Herpes Labialis (Cold Sores)

C.W. Lynde¹, MD, FRCPC, E.E. Thomas², MD, PhD, FRCPC

1. University Health Network, (Western Division) and Department of Dermatology, University of Toronto, Toronto, ON, Canada
2. Department of Pathology, University of British Columbia and Children’s and Women’s Hospital, Vancouver, BC, Canada

Background

Cold sores are caused by the herpes simplex virus (HSV). There are two subtypes of HSV (HSV-1 and -2). Although HSV-1 is the most common cause of cold sores, there is a significant overlap in the epidemiology of the two subtypes and approximately 10% of
cold sores in adults are caused by HSV-2. Socioeconomic status and age influence the frequency of HSV-1 infection. Seroconversion occurs during childhood in developing countries and in lower socioeconomic populations.

Approximately 1/3 of children have been infected by 5 years of age; this frequency increases to 70%-80% by early adolescence. In developed countries approximately 20% of children are infected prior to the age of 5 and the antibody prevalence increases to 40%-60% in the second and third decades of life. Once an individual has been infected with HSV-1, the virus lies dormant in nerve cells and reactivation may recur, particularly around times of stress. The recurrent infection can manifest as classical cold sores but may also result in asymptomatic shedding. Reactivation is estimated in approximately 30% of HSV infected individuals.

Symptoms

• Recurrent clusters of small blisters localizing along the vermilion border of the lips can also occur near the nose, chin and in the mouth especially in the immunosuppressed.
  – outbreaks may occur in the eye or be widespread in eczema herpeticum
  – most common initiating factor in recurring erythema multiforme.
• Prodromal symptoms in the form of pain or tingling often occur 1-2 days before blisters appear.
• The blisters often break or ooze, weeping a clear fluid, containing infectious virus.
• Crusting can be prolonged if secondary bacterial infection occurs.
• The blisters generally heal within 7-10 days.

Diagnosis

The diagnosis is usually made clinically. Same day laboratory confirmation is provided by direct immunofluorescence, which distinguishes between HSV-1 and -2. The ideal sample for this test is obtained by collecting scalpel scrapings from the blister base, which is then smeared onto a glasslide and air dried before submitted to the laboratory. The virus can also be cultured, but results will take 3-7 days.

Causes of Herpes Labialis

• Most frequently caused by HSV-1 (genital herpes are more often caused by HSV-2).
• Recurrences are often triggered by stress, exposure to the sun, or fever.
• Some patients report that eating foods with high concentrations of arginine (such as nuts, sunflower seeds and chocolate) increases the likelihood of an outbreak.
• HSV-1 is spread through kissing or by using utensils, toothbrushes or towels that have been in contact with open sores.

Prevention

Prevention of future outbreaks is an important concern. Patients should:

• Wash hands carefully and frequently when they have a cold sore
• Limit sun exposure and apply sun block frequently to lips and surrounding skin before exposure
• Avoid triggering situations
• Exercise caution when touching other parts of the body, particularly genitals and eyes.

Treatment

• Most cold sores will clear up on their own after 7-10 days. The following actions sometimes help to minimize the pain and discomfort associated with cold sores:
  – applying an over-the-counter cream to the affected area
  – using rubbing alcohol to dry the lesions
  – taking ibuprofen or acetaminophen for the pain
  – applying ice or heat to the blisters
  – avoiding picking or squeezing the blisters.
• Treatment options are focused on reducing the discomfort associated with cold sores and lessening the duration of the outbreak. Newer approaches aim to prevent the outbreak from progressing from the prodrome stage.
• Take into consideration the difference in cost, viral resistance and convenience to the patient.
• In Canada, prescription drugs include acyclovir cream or capsules (Zovirax®), famciclovir (Famvir®), penciclovir cream (Denavir®), valacyclovir caplets (Valtrex®).

Topical

• Acyclovir cream (Zovirax®)
  – apply 4-6 times per day
  – shown to be effective in reducing the severity of cold sores in the immunocompromised.
• Docosanol cream (Abreva®)
  – apply 5 times per day at prodrome
  – OTC
  – shown to have a positive effect in one trial.

Oral

• Acyclovir (Zovirax®)
  – 400mg 5 times a day shown to reduce the duration of infection by 27%.
• Famciclovir (Famvir®)
  – indicated for the treatment of recurrent episodes of mucocutaneous herpes simplex virus infections in HIV-infected patients (500mg b.i.d. x 7 days).
  – expanded indications are currently being explored in clinical trials.
  – famciclovir 500mg t.i.d. has been shown to reduce the time of active lesions by 48%. [Spruance, et al. J Infect Dis 179:303-10 (1999).]
  – combination with topical steroids to the lesion may enhance benefit but the best topical is not yet established.
• Valacyclovir (Valtrex®).
  – 2g every 12 hours for two doses will prevent outbreak of cold sores if taken early in the prodrome. [Spruance, et al. Antiviral Res 53:a53 (2002).]
• Both valcyclovir and famcyclovir have been shown to reduce orofacial herpes outbreaks after laser resurfacing.[Plastic Reconstr Surg 104:1103-80 (1999).] Both of these drugs have been used world wide for the prophylaxis and treatment of cold sores.
• Oral antivirals can be taken daily to prevent recurring blisters for those patients who experience frequent episodes.

The Oral Antiviral Family

Acyclovir is a “nucleoside analogue” (it can insert itself into virus DNA during viral replication) and specifically targets virus infected cells. It prevents the production of new virus by stopping viral DNA from properly forming. Famciclovir and valacyclovir work in a similar manner to acyclovir. Because of the way they act, these three drugs require the virus to reactivate in order to be effective.

Therefore, they are only effective against virus that has escaped from the nerve-cell and is replicating in other parts of the body. Thus, they do not cure a ‘dormant’ (latent) HSV infection, since the latent virus is not replicating. There is no antiviral treatment available that can eradicate latent HSV infection.

Conclusion

Cold sores can be an embarrassment. They can provide a source of herpes that can autoinoculate into the eye as well as infect others. In atopic dermatitis it can be become very widespread and can also produce erythema multiforme. Treatment both topically and
systemically can modestly reduce the duration and intensity of the outbreak. The use of topical antivirals as prophylaxis is ineffective. Significant advances in recent studies have shown that high dose therapy in the early prodrome can prevent the eruption.