Synonym: glandular fever

Infectious mononucleosis (IM) is usually a self-limiting infection, most often caused by Epstein-Barr virus (EBV), which is a human herpes virus. However, approximately 10% of those with IM are not acutely infected with EBV and many of these have symptoms attributable to cytomegalovirus (CMV) infection.¹ IM is particularly common in adolescents and children.²

Epidemiology

• Clinical infection is most common in populations with many young adults, such as active-duty military personnel and college students.³
• The incidence of infectious mononucleosis (IM) shows no consistent seasonal peak.³
• The incubation period is between 1 and 2 months.⁴

Presentation

Most patients have few, if any, symptoms (most adults show serological evidence of previous Epstein-Barr virus (EBV) infection):

• Low-grade fever, fatigue and prolonged malaise. Fatigue and malaise may persist for several months after the acute infection has resolved.³
• Sore throat; tonsillar enlargement is common, classically exudative, and may be massive; palatal petechiae and uvular oedema.
• Fine macular non-pruritic rash, which rapidly disappears.
• Transient bilateral upper lid oedema.
• Lymphadenopathy, especially neck glands.
• Nausea and anorexia.
• Arthralgias and myalgias occur but are less common than in other viral infectious diseases and are rarely severe.
• Other symptoms include cough, chest pain and photophobia.
• Older adults and elderly patients often have few throat symptoms or signs and have little or no lymphadenopathy.
• Later signs include:
  • Mild hepatomegaly and splenomegaly (splenic enlargement returns to normal or near normal usually within three weeks after the clinical presentation) with tenderness over the spleen.
  • Jaundice occurs in fewer than 10% of young adults, but in as many as 30% of infected elderly patients.

Differential diagnosis

• Exudative pharyngitis is commonly confused with group A streptococcal pharyngitis.
• Bilateral periorbital oedema without generalised oedema may also be due to Kawasaki disease, allergic reactions or bilateral periorbital cellulitis.
• Other causes of prominent lymphadenopathy (see also separate article Neck Lumps and Bumps), including leukaemia, cancers of the head and neck and lymphomas.
• Atypical lymphocytes must be differentiated from abnormal lymphocytes, which are associated with lymphoreticular malignancies. Atypical lymphocytes are associated with various viral and non-infectious diseases, as well as drug reactions.⁴
• Other causes of abnormal liver function tests.
• Patients with negative Paul-Bunnell or Monospot® reactions for six weeks and those with a negative Epstein-Barr virus (EBV)-specific test result, should be tested for the causes of heterophile-negative infectious mononucleosis (IM). A growing number of pathogens have been associated with heterophile-negative mononucleosis-like illnesses, e.g. CMV, rubella, human herpesvirus 6, HIV infection, adenovirus, herpes simplex virus, Streptococcus pyogenes, and Toxoplasma gondii.⁵

Investigations⁴

Epstein-Barr virus (EBV) infectious mononucleosis (IM) can be diagnosed using a variety of unrelated non-EBV heterophile antibodies and specific EBV antibodies.

Heterophile antibodies

Following IM caused by EBV, 85-90% of patients produce IM heterophile antibodies (antibodies against an antigen produced in one species that react against antigens from other species). The heterophile antibodies are not specific for the virus. These antibodies can be detected by:

• Paul-Bunnell test: sheep red blood cells agglutinate in the presence of heterophile antibodies.
• Monospot® test: horse red blood cells agglutinate on exposure to heterophile antibodies. The Monospot® uses this in conjunction with the principle of the Davidsohn differential test. Sensitivity and specificity for Monospot® are 85% and 100% respectively.⁴

Positivity increases during the first six weeks of the illness and so the heterophile antibody test results may be negative early in the course of EBV IM. The titre does not correlate with the severity of the disease. Agglutinins usually remain in the blood for 4 to 8 weeks but may remain positive in low levels for up to one year.

False-positive results

Although virtual 100% specificity exists with the Monospot® test, other disorders may rarely produce a false-positive result:⁴

• Infection, e.g. toxoplasmosis, rubella, cytomegalovirus (CMV), HIV, herpes simplex virus, malaria, viral hepatitis.
• Malignancy, e.g. lymphomas (particularly Burkitt's lymphoma), leukaemias, cancer of the pancreas.
• Connective tissue diseases, e.g. rheumatoid arthritis, systemic lupus erythematosus.

False-negative results

• May occur if testing is performed too early in the course of the illness. The false-negative rate is as high as 25% in the first week of infection, 5-10% in the second week, and 5% in the third week of infection.³
• Heterophile antibody tests are less sensitive in patients younger than 12 years.³ False-negative results are particularly common in children aged younger than two years. One study found fewer than half of children aged under four to have detectable heterophile antibodies at any time.⁶
• False-negative results are also more likely to occur in elderly patients.⁴

EBV-specific antibodies

• Patients who remain heterophile negative after six weeks with a mononucleosis illness are considered to be heterophile-negative IM and should be tested for EBV-specific antibodies.⁴
• EBV-specific antibody tests may also be useful if a false-positive heterophile antibody test result is suspected.³ Patients who are heterophile-positive but specific antibody negative should be considered for testing for possible causes of false-positive heterophile-antibodies (see list of causes under 'False-positive results', above).
• The antibody response to specific EBV serological testing consists of measuring the antibody response to surface and core EBV viral proteins. The most useful EBV-specific antibodies are the viral capsid antigens (VCAs) and the EBV nuclear antigen (EBNA):⁷
  • There is a high (90%) agreement between the heterophile antibody tests and the VCA-IgM ELISA, but the VCA-IgM ELISA is more sensitive.⁸
  • IgM antibodies directed against the VCA of EBV are useful in differentiating recent infection from previous infection. Following acute infection, the increase in IgM levels peaks after 4-8 weeks and IgM usually remains positive for as long as one year.
  • Antibodies to EBNA are usually not detectable until six to eight weeks after the onset of symptoms but can help to establish whether infection is recent.
• EBV IgG VCA antibodies rise later than the IgM VCA antibodies but remain elevated with variable titres for life.
• Persistent IgG does not indicate chronic IM and is not relevant in the assessment of chronic fatigue syndrome.⁹
• False-positive VCA antibody titre results may occur with other herpes viruses, e.g. CMV, or with unrelated organisms, e.g. Toxoplasma gondii. However, false-positive cross-reactivity to specific EBV antibodies is very rare.⁴
• There may be false-negative results early in the course of the infection and in young children (less than two years old).

