Salicylic acid is a keratolytic agent that destroys the epidermis infected by the virus. It is available in different vehicles at concentrations of between 10% and 30%. Topical salicylic acid is still the treatment with the best evidence base and it is the only option approved by the US Food and Drug Administration for warts.8 It is therefore considered the treatment of choice. Approximately two-thirds of all warts clear within 3 to 6 months of treatment with topical salicylic acid.8 One systematic review of 6 randomized controlled trials comparing salicylic acid with placebo for the treatment of warts in adults and children reported cure rates of 75% and 48%, respectively.9 A Cochrane review of a meta-analysis of 6 studies with 486 participants showed statistically significant results in favor of the topical application of salicylic acid for warts in any location.10 Although no adverse effects have been reported (with the exception of local irritation), in one study that compared 60% salicylic acid and monochloroacetic acid versus placebo, a patient developed cellulitis in the treated area.11

Cryotherapy consists of freezing the wart with liquid nitrogen for 10 to 20seconds every 2 to 3 weeks. Although the exact mechanism of action is unknown, the freezing is thought to cause local irritation, thereby stimulating an immune response. One multicenter clinical trial found no significant differences between the efficacy of cryotherapy with liquid nitrogen and 50% salicylic acid in patients with plantar warts. The fact that cryotherapy is more expensive, however, would appear to tip the balance in favor of salicylic acid.12 Another randomized controlled trial compared the efficacy of cryotherapy, salicylic acid, and a wait-and-see approach for common and plantar warts. The authors found that cryotherapy was more effective for nonplantar warts, but observed no clinically significant differences after 13 weeks of treatment. Finally, patients treated with cryotherapy experienced more adverse effects than those in the other 2 groups.13 Some authors are of the opinion that cryotherapy should not be used for longer than 3 months or for more than 4 procedures, as there is no evidence of any benefit of continuing treatment for longer, particularly in the case of warts on the hands and feet.14 The main disadvantage of cryotherapy is that the procedure can be painful and cause blistering; there is also a risk of residual scarring, hyperpigmentation, and hypopigmentation (Fig. 2).

Figure 2.

Blood-filled blisters after cryotherapy applied to 2 warts located on the lateral and dorsal aspect of a finger.

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Cantharidin is a blistering agent produced by beetles of the order Meloidae Coleoptera. It is used at a concentration of 0.7% or 1% and once applied should be covered with an occlusive dressing for 24hours. Cure rates of over 80% have been reported for common, plantar, and periungual warts.15 Although the application of cantharidin itself is not painful, the resulting blistering may be accompanied by erythema, pain, pruritus, and postinflammatory hyperpigmentation. More severe though less frequent adverse effects have been described, such as lymphangitis, bacterial cellulitis, and scarring.16

Surgical treatment of warts involves the radical eradication of lesions by conventional surgery, electrosurgery, or curettage. One of the advantages of surgery is that it provides a rapid solution and can therefore be beneficial in the case of recalcitrant or isolated warts. It is, however, associated with high rates of bleeding, scarring, and bacterial infections, and estimated recurrence is around 20%.17 One study showed a higher overall clearance rate for curettage and electrodesiccation (94%) than for podophyllin (41%) or cryotherapy (79%). Recurrence rates, however, were similar for the 3 treatments.17

Electrocoagulation causes heat-induced tissue destruction. Although it is very useful for treating filiform or small isolated warts, it is not a mainstay treatment for children,18 as it requires the use of local anesthesia and can leave a scar.

Phototherapy causes direct tissue destruction through exposure to different light sources. It is a painful procedure that is not available at all hospitals. As such it is not considered a first-line option for pediatric patients.

Glutaraldehyde is an antiviral agent. A 10% or 20% solution is applied daily over a period of 3 months.23 A cure rate of 72% was reported in a series of 25 patients with recalcitrant warts.23 There have been reports of deep necrosis after repeated application23 and of contact dermatitis.25

Formaldehyde, another antiviral agent, is applied once daily in a 0.7% gel or at a concentration of 3% to 10% in solution. One open-label study of 646 children treated with formaldehyde reported a cure rate of 80%.23 The substance is allergenic and can cause contact sensitization.

