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Infectious mononucleosis

Author: Dr Sarah Hill, Dermatology Registrar, Waikato Hospital, Hamilton, New Zealand, 2007. Updated by Dr Catherine Tian, House Officer Auckland City Hospital. DermNet New Zealand Editor in Chief: Associate A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Medical Editor: Dr Helen Gordon, Auckland, New Zealand. Copy edited by Gus Mitchell. August 2020.

Infectious mononucleosis — codes and concepts

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What is infectious mononucleosis?

Infectious mononucleosis is a common infectious disease caused by Epstein-Barr virus (EBV). It is also more commonly known as glandular fever.

Who gets infectious mononucleosis?

Infectious mononucleosis typically affects young adults aged 15–25 years [1]. It is equally common in both sexes and affects all races [1–2]. Up to nearly 95% of people have had EBV infection by the time they are adults. The disease occurs worldwide with no seasonal predilection [3].

What causes infectious mononucleosis?

EBV is a human herpes type 4 DNA virus. EBV is implicated in a wide range of human diseases, many of which have mucocutaneous manifestations that can be acute or chronic.

How is infectious mononucleosis transmitted?

EBV is passed from person to person by saliva through intimate contacts such as kissing, or via objects such as a toothbrush or drinking glass. The virus survives on an object while it remains moist. EBV can also be spread through blood and semen during sexual contact, blood transfusion, organ transplantation, and other procedures [3].

What are the clinical features of infectious mononucleosis?

The clinical manifestations of infection are dependent on the interaction between virus and host immune system. The incubation period from contact until symptoms is usually 1–2 months [6].

Primary infection with EBV

Primary infection with EBV starts with a prodromal phase of low-grade fever, malaise, arthralgia, and myalgia. Tonsillitis and pharyngitis (frequently accompanied by enlarged tonsils with pus), cervical lymphadenopathy, fever, leukocytosis, and hepatosplenomegaly may follow 4–6 weeks later.

Infectious mononucleosis can cause wide-ranging symptoms (see below), which can persist for up to 4 months [4–7].


  • Splenomegaly (enlarged spleen), typically in the second and third weeks
  • Associated abdominal pain or discomfort


  • Arthritis in one or more joints


  • Glomerulonephritis

Nervous system

  • Aseptic meningitis
  • Facial palsy
  • Transverse myelitis
  • Peripheral neuritis, optical neuritis
  • Cerebellitis
  • Guillain-Barré syndrome
  • Meningoencephalitis

Gastrointestinal tract

  • Hepatomegaly
  • Hepatitis with or without elevated transaminase, and or hyperbilirubinemia (causing jaundice)


  • Airway obstruction
  • Interstitial pneumonia


  • Pericarditis


Blood system

What are the cutaneous features of infectious mononucleosis?

The typical exanthem of mononucleosis is an acute and generalised maculopapular eruption.

  • It affects 4.2 to 13% of patients who are not on antibiotics [4].
  • It usually presents as a faint, widespread, and non-itchy rash, appearing first on the trunk and upper arms, extending to involve the face and forearms.
  • The rash may also be morbilliform, papular, scarlatiniform, vesicular, or purpuric [5,6].
  • It resolves after about a week [6].

A more intense and extensive cutaneous eruption arises in 27–90% of patients with infectious mononucleosis 2–10 days after starting antibiotics [7]. These include ampicillin, amoxicillin, cephalosporins, tetracyclines, and macrolides such as erythromycin [7–15]

  • The drug eruption is an itchy maculopapular or morbilliform rash
  • It affects extensor surfaces and pressure points, face, neck, trunk, palms, and soles
  • It can involve the mucous membranes [12]
  • The rash usually resolves within a week of discontinuing the antibiotic.

The exact mechanisms of antimicrobial rash in infectious mononucleosis remain unclear. The virus is thought to induce loss of tolerance by the immune system, resulting in a hypersensitivity reaction to the drug [9,10]. Drug allergy is usually transient [16]. However, re-exposure to the antibiotic may sometimes result in recurrence of rash years later [12].

Skin signs of EBV infection

Latent EBV

Following the acute symptomatic phase, EBV persists in memory B cells in the tonsils and peripheral circulation of the infected host in a latent non-lethal carrier state throughout life [2,3].

How is infectious mononucleosis diagnosed?

The clinical features and a positive heterophile test are usually sufficient to diagnose infectious mononucleosis.

The heterophile antibodies (Monospot)

  • Heterophile antibodies are usually positive 2–9 weeks after infection; the sensitivity is 70–92% in the first two weeks [13–14].
  • They can persist for a year or more.
  • Approximately 40% of children < 4 years of age do not develop heterophile antibodies following primary EBV infection [14].
  • They are nonspecific and may be present in other infections, malignancies, and autoimmune diseases.

Other blood tests

  • Lymphocyte levels are increased with at least 10% being atypical (other viral infections tend to have reduced lymphocytes) [14,15].
  • Immunoglobulin (Ig)M to viral capsid antigen (VCA) during the active phase of infectious mononucleosis is found in 75% of patients and usually disappears within 4–6 weeks [14].
  • VCA IgG antibodies reach a maximum about 2–4 weeks after the onset of symptoms and then decline slightly. They can persist lifelong [13,14].
  • Other tests evaluate EBV early antigen (EA) and nuclear antigen (EBNA) [14,15].
  • High EBV loads are found by polymerase chain reaction (PCR) in the oral cavity and blood during the acute cell lytic phase [15].
  • Liver function tests often show elevated transaminase levels.
  • Other tests will depend on which organs are affected by the infection.