Other investigations

• FBC: raised white cell count with lymphocytosis and a relative atypical lymphocyte count greater than 20%. Thrombocytopenia may occur.
• ESR: the ESR is elevated in most patients with infectious mononucleosis (IM) but is not elevated with group A streptococcal pharyngitis.
• LFTs: mild elevation of the serum transaminases (higher increases in serum transaminase levels suggests viral hepatitis).
• Throat swabs: growth of group A streptococci does not identify the cause of the pharyngitis; 30% of patients with IM have group A streptococcus in the oropharynx.
• Abdominal ultrasound may be required to assess for splenomegaly.
• Other investigations may be required to differentiate from other possible diagnoses, e.g. lumbar puncture if there is meningism. Abdominal ultrasound may be required to assess for splenomegaly.

Associated diseases

Epstein-Barr virus (EBV) is also associated with:

• Burkitt's lymphoma.
• B-cell lymphomas in patients with immunosuppression.
• Undifferentiated carcinomas, e.g. cancer of nasopharynx and cancer of salivary glands.
• Duncan's syndrome: rare, X-linked recessive; defective T cells fail to destroy EBV-infected cells; associated development of autoimmune disease and lymphoma.

Management

It is not recommended that affected children need to be excluded from schools and other childcare settings unless appropriate for their own wellbeing.¹⁰

• Advise patients to avoid contact sports for three weeks - because of the risk of splenic rupture.⁴
• Avoid alcohol for the duration of the illness.
• Advise paracetamol for analgesia and control of fever.
• No specific antiviral therapy is available.
• There is insufficient evidence to recommend steroid treatment for symptom control in infectious mononucleosis (IM).¹¹ Short courses of corticosteroids are beneficial for haemolytic anaemia, central nervous system involvement or extreme tonsillar enlargement.
• Ampicillin and amoxicillin cause an itchy maculopapular rash and should not be given in any patient who might have IM.
• Patients may require hospital admission for intravenous fluids.
• Surgery is usually advocated for spontaneous splenic rupture but non-operative management may be appropriate.¹²

Complications

• Extreme tonsillar enlargement may result in upper airway obstruction.
• Myocarditis and cardiac conduction abnormalities are rare complications.
• Splenic rupture is rare but potentially lethal.¹² Splenectomy increases susceptibility to various infections.
• Haemolytic anaemia, thrombocytopenia.
• Acute interstitial nephritis, glomerulonephritis.
• Neurological, including optic neuritis, transverse myelitis, aseptic meningitis, encephalitis, meningoencephalitis, cranial nerve palsies (especially facial palsy) or Guillain-Barré syndrome.
• Prolonged fatigue; depression.

Prognosis

• Usually asymptomatic or short duration and self-limiting.
• Fatigue and myalgia may persist for several, or even many, months after the acute infection has resolved.³
• If splenic rupture is recognised and surgery performed quickly, the prognosis is good.

Document references

1. Bravender T; Epstein-Barr virus, cytomegalovirus, and infectious mononucleosis. Adolesc Med State Art Rev. 2010 Aug;21(2):251-64, ix. [abstract]
2. Cohen JI; Epstein-Barr virus infection. N Engl J Med. 2000 Aug 17;343(7):481-92.
3. Ebell MH; Epstein-Barr virus infectious mononucleosis. Am Fam Physician. 2004 Oct 1;70(7):1279-87. [abstract]
4. Cunha BA; Infectious Mononucleosis, Medscape, Oct 2009
5. Hurt C, Tammaro D; Diagnostic evaluation of mononucleosis-like illnesses. Am J Med. 2007 Oct;120(10):911.e1-8. [abstract]
6. Sumaya CV, Ench Y; Epstein-Barr virus infectious mononucleosis in children. II. Heterophil antibody and viral-specific responses. Pediatrics. 1985 Jun;75(6):1011-9. [abstract]
7. Bell AT, Fortune B, Sheeler R; Clinical inquiries. What test is the best for diagnosing infectious J Fam Pract. 2006 Sep;55(9):799-802. [abstract]
8. Sumaya CV; Serologic and virologic epidemiology of Epstein-Barr virus: relevance to chronic fatigue syndrome. Rev Infect Dis. 1991 Jan-Feb;13 Suppl 1:S19-25. [abstract]
9. Myrmel H; Comparison of tests for heterophile antibodies with a test for specific IgM-antibodies to Epstein-Barr virus. Brief report. APMIS. 1988 Mar;96(3):280-1. [abstract]
10. Guidance on Infection Control in Schools and other Childcare Settings, Health Protection Agency (April 2010)
11. Candy B, Hotopf M; Steroids for symptom control in infectious mononucleosis. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004402. [abstract]
12. Brichkov I, Cummings L, Fazylov R, et al; Nonoperative management of spontaneous splenic rupture in infectious Am Surg. 2006 May;72(5):401-4. [abstract]