Retinoids are vitamin A derivatives (retinol) with cellular and biologic actions that include regulation of epidermal proliferation and differentiation. They are used both systemically—acitretin at a dose of 0.5 to 1mg/kg/d for a maximum of 3 months—and topically—tretinoin 0.05% applied once daily.23 In one observational study, 80% of children (16/20) treated with oral etretinate for 3 months achieved total wart clearance.18 In a case-control study of 50 children treated with tretinoin 0.05% or nothing, those who received the treatment achieved a clearance rate of 85%, compared with a 32% rate in the control group.26 Tretinoin 0.05% is a good option for flat facial warts.18 However, considering the caution that must be applied when using oral retinoids, particularly in teenage girls, and the fact that there is little evidence on their efficacy, etretinate is not recommended in children.18

Oral cimetidine is an H2 blocker that acts as a T cell–immunomodulator. It appears to inhibit suppressor lymphocyte function, thereby enhancing T-cell immunity.27 Cimetidine is administered orally at daily doses of 20 to 40mg/d, with a maximum dose of 600mg per day. One double-blind study found no statistically significant differences between oral cimetidine 400mg administered 3 times a day for 12 weeks and placebo for warts in patients aged over 12 years, while another randomized trial found no differences between cimetidine 40mg/kg/d versus placebo in women and children aged between 4 and 39 years.8 Gastrointestinal complaints such as nausea and epigastralgia were the most common adverse effects described.28

Candida antigen is a substance derived from purified extracts of Candida albicans. It is typically injected intralesionally, either pure or diluted to a concentration of 50% in lidocaine. The dose is 0.2 to 0.3mL and at least 3 applications—separated by 3 weeks—are required.29,30 Intralesional injections induce a localized HPV-specific cell-mediated response that targets both the injected wart and warts located at a distance. In a recent Spanish study of Candida antigen immunotherapy in 220 children, after a mean of 2.73 intralesional injections, 70.9% of children achieved complete resolution, 16.8% achieved partial resolution, and 12.2% did not respond.29 Of particular note was that the fact that over half of the patients with multiple lesions achieved complete resolution of lesions located at a distance, i.e., lesions that had not been directly treated. In a study of 100 patients of all ages at the Mayo Clinic, 80% of patients responded to treatment, with 39% achieving complete response and 41% achieving partial response.30

Candida antigen immunotherapy is normally well tolerated and does not leave sequelae,29,30 although there have been reports of pain, swelling, and purple discoloration in distal fingertips in the case of subungual warts 24hours after the injection; the effects disappeared, without sequelae.31 There has also been a report of vitiligo at the injection site of Candida antigen in an 8-year-old girl.32

The exact mechanism of action of imiquimod is unknown, but it is assumed to involve stimulation of both innate and cell-mediated immunity.33 In one study of recalcitrant subungual and periungual warts, 80% of patients treated with a preparation of salicylic acid followed by imiquimod 5% cream with an occlusive dressing 5 times a week for 16 weeks achieved complete resolution. The most common adverse reactions were local erythema, pruritus, and a burning sensation.34

Intralesional interferon is approved for the treatment of anogenital warts caused by HPV in adults, but it is not recommended for children due to its high toxicity and the limited experience with its use.22

Zinc sulfate appears to act as an immunomodulating agent via the polyclonal activation of lymphocytes. It is used at a dose of 10mg/kg/d to treat warts. One comparative double-blind study found that zinc sulfate 10mg/kg/d appeared to be more efficacious than cimetidine in children and adults with multiple or recalcitrant warts. However, given the few patients analyzed, no definitive conclusions can be drawn regarding the efficacy of zinc sulfate for the treatment of warts.28

Diphenylcyclopropenone is an allergic contact sensitizer used to treat resistant warts. Initial sensitization is required. To achieve this, diphenylcyclopropenone 2% is applied to a 1-cm2 area and covered for 48hours. The actual treatment consists of applying diphenylcyclopropenone 1% to the affected warts (or 2% for plantar warts) and covering these for 8hours. The process is repeated at intervals of 1 to 4 weeks.35 One retrospective study analyzed the 3-weekly application of diphenylcyclopropenone at concentrations of 0.5% to 5% in 25 patients (including adolescents) with recalcitrant warts. Fourteen patients (56%) achieved complete resolution after a mean of 4 cycles, while the remaining patients (44%) showed no improvement.36 Adverse effects are uncommon, but there have been reports of blisters, urticaria, and exacerbation of atopic dermatitis.35,36

5-fluorouracil is a fluorinated pyrimidine that is effective against viral warts because it blocks DNA and RNA synthesis of viral particles and reduces epidermal proliferation.37 It can be applied topically, with daily applications, or injected into the lesion with local anesthesia. Although several studies have shown it to be effective,37 it has not been tested in children.18 The most common adverse effects observed with both topical and systemic 5-fluorouracil are local irritation, moderate to severe pain during application, blistering, and onycholysis in periungual lesions.10

