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, and a positive serologic test for EBV-specific antibodies. Primary care physicians play an important role in the diagnosis of IM as they encounter the vast majority of patients with EBV-related disease.[33]

History and exam

EBV infection can be asymptomatic, cause mild, nonspecific symptoms, or cause IM with symptoms and fatigue lasting up to 6 months or more.

IM is characterized 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 pediatric 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 nonspecific 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 neurologic disorder without typical concomitant IM signs, and in some cases a neurologic 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 anemia, agranulocytosis, renal dysfunction, genital ulceration, hepatitis, cholecystitis, acute liver failure, psychotic episodes, depression, allergies, Hodgkin lymphoma, Burkitt lymphoma, and other neoplasms.[10]

Laboratory investigations

Order a complete 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]​ Anemia and reticulocytosis indicate the development of hemolytic anemia secondary to EBV infection. Hematologic abnormalities can be absent in young children. Liver function tests may reveal transaminase elevations in patients with liver involvement.

The Centers for Disease Control and Prevention recommend that the Monospot test is not used to confirm the presence of EBV. The antibodies detected by the Monospot test can be caused by conditions other than infectious mononucleosis and do not confirm the presence of EBV infection.[38]​

Order serologic 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][39][40]​ 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.[41] 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.[42]

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.[43]

Serologic tests are the methods of choice to come to an unequivocal diagnostic conclusion, while RT-PCR plays a minor role in diagnosis.[44]

If results do not confirm EBV as a cause of the symptoms, seek an alternative diagnosis.

Imaging

Do not routinely order abdominal ultrasound in athletes with infectious mononucleosis to detect splenomegaly because comparing an individual’s splenic size to population norms is not a valid method to assess splenic enlargement.[45][46][47]​​​​ There is a lack of evidence-based protocols for returning to contact sports but the Centers for Disease Control and Prevention recommend avoiding contact sports until the patient has fully recovered.[47][48]

Perform a computed tomography scan of the abdomen when splenic rupture is suspected.

Venepuncture and phlebotomy: animated demonstration
Venepuncture and phlebotomy: animated demonstration

How to take a venous blood sample from the antecubital fossa using a vacuum needle.

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