• Typically, an insidious onset over several days to weeks but may be abrupt onset
• Prodromal fatigue, malaise, arthralgias, and myalgias with a biphasic or “waxing and waning” course
• Prominent or “worst ever” sore throat and fever. Airway edema may be reported as difficulty breathing or respiratory distress
• Swollen lymph nodes
• Headache
• Significant abdominal pain is uncommon but when present should raise concern about marked splenic enlargement or splenic rupture
• Varied rashes can be seen in 18-34% of children and adolescents (not associated with antibiotics)
• Administration of ampicillin or amoxicillin in patients with IM is associated with development of a rash

• Malaise and /or fatigue (90-100%)
• Pharyngitis (65-85%) and tonsillar enlargement
• Fever (80-95%)
• Eyelid edema (15-35%)
• Symmetric tender lymphadenopathy (100%)
• Hepatomegaly (15-25%)
• Splenomegaly (50-60%)
• Nonspecific rashes
• Morbilliform rash can be seen if the patient has been given ampicillin or amoxicillin:
  • Typically develops 5-9 d after the onset of antibiotic therapy (should not be interpreted as a penicillin allergy)
• Petechia can occur on the skin or at the junction between the hard and the soft palate
• Complications found on exam:
  • Airway compromise due to edema (1-5%)
  • Severe abdominal tenderness may be due to splenic rupture (may also cause referred pain to left shoulder)
  • Jaundice (∼5%) due to hepatitis or hepatic failure
    • Hepatitis is the most common complication
  • Neurologic findings consistent with:
    • Encephalitis or cerebellitis
    • Aseptic meningitis
    • Guillain-Barre syndrome
    • Optic neuritis
    • Bell palsy
• Anemia (palor): May be due to hemolytic anemia, thrombocytopenia, agranulocytosis, hemophagocytic lymphohistiocytosis (HLH)
• Orchitis
• Neck tenderness and /or limited range of motion due to pain: Secondary bacterial such as jugular vein thrombosis (Lemierre syndrome due to Fusobacterium necrophorum), soft tissue infection such as retropharyngeal or peritonsillar abscesses
• Signs of shock: May be due to dehydration or a secondary anaerobic sepsis

• WBC with differential:
  • Typically, a modest elevation in total WBC between 10,000-20,000, which peaks during week 2 of the illness; occasionally can be 30,000-50,000. A rare occurrence is the development of severe agranulocytosis, associated with recurrence or persistence of fever, and redevelopment of cervical adenopathy approximately 1 mo after onset of disease
• Lymphocyte count—findings suggestive of IM:
  • >50% lymphocytes on differential
  • Absolute lymphocyte count >4,500
  • Elevated lymphocyte count with >10% atypical lymphocytes (up to 90% of patients)
• Liver function tests:
  • Elevated with transaminases up to 3 times normal found in 80-85% of patients in the 1st 2 wk
  • Significant elevations in bilirubin to the point of causing clinical jaundice in ∼5% of cases
• Monospot test detects presence of heterophile antibodies (which are not specific for EBV):
  • Moderately sensitive (85%) and highly specific (practically 100%)
  • Rarely false positives can occur with CMV, leukemia, lymphoma, rubella, hepatitis, HIV, or lupus
  • Most patients develop heterophile antibodies after ∼1 wk of illness
  • Small percentage of patients (<10%) never develop heterophile antibodies
  • Heterophile antibodies peak at 2-5 wk and may persist for several months
  • Positive test relates to a titer >1:40
  • Results likely to be negative in children <4 yo
• Testing does exist for EBV-specific antibodies but is expensive, time consuming, and rarely needed
  • Useful in patients with atypical/severe cases or when monospot testing is negative and confirmation of IM is desired
  • Acute infection is indicated by antibodies (IgG, IgM) against viral capsid antigens (VCAs) without antibodies against the Epstein-Barr nuclear antigen (EBNA) which are only present during the latency period 3-4 wk after onset of illness
  • Past infection indicated by negative IgM and positive EBNA

Sonography or CT scan of abdomen for significant abdominal pain to identify splenic rupture and to ensure no signs of appendicitis

• Significant airway edema that represents any level of potential airway compromise
• Neurologic or severe hematologic/hepatic complications
• Inability to take PO
• Pain control

• No airway compromise
• Mild hematologic complications or mild hepatitis
• Ability to take PO fluids
• Fever usually resolved within 10 d and lymph nodes and spleen within 4 wk; fatigue may continue for several weeks, although it may go on for 2-3 mo

• Infectious disease consultation may be useful if serology is not conclusive
• Significant complications or persistent symptoms