Can her prior herpes simplex infection be responsible for her current fever, sore throat, fatigue, and cervical lymphadenopathy with a negative heterophile (Monospot) test?

Can Herpes Simplex Infection Cause These Symptoms?

Yes, herpes simplex virus can cause pharyngitis, fever, fatigue, and cervical lymphadenopathy with a negative Monospot test, though this presentation is uncommon and HSV should be considered in the differential diagnosis when EBV testing is negative.

Clinical Context and Diagnostic Approach

HSV as a Cause of Pharyngitis

While HSV pharyngitis is less common than EBV-related infectious mononucleosis, it can present with an identical clinical picture:

• HSV can cause pharyngotonsillitis with fever, sore throat, and cervical lymphadenopathy, particularly in immunocompromised patients but also in immunocompetent individuals 1
• Disseminated HSV-2 infection has been documented presenting with pharyngotonsillitis, fever, and lymphadenopathy without any genital involvement 1
• HSV pharyngitis may occur in restricted epidemiologic settings and is not routinely tested for unless specifically suspected 2

When to Suspect HSV Over EBV

Key clinical indicators that should raise suspicion for HSV pharyngitis:

• Presence of pharyngeal vesicles or ulcerations on examination of the throat 2
• Negative Monospot test, especially if repeated 7-10 days later and still negative 2
• History of oral-genital contact or known HSV exposure 2
• Immunocompromised status (though HSV pharyngitis can occur in immunocompetent hosts) 1

The Monospot Test Limitation

The negative Monospot test is a critical piece of information:

• Up to 10% of Monospot tests are falsely negative in EBV infection 2
• False-negative Monospot tests are most common in younger children 2, 3
• In adolescents and adults, the Monospot has high specificity and sensitivity, making a negative result more meaningful 3
• If clinical suspicion for EBV remains high despite negative Monospot, EBV-specific serologic testing (IgM and IgG) should be performed on the same sample or repeated 7-10 days later 2

Recommended Diagnostic Algorithm

Step 1: Confirm or Exclude EBV

• Obtain EBV-specific serology (IgM and IgG) to definitively rule out or confirm EBV infection, since the Monospot can be falsely negative 2, 3

Step 2: Test for HSV if EBV is Negative

• Collect specimens from pharyngeal lesions if visible vesicles or ulcers are present 2
• HSV PCR or direct antigen testing from throat swabs is preferred over culture for higher sensitivity 2
• HSV-specific IgM and IgG serology can provide supportive evidence; presence of HSV-specific IgM in the context of compatible illness may be considered diagnostic 2
• Ensure testing differentiates between HSV-1 and HSV-2, as both can cause pharyngitis 2, 1

Step 3: Consider Other Causes

If both EBV and HSV testing are negative, consider:

• Cytomegalovirus (CMV), which commonly causes heterophile-negative mononucleosis-like illness 4
• Human herpesvirus 6 (HHV-6), HIV, adenovirus, Streptococcus pyogenes, and Toxoplasma gondii 4

Important Clinical Caveats

Rare but Documented Presentations

• HSV-2 can cause disseminated infection with pharyngotonsillitis, esophagitis, and systemic symptoms without genital lesions, particularly in patients with underlying conditions 1
• EBV itself can rarely cause genital ulcerations that mimic HSV, adding to diagnostic confusion 5

Testing Pitfalls to Avoid

• Do not rely solely on a single negative Monospot test to exclude EBV in patients with classic mononucleosis symptoms 2, 3
• HSV serology alone may not distinguish acute from past infection; PCR from lesions or pharyngeal specimens is more definitive for acute infection 2
• Tzanck smear and direct immunofluorescence for HSV are not recommended due to poor sensitivity 2

Treatment Implications

• If HSV pharyngitis is confirmed, antiviral therapy with acyclovir or valacyclovir is indicated, particularly in severe cases or immunocompromised patients 1
• Supportive care remains the mainstay for EBV-related infectious mononucleosis 6

Bottom Line

Her herpes history makes HSV a plausible cause of her current symptoms, especially with a negative Monospot test. The most prudent approach is to obtain EBV-specific serology to definitively exclude or confirm EBV infection, and if negative, pursue HSV testing with PCR from pharyngeal specimens and HSV-specific serology 2, 1, 4. This systematic approach ensures appropriate diagnosis and treatment while avoiding the pitfall of assuming all mononucleosis-like illnesses are due to EBV.