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What is infectious mononucleosis?
Infectious mononucleosis is a common infectious disease caused by Epstein-Barr virus (EBV). It is more commonly known as glandular fever.
Who gets infectious mononucleosis?
Infectious mononucleosis typically affects young adults aged 15–25 years. It is equally common in both sexes and affects all races. Up to nearly 95% of people have had EBV infection by the time they are adults. The disease occurs worldwide with no seasonal predilection.
What causes infectious mononucleosis?
Infectious mononucleosis is a contagious viral infection usually caused by EBV (human herpesvirus-4, HHV4), a gamma-herpesviridae DNA virus. EBV is implicated in a wide range of human diseases, many of which have mucocutaneous manifestations that can be acute or chronic.
Infectious mononucleosis can also be caused by cytomegalovirus (CMV) particularly in an older age group than the EBV-related patients.
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. Spread to children is presumed to be from parents or siblings who carry EBV and shed the virus intermittently.
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 6-7 weeks.
Primary infection with EBV
Infectious mononucleosis presents typically in 75% of young adults; 15% have an atypical presentation, and infection in 10% is asymptomatic. Children are often asymptomatic or presumed to have a non-specific viral infection.
There are two typical presentations:
- abrupt onset of severe sore throat with cervical lymphadenopathy
- gradual onset of low-grade fever, malaise, arthralgia, and myalgia.
Spleen and liver
- Splenomegaly (enlarged spleen), typically in the second and third weeks
- Associated abdominal pain or discomfort
- Hepatomegaly is rarely clinically palpable although is often detected on ultrasound
- Elevation of liver transaminases are common in up to 50%
- Overt hepatitis with jaundice and tender hepatomegaly occurs in 5-10%
- Older adults are more likely to develop hepatomegaly and jaundice than adolescents.
- Arthritis in one or more joints
- Aseptic meningitis
- Facial palsy
- Transverse myelitis
- Peripheral neuritis, optical neuritis
- Guillain-Barré syndrome
- Airway obstruction
- Interstitial pneumonia
- Periorbital and eyelid oedema (Hoagland sign)
- Autoimmune haemolytic anaemia
- Haemolytic uraemic syndrome
- Disseminated intravascular coagulation
- Cold agglutinins
- Aplastic anaemia
- Lymphoproliferative and other autoimmune haematological diseases.
What are the mucocutaneous features of infectious mononucleosis?
The typical exanthem of infectious mononucleosis is an acute, generalised maculopapular rash. The exanthem:
- Affects 4.2 to 13% of patients who are not on antibiotics
- Is usually faint and non-itchy, appearing first on the trunk and upper arms, extending to involve the face and forearms
- May be morbilliform, papular, scarlatiniform, vesicular, or purpuric
- Resolves after about a week.
A more intense and extensive cutaneous eruption appears in up to 90% of patients with infectious mononucleosis 2–10 days after starting antibiotics. These include ampicillin, azithromycin, amoxicillin, cephalosporins, tetracyclines, and macrolides such as erythromycin. Recent studies suggest the actual rate of this antibiotic rash is much lower than previously reported.
- 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.
- The rash usually resolves within a week of discontinuing the antibiotic.
The drug allergy is usually transient. However, re-exposure to the antibiotic may sometimes result in recurrence of rash years later.
Palatal petechiae are found on the hard and soft palate in 50% of young adults in the first few days of the illness.
Cholestatic jaundice due to liver involvement is itchy, resulting in excoriations and bruising.
Other less commonly reported skin signs of infectious mononucleosis include immune thrombocytopenic purpura, cold urticaria, and erythema nodosum.
Skin signs of infectious mononucleosis
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. Virus can be shed intermittently and infection may reactivate.
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 become positive 2–9 weeks after infection; the sensitivity is 70–92% in the first two weeks.
- 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.
- Heterophile antibodies 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.
- 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.
- VCA IgG antibodies reach a maximum about 2–4 weeks after the onset of symptoms and then decline slightly. They can persist lifelong.
- Other tests evaluate EBV early antigen (EA) and nuclear antigen (EBNA).
- High EBV loads are found by polymerase chain reaction (PCR) in the oral cavity and blood during the acute cell lytic phase.
- Liver function tests often show elevated transaminase levels.
- Other tests will depend on which organs are affected by the infection.
Abdominal ultrasonography can evaluate hepatosplenomegaly.
What is the differential diagnosis for infectious mononucleosis?
The main differential diagnoses of acute infectious mononucleosis are:
- Acute cytomegalovirus (CMV) infection
- Adenovirus infection
- Acute human immunodeficiency virus (HIV) infection.
Other differential diagnoses include streptococcal pharyngitis (which may co-exist), 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:
- Bed rest
- Adequate hydration
- Analgesics such as paracetamol and non-steroidal anti-inflammatory drugs (NSAID)
- Intravenous corticosteroids for airway obstruction, thrombocytopenia, or haemolytic anaemia.
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.
- Antibiotics may be prescribed to treat confirmed secondary bacterial infection.
Can be infectious mononucleosis prevented?
There is currently no vaccine to protect against EBV infection. Prevention involves social hygiene, and avoiding the sharing of drinks, food, or personal items.
What are the complications of infectious mononucleosis?
Infectious mononucleosis complications include:
- Group A beta-haemolytic streptococcal pharyngitis
- Peritonsillar abscess
- Rupture of the spleen – athletes are advised to avoid sport in the first three weeks of illness
- Chronic active EBV infection – recurrent or persistent symptoms resembling infectious mononucleosis seen predominantly in Asian children. Life-threatening complications can occur.
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 several months to feel completely well again. Prolonged lethargy, tiredness, and joint pain are common, often lasting 6 months or more.
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 other diseases can be caused by Epstein-Barr virus?
Other skin manifestations of EBV infection include:
- Papular acrodermatitis of childhood (Gianotti-Crosti syndrome)
- Erythema multiforme
- Erythema nodosum
- Urticaria, including cold urticaria
- Urticarial vasculitis
- Annular erythema
- Pityriasis lichenoides
- Hand dermatitis
- Reactive genital ulceration (Lipschütz ulcers)
- Linear IgA bullous dermatosis (chronic bullous disease of childhood)
- Oral hairy leukoplakia
- Hydroa vacciniforme
- EBV associated lymphoproliferative disorders including EBV positive mucocutaneous ulcer, lymphomatoid granulomatosis, EBV-positive diffuse large B-cell lymphoma, not otherwise specified
- Drug-induced hypersensitivity syndrome
Other diseases associated with EBV include:
- Burkitt lymphoma
- Non-Hodgkin lymphoma
- Hodgkin lymphoma
- Nasopharyngeal carcinoma
- T-cell lymphoma
- Nasal type angiocentric lymphoma.