Abdominal ultrasonography can evaluate splenomegaly.

What is the differential diagnosis for infectious mononucleosis?

The main differential diagnoses of acute infectious mononucleosis are [3]:

Other differential diagnoses include streptococcal pharyngitis, leukaemia, tonsillitis, diphtheria, the common cold, influenza, and COVID-19.

What is the treatment for infectious mononucleosis?

Treatment options for infectious mononucleosis are typically supportive in nature, such as:

Less common treatment options include:

  • Antiviral drugs, such as aciclovir or valaciclovir, are not used or useful for uncomplicated cases of infectious mononucleosis. They are sometimes prescribed for EBV meningitis, peripheral neuritis, hepatitis, or for haematological complications [1–3].
  • Antibiotics may be prescribed to treat confirmed secondary bacterial infection [10].

Can be infectious mononucleosis prevented?

There is currently no vaccine to protect against EBV infection. Prevention involves social hygiene, avoiding sharing drinks, food, or personal items.

What is the prognosis of infectious mononucleosis?

Recovery from the acute phase of the initial EBV infection in healthy and immunocompetent individuals is generally complete in a few weeks, but it can take up to several months to feel completely well again. Prolonged lethargy and tiredness are common [1,2].

EBV causes life-long infection as the virus remains dormant in B lymphocytes. Intact immune response prevents progressive disease due to EBV. However, immune suppression or another illness has the potential to reactivate the virus causing vague and subclinical symptoms and, rarely, aggressive disease. During this phase, the virus can be spread to others.

What are the other diseases caused by Epstein-Barr virus?

Other skin manifestations of EBV infection include [4–6]:

Other diseases associated with EBV include:

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Related information



  1. Luzuriaga K, Sullivan JL. Infectious Mononucleosis. N Engl J Med 2010; 362: 1993–2000. DOI: 10.1056/NEJMcp1001116. Journal
  2. Cohen J, Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. (eds). Epstein-Barr Infections, Including Infectious Mononucleosis. Harrison’s Principles of Internal Medicine (17th ed.) 380–91. New York: McGraw-Hill Medical Publishing Division.
  3. Eminger LA, Hall LD, Hesterman KS, Heymann WR. Epstein-Barr virus: dermatologic associations and implications: part II. Associated lymphoproliferative disorders and solid tumors. J Am Acad Dermatol. 2015;72(1):21-36. doi:10.1016/j.jaad.2014.07.035. PubMed
  4. Ikediobi NI, Tyring SK. Cutaneous manifestations of Epstein-Barr virus infection. Dermatol Clin. 2002;20(2):283-89. doi:10.1016/s0733-8635(01)00014-6. PubMed
  5. Balfour HH Jr, Holman CJ, Hokanson KM, et al. A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis. J Infect Dis. 2005;192(9):1505–12. doi:10.1086/491740. PubMed
  6. Dunmire SK, Hogquist KA, Balfour HH. Curr Top Microbiol Immunol. 2015;390:211–40. doi:10.1007/978-3-319-22822-8_9. PubMed Central
  7. Ebell MH. Epstein-Barr virus infectious mononucleosis. Am Fam Physician. 2004;70(7):1279-1287. PubMed
  8. Renn CN, Straff W, Dorfmüller A, Al-Masaoudi T, Merk HF, Sachs B. Amoxicillin-induced exanthema in young adults with infectious mononucleosis: demonstration of drug-specific lymphocyte reactivity. Br J Dermatol. 2002;147(6):1166-1170. doi:10.1046/j.1365-2133.2002.05021.x. PubMed
  9. Banerjee I, Mondal S, Sen S, Tripathi SK, Banerjee G. Azithromycin-induced rash in a patient of infectious mononucleosis - a case report with review of literature. J Clin Diagn Res. 2014;8(8):HD01-HD2. doi:10.7860/JCDR/2014/9865.4729. PubMed
  10. Renn CN, Straff W, Dorfmüller A, Al-Masaoudi T, Merk HF, Sachs B. Amoxicillin-induced exanthema in young adults with infectious mononucleosis: demonstration of drug-specific lymphocyte reactivity. Br J Dermatol. 2002;147(6):1166-1170. doi:10.1046/j.1365-2133.2002.05021.x. PubMed
  11. Carlson JA, Perlmutter A, Tobin E, Richardson D, Rohwedder A. Adverse antibiotic-induced eruptions associated with epstein barr virus infection and showing Kikuchi-Fujimoto disease-like histology. Am J Dermatopathol. 2006;28(1):48-55. doi:10.1097/ PubMed
  12. Chovel-Sella A, Ben Tov A, Lahav E, et al. Incidence of rash after amoxicillin treatment in children with infectious mononucleosis. Pediatrics. 2013;131(5):e1424-e1427. doi:10.1542/peds.2012-1575. PubMed
  13. Zsuzsanna, K. O.-N., & Varga, B.-C. E. (2015). Antibiotic induced cutaneous rash in infectious mononucleosis: overview of the literature. J Allergy Ther 2015;6:5. DOI: 10.4172/2155-6121.1000222 doi:10.4172/2155-6121.1000222. Journal
  14. Leung AK, Rafaat M. Eruption associated with amoxicillin in a patient with infectious mononucleosis. Int J Dermatol. 2003;42(7):553-555. doi:10.1046/j.1365-4362.2003.01699_1.x. PubMed
  15. Andersen Lund BM, Bergan T. Temporary skin reactions to penicillins during the acute stage of infectious mononucleosis. Scand J Infect Dis. 1975;7(1):21-28. doi:10.3109/inf.1975.7.issue-1.04. PubMed

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