Bleomycin has antibacterial, antiviral, and cytotoxic activity, and by blocking cellular and viral DNA synthesis, it causes acute tissue necrosis that stimulates an immune response.8 It is injected intralesionally at concentrations of between 0.25% and 1%. Bleomycin causes pain, erythema, and inflammation during the procedure and up to a week afterwards. Widely varying cure rates (in the range of 16% to 94%) have been reported for the treatment of warts and results must therefore be interpreted with caution.38 Two placebo-controlled studies reported that intralesional bleomycin was not effective.10 The resulting necrosis causes ulcers, scarring, residual hyperpigmentation, and nail changes.39 There has been a report of flagellated hyperpigmentation in a 31-year-old woman with a recalcitrant plantar wart treated with intralesional bleomycin.40 Intralesional bleomycin has not been extensively studied in the pediatric population and should therefore be avoided in young children.18

Cidofovir is an antiviral agent that acts via competitive inhibition of viral polymerase DNA. It is applied as a topical cream at a concentration of 1% or 3%. It has been found to be useful for resistant warts that do not respond to standard treatments.41 In one series of 7 children with warts on their hands and feet, treatment with topical cidofovir 1% applied once daily for 12 weeks resulted in complete resolution in 4 patients. However, further studies with more patients are needed to demonstrate the efficacy and safety of topical cidofovir in children.18

Podophyllin is an antimitotic agent derived from the plant Podophyllum peltatum. It is used at a concentration of between 10% and 25% in alcohol or benzoin, and causes tissue necrosis. It must be left on the affected area for between 1 to 4hours, and then removed. It is reapplied weekly for up to 6 weeks.17 Podophyllin has been successfully used to treat anogenital warts, but in a study of 382 adults and children, it was found to be equivalent to salicylic acid for the treatment of plantar warts.42 Nevertheless, because it has been associated with neurotoxicity and myelotoxicity, it is not recommended for pediatric patients.18

Local hyperthermia is a simple treatment, particularly for multiple lesions. The affected area is soaked in water at a temperature of between 44°C and 47°C for 30minutes once a day for 3 consecutive days. This process is repeated 2 weeks later. Although the exact mechanism of action involved is not known, some authors have suggested that the local heat might trigger the death of HPV-infected keratinocytes.43 The same authors observed that hyperthermia caused the migration of mature Langerhans cells, stimulating a specific immune system response against infected keratinocytes. No serious adverse effects have been reported, although patients may experience a burning sensation and local erythema.

The mechanism of action underlying the use of duct tape to treat warts is not known, but like other treatments, it would appear to involve the stimulation of the immune system in response to local irritation. The wart is covered with duct tape (or a plaster) for 6 days, after which it is soaked in water, pared down, and left uncovered for 12hours. The cycle is repeated until the wart disappears. One prospective study that compared the effectiveness of duct tape versus standard local cryotherapy to treat warts in pediatric patients reported that duct tape occlusion was significantly more efficacious than cryotherapy. Of the 26 children who received this treatment, 22 (85%) achieved complete resolution of warts compared with 15 (60%) of the 25 children treated with cryotherapy (P=.05).6 These high cure rates, however, should be viewed with caution considering the absence of well-designed studies with large samples.

Polyphenon E is a green tea leaf extract (Camellia sinensis) that appears to induce cell cycle arrest, activate apoptosis, inhibit HPV transcription, and stimulate cell-mediated immunity. The combination of these actions results in the eradication of both clinical and subclinical HPV-infected cells. Polyphenon E is available as an ointment (15%) and is applied 3 times a week for a maximum of 16 weeks.20

Various components of garlic (Allium sativum) have been shown to have antiviral activity and to inhibit the proliferation of HPV-infected cells. In one placebo-controlled study, the application of garlic extracts resulted in complete resolution of warts, without recurrence after 3 to 4 months.8

Hypnosis has been used to treat warts in children and adults for years. It is believed to stimulate the immune system, leading to the resolution of lesions. No studies, however, have determined whether the warts heal because of hypnosis or simply because of spontaneous regression.8

It has been calculated that warts resolve spontaneously within 2 years in approximately two-thirds of patients,8 and hence many dermatologists prefer to adopt a watch-and-see approach rather than prescribe an active treatment. Such an approach, however, is not always possible as lesions can become ugly and cause stigmatization, leading many parents and/or patients to opt for treatment.