Introduction
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
Epstein-Barr virus (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 infectious mononucleosis. 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 infectious mononucleosis (IM) as a recognizable clinical syndrome due to Epstein-Barr virus (EBV) is estimated at 45 per 100,000 patients.
International
The worldwide incidence of infectious mononucleosis is unknown, but in developing countries, 90% of children experience an asymptomatic Epstein-Barr virus infection when younger than 5 years and are not susceptible to mononucleosis that is associated with Epstein-Barr virus.
Mortality/Morbidity
- Fatalities secondary to infectious mononucleosis (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 Epstein-Barr virus infection as an adult is a risk factor for the development of multiple sclerosis.1,2
- 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 infectious mononucleosis most often is an immunopathologic response to an infection with Epstein-Barr virus. 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 Epstein-Barr virus infection usually present with nonspecific complaints (eg, fever, fatigue, malaise, myalgias).
Clinical
History
- Infectious mononucleosis may have a varied clinical presentation, but the symptoms usually consist of fever, pharyngitis, and lymphadenopathy.
- The incubation period of infectious mononucleosis 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 infectious mononucleosis and admit a history of antecedent prodromal symptoms.
- Abrupt onset of infectious mononucleosis 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 infectious mononucleosis, 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 infectious mononucleosis in approximately 5% of cases.
- A macular erythematous rash may occur in patients with infectious mononucleosis 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 infectious mononucleosis 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 infectious mononucleosis, but these complications are not common.
- Petechiae may occur.
- Jaundice may occur.
- Severe abdominal pain is uncommon in patients with infectious mononucleosis, 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 in infectious mononucleosis, 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 infectious mononucleosis, 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 infectious mononucleosis.
- 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 infectious mononucleosis.
- Jaundice may occur.
Causes
Numerous etiologies exist.
- In more than 90% of cases, infectious mononucleosis is secondary to Epstein-Barr virus (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 infectious mononucleosis – 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
More on Mononucleosis |
 Overview: Mononucleosis |
| Differential Diagnoses & Workup: Mononucleosis |
| Treatment & Medication: Mononucleosis |
| Follow-up: Mononucleosis |
| References |
| Next Page » |
References
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].
Szoko M, Matolcsy A, Kovacs 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].
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. 14th ed. McGraw Hill; 1998:1089-91.
Cozad J. Infectious mononucleosis. Nurse Pract. Mar 1996;21(3):14-6, 23, 27-8. [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. 4th ed. Mosby-Year Book; 1997:2540-2541.
Further Reading
Keywords
infectious mononucleosis, IM, Epstein-Barr virus, EBV, Herpesviridae, tonsillitis, lymphadenopathy, hepatomegaly, splenomegaly, hepatosplenomegaly, African Burkitt lymphoma, nasopharyngeal cancers, hepatic failure, myocarditis, edema of the Waldeyer ring, meningitis, encephalitis, hemiplegia, psychosis, cranial nerve palsies, Guillain-Barré syndrome, transverse myelitis, peripheral neuritis, autoimmune hemolytic anemia, pancytopenia, red cell aplasia, severe thrombocytopenia, agranulocytopenia, papular erythematous eruption, macular erythematous rash, erythema nodosum, erythema multiforme, petechiae, adenovirus, cytomegalovirus, CMV, group A beta-hemolytic streptococci, hepatitis A, human herpes virus, human immunodeficiency virus, HIV, rubella, Toxoplasma gondii, lymphomas, leukemias
