Vincent angina
Viral hepatitis A
Viral hepatitis B
Lymphoma
Leukemia
Human herpes virus 6
Roseola
Drug reactions

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• White blood cell (WBC) count
• • The WBC count and differential can be useful in establishing a diagnosis of IM.
  • WBC count results usually show a modest elevation, with a peak of 10,000-20,000 during the second or third week of the illness.
  • Findings consistent with IM include a differential that demonstrates greater than 50% lymphocytes, an absolute lymphocyte count greater than 4500, or an elevated lymphocyte count with greater than 10% atypical lymphocytes.
• Liver function tests (LFTs) are abnormal in more than 90% of patients with IM.
• • Serum transaminase and alkaline phosphatase levels usually are modestly elevated.
  • The serum bilirubin may be increased in approximately 40% of patients, but jaundice only occurs in approximately 5% of IM cases.

Other Tests

• The heterophile test is the most common and specific test to confirm the diagnosis of IM.
• • Paul and Bunnell first described the presence of heterophile antibody in patients with IM in 1932. The heterophile antibody is an IgM antibody produced by infected B lymphocytes.
  • It is not directed against EBV or EBV-infected cells, but it is a result of the infection and the subsequent transformation of the B cell to a plasmacytoid state.
  • In the heterophile test, human blood is first absorbed by a guinea pig kidney. Then it is tested for agglutination activity that is directed against horse, sheep, or cow erythrocytes. Successive dilutions yield a titer; a titer of 40 or greater is considered a positive test.
  • The heterophile antibody is present in 40-60% of patients with IM in the first week of the illness and in 80-90% of cases by the third or fourth week.
  • Repeated testing may be indicated in patients with the clinical syndrome who tested negative early in the course of the illness. As few as 50% of patients who are younger than 4 years may develop the heterophile antibody.
  • The heterophile response usually persists for 3 months, although it may be present for as long as a year following onset. While the heterophile test is a quantitative assay, the various Monospot tests are qualitative.
  • Monospot tests are slightly more sensitive (85%) than the heterophile assay, but false-positive findings may occur in children or in patients with other viral illnesses.
• EBV specific antibodies
• • While these assays are more expensive and time consuming, they may be indicated in patients with atypical presentation in whom EBV infection is suspected or in patients who present with persistently negative heterophile testing despite a clinical presentation consistent with EBV-related illness.
  • Young children, in particular, usually do not demonstrate heterophile antibodies, and EBV-specific antibodies may be the only serologic markers in such cases.
  • The EBV-specific antibodies are directed against EBV antigens, which develop in a typical time course reflective of the viral replication cycle.
  • These antigens are classified as early, late, or latent, depending on the phase of viral replication in which they appear. They also are differentiated by their location within the infected cells and by their response to methanol treatment.
  • Early antigens (EAs) become detectable 3-4 weeks following the onset of symptoms in approximately 70% of patients, especially those with severe symptoms.
  • Antibodies to these antigens include anti–EA-D antibody, which is found in a diffuse pattern within the cytoplasm and nucleus, and the anti–EA-R antibody, which is restricted to the cytoplasm of infected cells.
  • These antibodies usually persist for 3-6 months. EA-D antibodies are markers for patients with chronic active EBV infection and are prominent in patients with EBV-associated nasopharyngeal carcinomas. EA-R antibodies are less commonly detected in patients with chronic active EBV disease.
  • Viral capsid antigen (VCA) is considered a late phase antigen and represents viral structural protein. Immunoglobulin M (IgM) anti-VCA antibody is detectable at the onset of symptoms and persists for 1-3 months.
  • Immunoglobulin G (IgG) anti-VCA antibody also appears early in the course of the illness and reaches a peak 2-3 months following the outset. It then gradually declines to a steady state level, which persists for life. Antibodies to nuclear antigens (anti-EBNA) are considered latent phase markers.
  • These antibodies appear 3-6 weeks after the onset of disease and persist for life in patients who are immunocompetent. They may be undetectable in patients with chronic active disease.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Emergency Department Care

Treatment of patients with IM generally is supportive, consisting primarily of rest, analgesics, and antipyretics.

• Because of the risk of splenic rupture, health care providers should avoid vigorous abdominal examination and palpation in patients with IM.
• Certain clinical situations may warrant the administration of corticosteroids. Several studies have suggested that corticosteroids may be beneficial to patients with IM, but the routine use of these agents in patients with uncomplicated disease should be avoided because these medications may adversely affect cell-medicated immune responses, thereby increasing the risk of bacterial superinfection.
• • Patients with complications due to IM who may benefit from corticosteroids include those with massive edema of the Waldeyer ring with a potential for airway obstruction, patients with autoimmune hemolytic anemia, or those with severe thrombocytopenia.
  • Other complications that may warrant such therapy include severe involvement of the heart or central nervous system (CNS).

Consultations

Appropriate consultations should be obtained in patients with IM who have significant complications or in cases that present in an atypical fashion, suggesting another serious process.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The treatment of IM is largely supportive except when coexisting complications may indicate the use of corticosteroids.

