Can blisters on the vermillion border of the upper lip be caused by conditions other than Herpes Simplex Virus (HSV)?

Blisters on the Vermillion Border: Non-HSV Etiologies

Yes, several serious conditions can cause blisters on the vermillion border of the upper lip besides HSV, most notably Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), which represents a medical emergency requiring immediate recognition, and Varicella Zoster Virus (VZV), which presents with distinctive dermatomal distribution. 1

Critical Non-HSV Causes

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)

SJS/TEN characteristically affects the vermillion border with painful mucosal erythema that progresses to blistering, ulceration, and hemorrhagic sloughing with dark adherent crusts—a pattern distinctly different from typical HSV lesions. 1

• The mouth is the most frequently affected mucosal membrane in SJS/TEN, often presenting before skin involvement becomes apparent 2
• Look for systemic symptoms (fever, rigors, myalgias), widespread purpuric macules or flat atypical targets on the skin, and involvement of other mucosal surfaces (eyes with conjunctivitis/iritis, genitourinary tract) 2
• The presence of hemorrhagic crusting, involvement beyond just the lip margin, or systemic constitutional symptoms should immediately raise suspicion for SJS/TEN rather than HSV 1
• This is a life-threatening condition with significant mortality risk that requires immediate hospitalization 1

Varicella Zoster Virus (VZV)

• VZV can cause vesicular lesions on the vermillion border, but typically presents with dermatomal pain preceding the lesions and unilateral distribution following the trigeminal nerve distribution 1
• The lesions are pleomorphic or pseudodendritic (nonexcavated), contrasting with HSV's excavated dendritic pattern 2
• Associated findings include vesicular dermatomal rash or ulceration of eyelids on the same side 2
• In primary VZV infection (chickenpox), vesicles can form at the limbus and conjunctiva, with potential for necrosis and scarring 2

Diagnostic Approach

Clinical Red Flags That Suggest Non-HSV Etiology

Clinical diagnosis alone is unreliable for vesicular lip lesions—laboratory confirmation should always be sought 1:

• Bilateral involvement with systemic symptoms → Consider SJS/TEN 2, 1
• Unilateral dermatomal distribution with severe pain → Consider VZV 1
• Hemorrhagic crusting or sloughing → Consider SJS/TEN 1
• Multiple mucosal surfaces involved (eyes, genitals, mouth) → Consider SJS/TEN 2
• Recent drug exposure (especially sulfonamides, anticonvulsants, allopurinol, NNRTIs) → Consider SJS/TEN 2

Laboratory Confirmation Requirements

Open vesicles with a sterile needle, collect fluid with a swab, and submit for both viral culture and nucleic acid testing (HSV/VZV DNA PCR) plus antigen detection 1:

• Viral culture remains useful but PCR is more sensitive 1
• Direct fluorescent antibody testing can provide rapid results 3
• Laboratory confirmation is mandatory in immunocompromised patients where morphology alone cannot reliably distinguish etiologies 1
• Skin biopsy showing confluent epidermal necrosis with basal cell vacuolar degeneration supports SJS/TEN diagnosis 2

Additional Differential Considerations

Other Vesiculobullous Conditions

• Erythema multiforme major (EMM): Distinguished from SJS by typical raised target lesions predominantly on extremities, though both can have mucosal involvement; EMM is mostly HSV-related rather than drug-induced 2
• Mycoplasma pneumoniae-associated mucositis: Predominantly affects mucous membranes with minimal cutaneous involvement, more common in children 2
• Drug hypersensitivity reactions: Can present with maculopapular confluent rash progressing to blistering, often with eosinophilia 2

Non-Vesicular Lip Conditions (Less Likely Given "Blister" Description)

• Contact cheilitis, plasma cell cheilitis, and exfoliative cheilitis typically do not present as true vesicles 4
• Cheilitis glandularis affects labial salivary glands but does not typically cause vesicular eruptions 4

Management Implications

Immediate Actions for Suspected SJS/TEN

• Stop all potentially causative medications immediately 2
• Apply white soft paraffin ointment to lips every 2 hours 2
• Use mucoprotectant mouthwashes three times daily 2
• Arrange immediate hospital admission to burn unit or intensive care setting 2
• Daily oral examination and gentle cleaning with warm saline to prevent fibrotic scarring 2

VZV-Specific Treatment

• Oral antivirals at higher doses than HSV: acyclovir 800 mg five times daily for 7 days, valacyclovir 1000 mg every 8 hours for 7 days, or famciclovir 500 mg three times daily for 7 days 2
• Topical antivirals alone are not helpful for VZV but may be used as adjunctive therapy 2
• Immunocompromised patients require more aggressive treatment 2

Common Pitfalls to Avoid

• Do not assume all vesicular lip lesions are HSV—this delays recognition of life-threatening conditions like SJS/TEN 1
• Do not use topical corticosteroids if HSV is in the differential, as they potentiate HSV infection 2
• Do not rely on clinical appearance alone in immunocompromised patients—always obtain laboratory confirmation 1
• Do not miss the early signs of SJS/TEN (fever, malaise, mucosal involvement) before extensive skin detachment occurs 2