What is the diagnosis and treatment for a patient with a severe sore throat, swollen lymph nodes, negative streptococcal (strep) test and mononucleosis (mono) test, and multiple cold sores on the lower lip?

Primary Herpes Simplex Virus (HSV) Pharyngitis

This patient most likely has primary herpes simplex virus pharyngitis, given the severe sore throat, swollen lymph nodes, negative strep and mono tests, and the pathognomonic finding of multiple cold sores (herpes labialis) on the lower lip. 1

Diagnostic Reasoning

The clinical presentation strongly suggests HSV pharyngitis rather than other viral or bacterial causes:

• Herpes simplex virus is a recognized cause of acute pharyngitis, particularly when accompanied by oral lesions 1
• The presence of multiple cold sores (herpes labialis) on the lower lip is the key diagnostic feature that distinguishes this from other viral pharyngitides 1
• Negative strep tests (twice) effectively rule out group A streptococcal pharyngitis, as rapid antigen detection tests have approximately 95% specificity, making false positives highly unusual 1
• Negative mono test makes Epstein-Barr virus infectious mononucleosis unlikely, though false-negative heterophile antibody tests can occur early in infection 2
• The severe pharyngitis with prominent lymphadenopathy fits the pattern of primary HSV infection, which tends to be more severe than recurrent episodes 1

Treatment Recommendations

Initiate oral antiviral therapy with valacyclovir 2 grams twice daily for 1 day for the herpes labialis, combined with symptomatic management for the pharyngitis. 3

Antiviral Therapy

• Valacyclovir 2 grams twice daily on Day 1 is FDA-approved for cold sores (herpes labialis) and shortens the mean duration of cold sore episodes by approximately 1 day compared to placebo 3
• Treatment should be self-initiated at the earliest symptoms and prior to any signs of lesion development, though this patient has already developed visible lesions 3
• The 1-day regimen (2 grams twice daily on Day 1 only) is as effective as the 2-day regimen and is preferred 3

Symptomatic Management

• Ibuprofen or naproxen (NSAIDs) are recommended as first-line analgesics for pain control in acute pharyngitis 1, 4
• Acetaminophen is an acceptable alternative if NSAIDs are contraindicated 1, 4
• Adequate hydration and rest are important supportive measures 2
• Throat lozenges may provide additional symptomatic relief 4

What NOT to Do

• Do not prescribe antibiotics, as both strep tests were negative and the clinical picture is consistent with viral pharyngitis 1, 4
• Do not prescribe corticosteroids routinely for viral pharyngitis, as they are not recommended except in cases of respiratory compromise or severe pharyngeal edema 1
• Aspirin should be avoided in children due to Reye's syndrome risk 1

Important Clinical Caveats

When to Reassess

Red flags requiring urgent reassessment include: 5

• Development of difficulty swallowing or breathing (suggests possible airway compromise)
• Severe unilateral throat pain with trismus (suggests peritonsillar abscess)
• Neck swelling or tenderness (raises concern for Lemierre syndrome or deep space infection)
• High fever or systemic toxicity

Expected Clinical Course

• Viral pharyngitis typically resolves in less than 1 week 5, 4
• Cold sore lesions treated with valacyclovir heal in approximately 4 days 3
• Fatigue and malaise may persist longer if this represents primary HSV infection 2

Alternative Diagnoses to Consider

If symptoms worsen or do not improve:

• Primary HIV infection (acute retroviral syndrome) can present with severe pharyngitis, lymphadenopathy, and oral ulcers 6
• Cytomegalovirus pharyngitis may present similarly to infectious mononucleosis with negative heterophile antibody 1
• Consider repeat mono testing in 5-7 days if symptoms persist, as false-negative heterophile antibody tests are common early in EBV infection 2

Key Pitfall to Avoid

The most common error is prescribing antibiotics for viral pharyngitis. Up to 70% of patients with sore throats receive antibiotic prescriptions, yet only 20-30% actually have group A streptococcal pharyngitis 1, 4. With two negative strep tests and the presence of cold sores indicating HSV infection, antibiotics are not indicated and expose the patient to unnecessary adverse effects and costs 1, 4.