Approach
IM may develop in people with a primary Epstein-Barr virus (EBV) infection, but this is not universal and depends on age of acquisition and other host factors. Diagnosis is confirmed by the classic presentation of fever, pharyngitis, and lymphadenopathy, along with atypical lymphocytosis, a positive agglutination test for heterophile antibodies, and a positive serological test for EBV-specific antibodies.General practitioners play an important role in the diagnosis of IM as they encounter the vast majority of patients with EBV-related disease.[33]
History and examination
EBV infection can be asymptomatic, cause mild, non-specific symptoms, or cause IM with symptoms and fatigue lasting up to 6 months or more.
IM is characterised by the classic triad of fever, pharyngitis, and lymphadenopathy. Suspect the diagnosis in people aged 10 to 30 years old presenting with these symptoms. Fatigue/malaise is also extremely common and occurs in approximately 82% of patients.[34]
A rash occurs in 10% of adults, but may be present in up to one third of paediatric patients.[34] It generally appears in the first days of illness and lasts for 1 week, and can be erythematous, maculopapular, or morbilliform. Other uncommon signs include splenomegaly, myalgia, hepatomegaly, and jaundice.[34][35] Older adults may present with hepatitis or fever of unknown origin.[6][7] Splenic rupture has been reported in patients with IM at the initial presentation or before the development of the typical symptoms.[5]
A gradual development of illness is typical, but in some patients there may be an abrupt onset. Younger children may present with similar symptoms to adults, but more often their infection is subclinical or mild, with non-specific symptoms. Symptoms of non-EBV mononucleosis syndrome are usually less pronounced. The mild prodrome lasting a few days and including malaise, fatigue, and sometimes fever, progresses to the acute phase. The clinical presentation of IM in immunocompromised children and adults may be similar to the presentation of the disease in immunocompetent people.
Symptoms of IM may resolve within days, or may persist for up to 3 to 4 weeks (up to 8 weeks in some). Occasionally, a biphasic illness may occur, with worsening of symptoms after an initial improvement. The complete resolution of some symptoms of IM, such as fatigue, may take several months.
Patients may present with a neurological disorder without typical concomitant IM signs, and in some cases a neurological disorder (e.g., facial nerve palsy, Guillain-Barre syndrome, encephalitis) could be the sole manifestation of EBV infection in children.[8][9] Other rare manifestations in children include acute dacryocystitis, upper airway obstruction, pneumonia, acute myocarditis, aplastic anaemia, agranulocytosis, renal dysfunction, genital ulceration, hepatitis, cholecystitis, acute liver failure, psychotic episodes, depression, allergies, Hodgkin's lymphoma, Burkitt's lymphoma, and other neoplasms.[10]
Laboratory investigations
Order a full blood count in all patients initially. Lymphocytosis of at least 50%, and atypical lymphocytosis of 10% or more, are characteristic of the diagnosis.[36][37] Anaemia and reticulocytosis indicate the development of haemolytic anaemia secondary to EBV infection. Haematological abnormalities can be absent in young children. Liver function tests may reveal transaminase elevations in patients with liver involvement.
Order an agglutination test, such as Monospot, in all patients to help confirm the diagnosis. A positive test demonstrates the existence of heterophile antibodies, and is readily available in most laboratories. In a multicentre evaluation of 6 different commercial tests for heterophile antibodies, sensitivities ranged from 81% to 95%, and specificities ranged from 98% to 100%.[38] In practice, these tests can be less sensitive in early stages of IM in adults. The false-negative rate is as high as 25% in the first week of illness, and 5% to 10% in the second and third week.[37][39] Nearly 10% of adult patients with IM will be persistently heterophile antibody negative. The test may also be negative in children under 4 years of age.[40] False-positive results can be seen in people with autoimmune diseases, cytomegalovirus, toxoplasmosis, rubella, and lymphoma, as well as in those with acute retroviral syndrome from an early HIV infection.
Order serological tests for EBV-specific antibodies directed against the viral antigens, such as viral capsid antigen (VCA) and EBV nuclear antigen (EBNA), in all patients to confirm the diagnosis. This test has a high sensitivity and specificity and is more sensitive than heterophile antibody test; the sensitivity of 6 commercial tests ranged from 95% to 99% and specificity from 86% to 100%.[37][38][39] It is often positive in young children with asymptomatic disease. The specific antigens are important for distinguishing between acute and past infection. VCA-immunoglobulin(Ig)M in most patients is detectable with symptom onset, peaks at 2 to 3 weeks, and becomes unmeasurable by 4 months. VCA-IgG peaks at 2 to 3 months and persists for life. Antibodies to early antigens (EA) rise in acute stage, become undetectable by 3 to 4 months, and may reappear with reactivation of EBV infection. EA antibodies are also detectable in some clinically healthy persons. EBNA antibodies rise in resolution phase, and remain detectable for life.[40] These antibodies develop after 6 to 8 weeks and can be used to identify past infection, or as evidence to rule out acute EBV infection.[41]
Real-time polymerase chain reaction (RT-PCR) has a high sensitivity and specificity, but is expensive and not commonly used in clinical practice. It may be useful in the diagnosis of serologically indeterminate EBV infections.[42]
Serologic tests are the methods of choice to come to an unequivocal diagnostic conclusion, while RT-PCR plays a minor role in diagnosis.[43]
If results do not confirm EBV as a cause of the symptoms, seek an alternative diagnosis.
Imaging
Ultrasonography of the abdomen is not a routine investigation but it can help detect splenomegaly when it is not evident on clinical examination. It can be used to monitor spleen size and also to check if it has returned to a normal size before allowing a patient to take part in contact sports.
Perform a computed tomography scan of the abdomen when splenic rupture is suspected.
How to take a venous blood sample from the antecubital fossa using a vacuum needle.
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