Drug Category: Corticosteroids

These agents are recommended in patients with severe edema of the Waldeyer ring with potential for airway obstruction, autoimmune hemolytic anemia, severe thrombocytopenia, or significant involvement of the heart or CNS.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admission rarely is necessary in patients with uncomplicated IM.
• Circumstances that warrant inpatient treatment include serious complications, as detailed below.

Further Outpatient Care

• Patients with uncomplicated IM should be advised to avoid participation in contact sports or vigorous exercise for at least one month due to the potential for splenic rupture.
• Routine follow-up care with primary care physicians is recommended to monitor symptomatic improvement and to watch for the development of complications.

Deterrence/Prevention

• The ubiquitous nature of EBV coupled with its typically benign and self-limited course renders deterrence a moot issue.

Complications

• Complications in patients with IM are uncommon but may be serious.
• Airway obstruction may develop in patients with severe inflammation and swelling of the tonsils and adenoids. This complication may occur in 1 of every 100-1000 cases and most often occurs in younger patients with IM. These patients should be identified and admitted. Corticosteroids are indicated in an effort to avoid intubation or the need for a surgical airway. Additionally, the development of peritonsillar abscess or massive retropharyngeal lymphadenopathy secondary to EBV mononucleosis has been reported.
• Splenic rupture is a serious complication of IM, but it occurs in fewer than 0.5% of cases. More than 90% of splenic rupture cases occur in male patients. In rare cases, splenic rupture has been reported in patients without other clinical symptoms of IM.
• CNS complications may occur early in the course, often during the first few weeks of the illness, and may include meningitis, encephalitis, seizures, nerve palsies, cerebellar syndrome, coma, transverse myelitis, and Guillain-Barré syndrome.
• Autoimmune hemolytic anemia is present in approximately 2% of patients with IM.
• Other complications involving the hematologic system include the development of pancytopenia, severe thrombocytopenia, agranulocytopenia, red cell aplasia, and hemolytic-uremic syndrome.
• Ophthalmic complications include conjunctivitis, episcleritis, and uveitis.
• Dermatologic complications include dermatitis, urticaria, and erythema multiforme.
• Other complications include psychosis, malabsorption, glomerulonephritis, nephrotic syndrome, bullous myringitis, orchitis, parotitis, monoarticular arthritis, and jaundice.
• Additional rare complications include cardiac involvement with myocarditis, pericarditis and ECG changes, fulminant hepatic disease, pneumonia, interstitial nephritis, and presentation as a cecal mass.

Prognosis

• Infectious mononucleosis is a self-limited illness. Spontaneous resolution typically occurs in 3-4 weeks.
• While malaise and fatigue may persist for several months, the vast majority of patients fully recover with no significant permanent sequelae.

Patient Education

• Patients diagnosed with IM should be educated as to the expected prognosis and time course of their illness.
• They should be instructed to avoid participation in contact sports and to refrain from vigorous physical activity for at least 1 month in order to minimize the possibility of splenic rupture.
• Routine follow-up care should be arranged to monitor patients for improvement or for the development of symptoms that are suggestive of complications.
• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center and Ear, Nose, and Throat Center. Also, see eMedicine's patient education articles Mononucleosis and Tonsillitis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Correct diagnosis is essential to avoid circumstances that predispose the patient to splenic rupture and to allow appropriate monitoring of patients for the development of other significant complications.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Cohen JI. Epstein-Barr virus infections, including infectious mononucleosis. In: Fauci AS, Braunwald E, Isselbacher KJ, Martin JB, eds. Harrison's Principles of Internal Medicine. 14^th ed. McGraw Hill; 1998:1089-91.
• Cozad J. Infectious mononucleosis. Nurse Pract. Mar 1996;21(3):14-6, 23, 27-8. [Medline].
• Goldacre MJ, Wotton CJ, Seagroatt V, Yeates D. Multiple sclerosis after infectious mononucleosis: record linkage study. J Epidemiol Community Health. Dec 2004;58(12):1032-5. [Medline].
• Haahr S, Plesner AM, Vestergaard BF, Hollsberg P. A role of late Epstein-Barr virus infection in multiple sclerosis. Acta Neurol Scand. Apr 2004;109(4):270-5. [Medline].
• Hickey SM, Strasburger VC. What every pediatrician should know about infectious mononucleosis in adolescents. Pediatr Clin North Am. Dec 1997;44(6):1541-56. [Medline].
• Rosen P, Ling L, Markovchick V, et al. Epstein-Barr virus (infectious mononucleosis). In: Rosen's Emergency Medicine, Concepts and Clinical Practice. 4^th ed. Mosby-Year Book; 1997:2540-2541.
• Szokó M, Matolcsy A, Kovács G, Simon G. Spontaneous splenic rupture as a complication of symptom-free infections mononucleosis. Orv Hetil. Jul 2007;148(29):1381-4. [Medline].
• Keramidas DC, Antoniou D, Marinos L. Infectious mononucleosis manifested as a cecal mass. J Pediatr Surg. Jul 2007;42(7):1295-7. [Medline].

Article Last Updated: Nov 29, 2007