What are the key clinical, laboratory, and treatment differences between bacterial pharyngitis (group A streptococcal infection) and infectious mononucleosis (Epstein‑Barr virus)?

Key Differentiating Features: Bacterial Pharyngitis vs. Infectious Mononucleosis

The most critical distinction is that bacterial (Group A Streptococcal) pharyngitis requires antibiotic treatment to prevent acute rheumatic fever and suppurative complications, while infectious mononucleosis is self-limited and requires only supportive care—making accurate differentiation essential to avoid both undertreatment of streptococcal disease and unnecessary antibiotic exposure in viral illness. 1

Clinical Presentation Differences

Group A Streptococcal Pharyngitis

• Sudden onset of severe sore throat with high fever (≥101°F/38.3°C) is characteristic 2, 3
• Tonsillopharyngeal erythema with patchy discrete exudates on tonsils 2, 3
• Tender, enlarged anterior cervical lymph nodes (localized to anterior chain) 2, 3
• Palatal petechiae ("doughnut lesions") and beefy red swollen uvula 3
• Absence of viral upper respiratory symptoms—no cough, rhinorrhea, hoarseness, or conjunctivitis 1, 2
• Peak age 5-15 years; uncommon in children <3 years and adults >40 years 2, 3
• Seasonal pattern: winter and early spring in temperate climates 2, 3
• Symptoms typically resolve within 3-5 days with or without treatment 3

Infectious Mononucleosis (EBV)

• Gradual onset with profound fatigue lasting weeks to months 4, 5, 6
• Generalized lymphadenopathy (not just anterior cervical)—particularly posterior cervical nodes are characteristic 1, 2, 7, 5
• Splenomegaly in approximately 50% of cases 5, 6
• Hepatomegaly in approximately 10% of cases 6
• Periorbital/palpebral edema (bilateral) occurs in one-third of patients 6
• Diffuse maculopapular rash in 10-45% of cases (not related to antibiotics) 6
• Pharyngeal erythema with diffuse injection but exudates are less common than in streptococcal infection 7
• Peak age 15-24 years (adolescents and young adults) 4, 5, 6
• Symptoms persist for several weeks, with fatigue potentially lasting 3 months 5, 6

Laboratory Findings

Bacterial Pharyngitis

• Throat culture or rapid antigen detection test (RADT) is diagnostic 1
• RADT has 79-88% sensitivity and 90-96% specificity 3
• Negative RADT must be confirmed with throat culture in children/adolescents due to lower sensitivity and rheumatic fever risk 1, 2
• Total leukocyte count typically >12,000/mm³ with neutrophilia and left shift 3
• No atypical lymphocytes 3

Infectious Mononucleosis

• Heterophile antibody test (monospot) has 87% sensitivity and 91% specificity 5, 6
• False-negative heterophile test in children <5 years and during first week of illness 5, 6
• Lymphocytosis with >50% lymphocytes and >10% atypical lymphocytes on peripheral smear 5, 6, 8
• Elevated liver enzymes increase suspicion when heterophile test is negative 5
• EBV viral capsid antigen (VCA) antibody testing is more sensitive and specific but more expensive 5
• Total leukocyte count typically <10,000/mm³ with relative lymphocytosis 3

Critical Diagnostic Algorithm

Step 1: Assess for viral features

• If cough, rhinorrhea, hoarseness, or conjunctivitis are present → do not test for GAS 1, 2
• These features strongly indicate viral pharyngitis 1, 2

Step 2: If viral features absent, assess for mononucleosis features

• Generalized lymphadenopathy (especially posterior cervical) 1, 2, 7
• Profound fatigue out of proportion to pharyngitis 2, 7
• Splenomegaly or hepatomegaly 5, 6
• Periorbital edema 6
• If present → order heterophile antibody test and complete blood count with differential 5

Step 3: If neither viral nor mono features predominate

• Perform RADT or throat culture for GAS 1, 2
• In children/adolescents, confirm negative RADT with throat culture 1, 2

Treatment Differences

Bacterial Pharyngitis (GAS-Positive)

• Penicillin V or amoxicillin for 10 days is first-line therapy 1, 2
• Treatment prevents acute rheumatic fever, suppurative complications, and reduces transmission 1
• For penicillin allergy: narrow-spectrum cephalosporin (non-anaphylactic) or clindamycin/macrolide (anaphylactic) 2, 3
• Full 10-day course is mandatory for bacterial eradication 1

Infectious Mononucleosis

• No antibiotics indicated—treatment is entirely supportive 5, 6
• Analgesics (acetaminophen or NSAIDs; avoid aspirin in children), adequate hydration, rest 2, 3
• Avoid contact sports and strenuous exercise for 3-8 weeks due to splenic rupture risk (0.1-0.5% incidence) 5, 6
• Corticosteroids and antivirals are not routinely recommended 5

Critical Pitfall: Amoxicillin-Associated Rash

Never prescribe amoxicillin or ampicillin if infectious mononucleosis is suspected 2

• 30-100% of EBV-infected patients develop a severe maculopapular rash when given aminopenicillins 3
• This rash is not a true penicillin allergy—it represents a non-IgE-mediated reaction requiring concurrent viral infection 3
• Patients should not be labeled penicillin-allergic based on this rash alone 3
• If rash develops, discontinue antibiotic immediately; rash resolves within 1-2 weeks without specific therapy 3

Common Clinical Pitfalls

• Relying on clinical impression alone leads to unnecessary antibiotics in 50-70% of cases because viral causes predominate 1, 3
• Assuming all exudative pharyngitis is bacterial is incorrect—viruses (adenovirus, EBV) frequently produce exudates 3
• Testing patients with obvious viral features (cough, rhinorrhea) leads to false-positive results from asymptomatic GAS carriers (10-15% of population) 1, 2
• Failing to recognize concurrent GAS carriage in mononucleosis patients—if both are confirmed, treat the streptococcal infection while managing mono supportively 7
• Testing or treating asymptomatic household contacts is not recommended 1, 3