Infectious mononucleosis

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. EBV (human herpesvirus 4) causes approximately 80-90% of cases of glandular fever, with the remainder due largely to cytomegalovirus, human herpesvirus 6, toxoplasmosis, HIV and adenovirus¹.

Epidemiology¹

• The annual incidence is approximately 5 cases per 1,000 persons. Over 95% of adults worldwide have been infected with EBV.

• Clinical infection is most common in populations with many young adults, such as active-duty military personnel and college students².

• Glandular fever is rare during the first year of life because of passive immunity received from maternal antibodies.

• Glandular fever is less commonly seen in developing countries.

• There is no seasonal variation or any male or female predisposition.

Presentation¹

The incubation period is four to eight weeks³.

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

• Low-grade fever, fatigue and prolonged malaise. Fatigue and malaise may persist for several months after the acute infection has resolved.

• 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.

• Arthralgia and myalgia 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 a minority of young adults but is more common in infected elderly patients.

Differential diagnosis

• Exudative pharyngitis is commonly confused with group A streptococcal pharyngitis. In one study of adolescent and adult patients presenting with sore throat, the presence of posterior cervical, inguinal or axillary adenopathy, palatine petechiae, splenomegaly, or atypical lymphocytosis was associated with an increased likelihood of mononucleosis⁴.

• 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 the separate Neck Lumps and Bumps article), 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 reactions¹⁵.

• Other causes of abnormal LFTs.

• Patients with negative Paul-Bunnell or Monospot® reactions for six weeks and those with a negative EBV-specific test result, should be tested for the causes of heterophile-negative IM. A growing number of pathogens have been associated with heterophile-negative mononucleosis-like illnesses - eg, CMV, rubella, human herpesvirus 6, HIV infection, adenovirus, herpes simplex virus, Streptococcus pyogenes and Toxoplasma gondii .
  

Investigations¹

• Children younger than 12 years, and immunocompromised at any age: check EBV viral serology after the person has been ill for at least 7 days.

• Children older than 12 years of age and immunocompetent adults: full blood count with differential white cell count and a monospot test (heterophile antibodies) in the 2nd week of the illness.

• Glandular fever is likely if monospot test positive or the FBC has more than 20% atypical or 'reactive' lymphocytes, or more than 10% atypical lymphocytes and the lymphocyte count is more than 50% of the total white cell count.

• If monospot test negative or not supportive of infectious mononucleosis due to EBV, repeat the test in 5–7 days.

• If clinical features of glandular fever and negative monospot test, or if a rapid diagnosis needed (eg urgent return to contact sports desired), arrange blood tests for EBV viral serology.

• If a second monospot test is negative:

  • Consider testing for CMV and toxoplasmosis if person is pregnant or immunocompromized.

  • Consider testing for HIV in at-risk people.

• Consider checking liver function tests (LFTs). Usually aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are elevated to 2–3 times the upper limit of normal.

EBV IM can be diagnosed using a variety of unrelated non-EBV heterophile antibodies and specific EBV antibodies.

Heterophile antibodies

Following IM caused by EBV, 70-90% 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 by⁶:

• 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 70-90% and 100% respectively.

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 4-8 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 result⁷:

• Infection - eg, toxoplasmosis, rubella, CMV, HIV, herpes simplex virus, malaria, viral hepatitis.

• Malignancy - eg, lymphomas (particularly Burkitt's lymphoma), leukaemias, cancer of the pancreas.

• Connective tissue diseases - eg, 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 infection⁸.

• Heterophile antibody tests are less sensitive in patients aged younger than 10 years. False negative results are particularly common in children aged younger than 2 years. 40% of children aged 4 years or younger do not have detectable heterophile antibodies at any time during EBV infection⁹.

EBV-specific antibodies⁶

• 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.

• EBV-specific antibody tests may also be useful if a false positive heterophile antibody test result is suspected⁸. 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)⁶:
  

  • There is a high agreement between the heterophile antibody tests and the VCA-IgM ELISA but the VCA-IgM ELISA is more sensitive.

  • 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 6-8 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 syndrome¹⁰.

• False positive VCA antibody titre results may occur with other herpes viruses (eg, CMV) or with unrelated organisms (eg, T. gondii). However, false-positive cross-reactivity to specific EBV antibodies is very rare⁶.

• There may be false negative results early in the course of the infection and in young children (aged less than 2 years).

Other investigations

• A real-time polymerase chain reaction identifying IM DNA has been developed. This may be useful in cases of diagnostic doubt or where rapid diagnosis is helpful, such as in patients with a high risk of splenic rupture¹¹.

• 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 IM but is not elevated with group A streptococcal pharyngitis.

• LFTs: mild elevation of the serum transaminases (higher increases in serum transaminase levels suggest 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 - eg, lumbar puncture if there is meningism. Abdominal ultrasound may be required to assess for splenomegaly.

Associated diseases

EBV is also associated with:

• Burkitt's lymphoma.

• B-cell lymphomas in patients with immunosuppression.

• Undifferentiated carcinomas - eg, cancer of the nasopharynx and cancer of the 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.

• Multiple sclerosis³.

Management

It is not recommended that affected children need to be excluded from schools and other childcare settings unless appropriate for their own well-being¹².

• Patients are traditionally advised to avoid contact sports for three weeks because of the risk of splenic rupture. An ultrasound study of 19 patients found that in 16 splenomegaly resolved in four weeks but in three it took eight weeks. The authors recommended that advice should be guided by ultrasound findings and this should perhaps be considered in patients who regularly participate in such sports¹³.

• 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 IM¹⁴. Short courses of corticosteroids are beneficial for haemolytic anaemia, central nervous system involvement or extreme tonsillar enlargement.

• There has been interest in the use of antivirals such as aciclovir and valaciclovir in the treatment of IM but to date trials have been unpromising³.

• 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 appropriate³.

• One study of military personnel suggested a role for vitamin D in shortening recovery times in patients with acute pharyngitis associated with infectious mononucleosis².

Complications

• Extreme tonsillar enlargement may result in upper airway obstruction.

• Myocarditis and cardiac conduction abnormalities are rare complications.

• Splenic rupture is rare but potentially lethal¹⁵. Splenectomy increases susceptibility to various infections.

• Haemolytic anaemia, thrombocytopenia.

• Acute interstitial nephritis, glomerulonephritis.

• Neurological, including optic neuritis, transverse myelitis, aseptic meningitis, encephalitis and meningoencephalitis, cranial nerve palsies (especially facial palsy) or Guillain-Barré syndrome.

• Prolonged fatigue; depression.

Prognosis¹

• Glandular fever is usually self limiting and lasts 2-4 weeks. Occasionally the disease course can be prolonged and lasting for many weeks or months.

• Fatigue usually lasts for a few weeks, but may persist for several months in a minority.

• EBV infection leads to a lifelong latent carrier state. The virus may reactivate but does not always cause symptoms. People who are immunocompromised are more likely to develop symptoms if EBV reactivates.