herpes infection

What Are These Vesicular Eruptions?

Alexander K. C. Leung, MD—Series Editor, and Benjamin Barankin, MD

A 6-year-old girl presented with vesicles on the right lower lip. On the day prior to the eruption of the vesicles, she experienced pain, burning, and tingling at that site, but she did not have associated fever, sore throat, or loss of appetite. Neither she nor her mother could recall her having such lesions before, although her mother reported having something similar. The girl’s past health was otherwise unremarkable, and she was not on any medications.

 On physical examination, vital signs were normal. Multiple vesicles were noted on the right lower cutaneous lip abutting the vermilion. There was no cervical lymphadenopathy. The rest of the physical examination was unremarkable.

What’s your diagnosis?


ANSWER: Herpes labialis  

Herpes labialis, also known as “cold sores” or “fever blisters,” is the most common clinical manifestation of recurrent herpes simplex virus (HSV) infection in children.1 The vast majority of cases are caused by HSV-type 1 (HSV-1).1 Because most initial HSV-1 infections are asymptomatic in early childhood and may be unrecognized, herpes labialis is often the initial manifestation of HSV-1 infection in children.2 The disease is characterized by recurrent vesicular eruptions primarily on the lips and perioral skin.3


The prevalence of herpes labialis is estimated to be 2.5 per 1000 patients per year.4 Approximately 30% of affected patients have relapses.5,6 The majority of patients with recurrent herpes labialis experience ≤ 2 episodes annually, but 5% to 10% of patients experience ≥ 6 episodes annually.1,5


The vast majority of cases of herpes labialis are caused by HSV-1, although infection by HSV-2 has been increasingly reported.1 HSV-1 is primarily transmitted by contact with infected oral secretions or active lesions of other individuals.7 On the other hand, HSV-2 is uncommon in children and is spread mainly through orogenital contact. Primary infection with HSV-1 usually occurs in childhood, with a peak between 2 and 3 years of age, and most infections in this age group are mild or subclinical.8-10 

Approximately one-third of children contract a primary HSV-1 infection by 5 years of age.11 After primary infection, the virus ascends the sensory nerve axon via retrograde flow, replicates, and establishes chronic latency within the trigeminal ganglion.4,6,12 When an appropriate trigger occurs, the virus reactivates, replicates in the trigeminal ganglion, and descends along the axon to the perioral epithelium to cause lesions of herpes labialis.3 Common triggers include fever, upper respiratory infection, emotional stress, fatigue, physical trauma, dental work, UV radiation, menstruation, pregnancy, and immunosuppression.1,5,10,13,14 

C21 or f91 has been identified as a candidate gene that increases susceptibility to herpes labialis.15 It has been shown that a lower natural killer cell percentage and toll-like receptor-3 hyporesponsiveness of natural killer cells are associated with increased susceptibility to recurrent herpes labialis.16  


In approximately 60% of patients, a prodrome including tingling, irritation, numbness, burning, pain, and pruritus occurs at the site of future lesion development.1,17 The prodrome usually lasts for a few to 24 hours and represents early viral replication localized to sensory nerve endings innervating the mucocutaneous dermatomes.1 Approximately 25% of recurrences abort at this stage.1 Classically, papules on an erythematous base appear abruptly within 24 hours of the prodrome and are most commonly localized at the outer vermilion border of the lip.7,12,17,18 The papules become vesicular within hours.17 The average number of vesicles is 3 to 5,18 and the vesicles rupture within 48 to 72 hours and progress to ulceration.3 A golden-brown crust appears within 72 to 96 hours and forms a scab.12 Infectivity is highest during the first 24 hours of the appearance of the initial lesion,12 though constitutional symptoms such as fever are characteristically absent. Pain is most severe during the vesicular stage and resolves in 4 to 5 days.18  


The diagnosis is mainly clinical. Lack of constitutional symptoms and classic lesions on the lips make the diagnosis of herpes labialis obvious.3 On occasion, viral culture, Tzanck smear, direct fluorescent antibody testing, and amplification of viral DNA using polymerase chain reaction may be performed to establish a definitive diagnosis.2 The gold standard for laboratory diagnosis is the viral culture. 


Herpes labialis has to be differentiated from herpetic gingivostomatitis, hand-foot-and-mouth disease, herpangina, aphthous stomatitis, angular cheilitis, chickenpox, impetigo, molluscum contagiosum, and streptococcal pharyngitis.3 


Herpes labialis can cause significant pain and discomfort. The lesion can be cosmetically unsightly and socially embarrassing, and the psychosocial impact can be profound.19,20  The condition has an adverse effect on the quality of life, especially for those with frequent relapses.21 

Herpes labialis is contagious. Autoinoculation of distant locations such as the fingers and genitalia can also occur.4 Other complications include bacterial superinfection, lip leukoderma, trigeminal nerve palsy, facial nerve palsy, cluster headaches, erythema multiforme, and psychotic episodes.3,8,22-25


The disease process typically resolves without scarring in 6 to 14 days.3,6 Recurrences are common and tend to affect the same location or closely related areas.3 The frequency and severity of outbreaks generally decreases after the age of 35.4 


Patients should be advised about the infectious nature of the lesion and hygienic measures to prevent viral transmission.1,3 Avoidance of known triggers such as emotional stress and UV radiation may diminish the number of recurrences.

