Adolescent with sore throat, fever, marked fatigue, tender anterior cervical lymphadenopathy and possible splenomegaly—what is the likely diagnosis, how should it be confirmed, and what is the recommended management?

Infectious Mononucleosis (Epstein-Barr Virus Infection)

The clinical presentation of an adolescent with sore throat, fever, marked fatigue, tender anterior cervical lymphadenopathy, and possible splenomegaly is classic for infectious mononucleosis caused by Epstein-Barr virus (EBV), and diagnosis should be confirmed with a complete blood count showing >40% lymphocytes with >10% atypical forms plus a rapid heterophile antibody (Monospot) test. 1

Clinical Diagnosis

Classic Triad and Key Features

• Infectious mononucleosis presents with the triad of fever, tonsillar pharyngitis, and cervical lymphadenopathy—particularly posterior cervical nodes, which distinguishes it from bacterial pharyngitis. 2, 3, 1

• Marked fatigue is a hallmark feature that differentiates EBV from Group A streptococcal pharyngitis; this profound fatigue typically resolves within three months but can be debilitating during acute illness. 4

• Splenomegaly occurs in approximately 50% of cases and is a critical finding because it carries risk of splenic rupture, the most feared complication. 4

• Hepatomegaly is present in approximately 10% of cases. 4

• Periorbital or palpebral edema, typically bilateral, occurs in one-third of patients and is a useful diagnostic clue. 4

Age and Epidemiology

• EBV infectious mononucleosis most commonly affects adolescents and young adults aged 15 to 24 years, making this age group the primary target population. 3, 1, 4

• The virus is transmitted primarily through saliva via intimate oral contact among teenagers and young adults. 3, 1, 4

Diagnostic Confirmation

Initial Laboratory Testing

Cost-effective, efficient initial laboratory testing includes a complete blood count with differential and a rapid heterophile antibody (Monospot) test. 1

Complete Blood Count Findings

• Peripheral blood leukocytosis is observed in most patients, with lymphocytes comprising at least 50% of the white blood cell differential count. 4

• Atypical lymphocytes constitute more than 10% of the total lymphocyte count—this finding is highly characteristic of EBV infection. 2, 1, 4

• The diagnostic threshold is >40% lymphocytes and >10% atypical lymphocytes on peripheral smear. 1

Heterophile Antibody Testing

• The rapid heterophile antibody (Monospot) test has a sensitivity of 87% and specificity of 91% and is the most widely used method for diagnosis. 1, 4

• A positive heterophile test combined with typical clinical features is usually sufficient to confirm the diagnosis. 3

• The heterophile antibody test can yield false-negative results during the first week of illness in adults and in children younger than five years. 1

When Monospot is Negative

• If the heterophile antibody test is negative but clinical suspicion remains high, check liver enzymes—elevated transaminases increase clinical suspicion for infectious mononucleosis. 1

• When confirmation is required in patients with mononucleosis-like illness and a negative Monospot test, serologic testing for EBV-specific antibodies is recommended. 4

• The presence of IgM antibody to EBV viral capsid antigen (VCA) is the most valuable serologic finding and is diagnostic of acute primary EBV infection. 2

• EBV viral capsid antigen-antibody testing is more sensitive and specific than the rapid heterophile antibody test but is more expensive and takes longer to process. 1

Recommended Management

Supportive Care Only

Treatment of infectious mononucleosis is supportive; routine use of antivirals and corticosteroids is not recommended. 1

• Reduction of activity and bed rest as tolerated are recommended during the acute phase. 4

• Analgesics (acetaminophen or ibuprofen) for pain and fever relief; avoid aspirin in adolescents due to Reye syndrome risk. 5

• Adequate hydration, warm saline gargles, and rest are appropriate supportive measures. 5

Activity Restriction to Prevent Splenic Rupture

Patients with infectious mononucleosis must not participate in athletic activity for three weeks from onset of symptoms; shared decision-making should be used to determine timing of return to activity beyond three weeks. 1

• Patients should be advised to avoid contact sports or strenuous exercise for 8 weeks or while splenomegaly is still present, whichever is longer. 4

• Spontaneous splenic rupture occurs in 0.1 to 0.5% of patients with infectious mononucleosis and is potentially life-threatening—this is the most feared complication. 2, 4

Antibiotic Avoidance

• Do not prescribe antibiotics for infectious mononucleosis; antibiotics are not indicated for viral pharyngitis. 5

• Avoid amoxicillin or ampicillin specifically—30 to 100% of patients with EBV infection who receive these drugs develop a severe, non-pruritic morbilliform rash that is not a true allergy but represents a benign drug-virus interaction. 5

Differential Diagnosis Considerations

Distinguishing from Group A Streptococcal Pharyngitis

• Group A streptococcal pharyngitis typically presents with sudden onset of severe sore throat, high fever (≥101°F), and tender anterior cervical lymphadenopathy—but marked fatigue and posterior cervical adenopathy favor EBV. 5

• The presence of cough, rhinorrhea, hoarseness, or conjunctivitis strongly suggests viral etiology and argues against bacterial infection. 5

• Generalized lymphadenopathy, especially enlargement of posterior cervical nodes, is characteristic of infectious mononucleosis and should prompt serologic testing rather than strep testing. 5

• Clinical signs alone are insufficient to differentiate viral from bacterial pharyngitis; however, the constellation of marked fatigue, posterior cervical adenopathy, and possible splenomegaly makes EBV far more likely than streptococcal infection. 5

When to Test for Group A Streptococcus

• If the heterophile antibody test is negative and EBV-specific antibodies are also negative, then perform rapid antigen detection test (RADT) or throat culture for Group A streptococcus. 5

• Do not routinely test for streptococcus when obvious viral features (marked fatigue, generalized lymphadenopathy, splenomegaly) are present—testing in this setting can yield false-positive results due to 10–15% asymptomatic GAS carriage. 5

Expected Clinical Course and Prognosis

• Infectious mononucleosis is generally a benign and self-limited disease; most patients have an uneventful recovery. 4

• Fatigue may be profound but tends to resolve within three months. 4

• Infectious mononucleosis is a risk factor for chronic fatigue syndrome in a minority of patients. 4

• Approximately 10% of those with mononucleosis-like illness will not be acutely infected with EBV; many of these individuals will have cytomegalovirus (CMV) infection instead. 6

Common Pitfalls to Avoid

• Do not prescribe antibiotics based on pharyngeal erythema and exudates alone—EBV frequently produces exudative tonsillitis that mimics bacterial infection. 5

• Do not administer amoxicillin or ampicillin to adolescents with sore throat before ruling out EBV—the resulting rash occurs in up to 100% of cases and causes unnecessary alarm. 5

• Do not clear patients for contact sports or strenuous activity before 8 weeks or resolution of splenomegaly—splenic rupture is rare but potentially fatal. 4

• Do not rely solely on a negative Monospot test during the first week of illness—repeat testing or obtain EBV-specific antibodies if clinical suspicion is high. 1

• Do not overlook the possibility of CMV as an alternative cause if EBV testing is negative—approximately 10% of mononucleosis-like syndromes are due to CMV. 6