Symptomatic treatment includes the use of analgesics and adequate hydration. Antiviral therapy shortens the duration of symptoms and may prevent dissemination and transmission.26 Such treatment needs to be initiated promptly to achieve favorable results.27 Oral antiviral medication is superior to topical therapy.3,10,28,29 Oral acyclovir, initiated within 2 days of onset, can shorten the pain and duration of the eruption.2 The recommended dose is 80 mg/kg/day in 5 divided doses (maximum 1200 mg/day) for 5 days.2 Oral valacyclovir and famciclovir are alternate options for individuals aged ≥ 12 years and ≥ 18 years, respectively.11 

However, antiviral treatment alone is not very effective, with only about 50% of studies showing a significant difference compared with placebo.6,7,27 A recent meta-analysis of 4 randomized clinical trials (n = 1891) showed that the addition of topical corticosteroids to antiviral therapy (oral or topical) has significant benefit compared with either antiviral therapy alone or placebo.27

Systemic nucleoside antiviral agents are effective in prevention of recurrent herpes labialis.29 Chronic suppressive therapy should be considered for patients with severe or frequent (6 or more episodes per year) recurrences.3 The recommended dose of acyclovir is 80 mg/kg/day in 3 divided doses (maximum 1000 mg/day) for a maximum of 12 months.2,11 

Other treatment options include topical acyclovir with or without hydrocortisone, topical docosanol, and rarely, laser phototherapy or photodynamic therapy.7,8,10,28,30 A preliminary study shows that calcium spirulan has antiviral activity and can inhibit the attachment of HSV-1 to human keratinocytes.14 Topical application of a cream containing calcium spirulan has the potential to be used as a topical prophylaxis against herpes labialis.14 

Alexander K. C. Leung, MD, is a clinical professor of pediatrics at the University of Calgary and a pediatric consultant at the Alberta Children’s Hospital in Calgary, Alberta, Canada.

Benjamin Barankin, MD, is a dermatologist and the Medical Director and Founder of the Toronto Dermatology Centre in Toronto, Ontario, Canada.


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9. Nakagawa H, Kusuyama T, Ogawa K. Primary oropharyngeal herpes simplex virus infection in adults: a profile of thirty-two immunoserologically confirmed cases. Clin Otolaryngol. 2015;40(4):393-396.

10. Sarnoff DS. Treatment of recurrent herpes labialis. J Drugs Dermatol. 2014;13(9):1016-1018.

11. Sanders JE, Garcia SE. Pediatric herpes simplex virus infections: an evidence-based approach to treatment. Pediatr Emerg Med Pract. 2014;11(1):1-19.

12. Woo SB, Challacombe SJ. Management of recurrent oral herpes simplex infections. Oral Surg Oral Med Oral Path Oral Radiol Endod. 2007;103(suppl:S12):e1-e18.

13. Goodson AG, Varedi A, Hull C, Grossman D. A safe and efficient model for ultraviolet radiation-induced herpes simplex labialis. Photodermatol Photoimmunol Photomed. 2015;31(3):170-172.

14. Mader J, Gallo A, Schommartz T, et al. Calcium spirulan derived from Spirulina platensis inhibits herpes simplex virus 1 attachment to human keratinocytes and protects against herpes labialis. J Allergy Clin Immunol. 2016;137(1):197-203.

15. Kriesel JD, Jones BB, Matsunami N, et al. C21 or f91 genotypes correlate with herpes simplex labialis (cold sore) frequency: description of a cold sore susceptibility gene. J Infect Dis. 2011;204(11):1654-1662.

16. Yang CA, Raftery MJ, Hamann L, et al. Association of TLR3-hyporesponsiveness and functional TLR3 L412F polymorphism with recurrent herpes labialis. Hum Immunol. 2012;73(8):844-851.

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18. Vander Straten M, Carrasco D, Lee P, Tyring SK. A review of antiviral therapy for herpes labialis. Arch Dermatol. 2001;137(9):1232-1235.

19. Birek C, Ficarra G. The diagnosis and management of oral herpes simplex infection. Curr Infect Dis Rep. 2006;8(3):181-188. 

20. Raborn GW, Chan KS, Grace M. Treatment modalities and medication recommended by health care professionals for treating recurrent herpes labialis. J Am Dent Assoc. 2004;135(1):48-54.

21. Dreno B, Malkin JE, Saiag P. Understanding recurrent herpes labialis management and impact on patients’ quality of life: the HERPESCOPE study. Eur J Dermatol. 2013;23(4):491-499.

22. Orgaz-Molina J, Arias-Santiago S. Erythema multiforme associated with herpes labialis. CMAJ. 2013;185(16):1428.

23. Park EP, Boulmay BC. Images in clinical medicine. Herpes labialis and facial-nerve paralysis. N Engl J Med. 2014;370(11):1048.

24. Turner MJ, Adams BB. Herpes labialis-induced lip leukoderma. Cutis. 2014;93(1):e1-e2.

25. Umehara T, Oka H, Toyoda C, Mochio S. Pearls and oy-sters: trigeminal neuropathy associated with herpes labialis. Neurology. 2012;79(19):e173-e175.

26. Rahimi H, Mara T, Costella J, Speechley M, Bohay R. Effectiveness of antiviral agents for the prevention of recurrent herpes labialis: a systemic review and meta-analysis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113(5):618-627.

27. Arain N, Paravastu SC, Arain MA. Effectiveness of topical corticosteroids in addition to antiviral therapy in the management of recurrent herpes labialis: a systematic review and meta-analysis. BMC Infect Dis. 2015;15:82. 

28. Ramalho KM, Rocha RG, Correa-Aranha AC, et al. Treatment of herpes simplex labialis in macule and vesicle phases with photodynamic therapy. Report of two cases. Photodiagnosis Photodyn Ther. 2015;12(2):321-323.

29. Wong YJ, Veitz-Keenan A. Systemic nucleoside antiviral agents may be effective in prevention of recurrent herpes labialis. Evid Based Dent. 2013;14(2):54.

30. Eduardo CP, Aranha AC, Simões A, et al. Laser treatment of recurrent herpes labialis: a literature review. Lasers Med Sci. 2014;29(4):1517-1529.