W. Steven Pray, PhD, DPh; Joshua J. Pray, PharmD

Disclosures

Introduction

The American public often thinks of warts as nothing more than a minor nuisance. There is little awareness that some types (e.g., genital warts) are harbingers of fatal illnesses. Further, warts may be treated by a host of modalities. Recent evidence suggests that some therapies traditionally considered highly efficacious deserve reassessment.

The Etiology of Warts

Viral in origin, warts are caused by the 8kb, circular, double-stranded DNA human papillomavirus (HPV).[1—4] There are more than 100 HPV subtypes, each with a different body site and potential for malignancy.[2]

Prevalence of Warts

About 10% of children and adolescents have warts at any one time.[2] As many as 22% of children will contract warts during childhood.[3]

Epidemiology of Warts

While warts can affect anyone, a few epidemiological variables are known. Certain age-groups are more prone to warts. Those ages 9 to 16 years are at highest risk.[2] The peak age is 14.5 years for males and 13 years for females.[1] Only those who are sexually active are at risk of genital warts. People who work with raw meat are at particularly high risk of butcher's warts.[5] Since HPV has not been found in the tissues of the animals, butcher's warts are thought to be caused by occupational trauma, perhaps combined with the cold and moist conditions under which the job is performed.

Varieties of Warts

Warts can be categorized using several systems. The most widely used is a mixture of appearance and location. This taxonomy separates warts into four distinct groups.[1]

Common warts (verruca vulgaris) are the most frequently occurring wart, comprising 70% of the total number.[6] Their favored site is the hands, although they can manifest anywhere on the body, including mucous membranes.[2] The preference for the hands partially reflects the high likelihood that hands will contact a contaminated environmental surface during play or work. It is also caused by the natural tendency for young children to pick or scratch at existing warts, spreading them to unaffected skin, a process known as autoinoculation. Common warts may also occur beneath the fingernails. Known as subungual warts, they are shielded from effective treatment by the nail, and some treatments are not appropriate, as they may damage the nail.

Plantar warts (verruca plantaris) are also common, affecting 4.5% of the population.[3] By definition, plantar warts occur on the weight-bearing surfaces of the feet, such as the heels, toes, and mid-metatarsals. Their location reflects the site of epidermal penetration. Because weight-bearing areas are most prone to minor injury upon ambulation, they are most likely to develop plantar warts. The scenario is deceptively simple. The patient who already has a wart walks barefoot, leaving behind viral particles. As subsequent unshielded feet walk on that surface, the parts that are most likely to be inoculated with virus are those that contact the surface (i.e., weight-bearing areas).

The location also determines the appearance of the plantar wart. As the plantar wart grows, it is subjected to continual, repeated pressure due to continued ambulation. This causes the wart to grow inward (endophytic) rather than outward like a common wart or genital wart (exophytic). At times, several plantar warts accumulate beneath the surface of the epidermis, with the surface resembling one large wart.[3] These mosaic warts are difficult to treat due to the multiple foci of viral reservoirs.

Flat warts (verruca plana) are most often found on the face, neck, and extremities.[2] As implied by the name, these warts do not protrude above the skin surface. Rather, they are so flat that they appear not be hyperkeratotic; if they are pigmented, patients may mistake them for solar lentigines or sun freckles (ephelides).[2] They range in size typically from 2 to 5 mm and may vary in color from the patient's skin tone to red or brown. Damaging a flat wart (e.g., shaving the neck) may cause the virus to spread, eventually leading to crops of several hundred flat warts.

One percent of sexually active adults experience genital warts (condyloma acuminata).[6] Genital HPV is the most common sexually transmitted disease (STD) in the United States and is associated with cervical carcinoma. Despite this, fewer than one third of people living in the U.S. are aware of genital HPV.[7] It is the least-known STD among college students. Similarly, few women know that genital warts are more common in those with early sexual debut, greater number of sexual partners, and users of tobacco and oral contraceptives. They fail to understand that HPV may be contracted without engaging in full sexual intercourse or when the male has worn a condom. In one study, investigators found that media coverage of genital warts often failed to present basic information, such as its link to cervical carcinoma.[7] Genital warts are a marker of sexual abuse when they occur in children, especially those older than age 3 years.[2]

Natural History of Wart Infections

HPV viral particles enter the skin through tears or abrasions, although the process through which they enter the basal or proliferative layer of squamous cells has not been elucidated.[2,3] The virus inserts DNA into the genome of the host, triggering an abnormal replication of cells. The virus also increases blood flow to the area to facilitate the abnormally rapid growth.[3] HPV can have a sustained inoculation period before warts manifest. While warts may become noticeable to the patient within a matter of weeks, some do not grow for at least 18 months.[2] Left untreated, most disappear on their own without scarring, a phenomenon known as involution or spontaneous regression. About 30% of warts clear within six months, 66% disappear within two years, and 75% clear by three years.

Confirmation of Wart Infection

Several conditions can mimic warts, including self-treatable problems, such as corns or calluses, and more serious conditions, such as seborrheic keratoses, lichen planus, epidermal nevi, molluscum contagiosum, and squamous cell carcinoma. Warts can be recognized by two features: (1) They erode skin patterns. Thus, print ridges of the foot (in the case of plantar warts) are obliterated. (2) If a physician pares a wart with a scalpel, it will exhibit pinpoint areas of bleeding.[8] (Patients should be warned against unsafe home removal methods such as paring the wart with a knife or razor blade.)

If the lesion is not clearly a wart, the patient should be referred. Physicians can confirm the diagnosis by techniques such as biopsy followed by immunoperoxidase staining, polymerase chain reaction, in situ hybridization, or hybrid capture.[1]

The Spectrum of Wart Treatments

There is no cure for warts.[6] Current therapies are divided into two groups: destructive therapies and immunomodulators.[6] Destructive techniques encompass most traditional prescription interventions, such as podophyllin, podophyllotoxin, monochloroacetic/ trichloroacetic/bichloroacetic acid, 5-fluorouracil, bleomycin, retinoids, contact sensitizers, glutaraldehyde, formaldehyde, and cantharidin, as well as physical modalities, such as surgical excision, lasers, or adhesive/duct tape.[6] Physicians may also use cryotherapy, in which the wart is exposed to liquid nitrogen for one to four treatments, separated by one to three weeks. Local anesthesia may be required for pain. The pharmacist can recommend salicylic acid and several OTC home cryotherapy products when destructive therapy is contemplated. Immu-nomodulators include prescription agents such as interferon, imiquimod (for genital warts), cidofovir, and vaccines.

Investigators completed a comprehensive Cochrane Database review of nongenital wart treatments to assess the quality of existing evidence that documented their efficacy.[9] The results were surprising. Only randomized controlled trials of local treatments in immunocompetent hosts were included. Fifty-two trials met the criteria for review. In 17 of those, the cure rate for placebo averaged 30% after 10 weeks. Salicylic acid appeared to be the top performer, with six placebo-controlled trials finding that it had a cure rate of 75%, as opposed to only 48% in controls. Analysis of cryotherapy trials, which seldom met the criteria required, discovered that the treatment was no better than salicylic acid or duct tape, a significant finding considering the morbidity associated with cryotherapy. There was limited or inconsistent evidence for the efficacy of intralesional bleomycin, 5-fluorouracil, intralesional interferons, or photodynamic therapy. Given the potential hazards or toxicities of these treatments, their use should be reassessed. The topical contact sensitizer dinitrochlorobenzene exhibited evidence of efficacy but was not superior to salicylic acid, which is much safer.

Conclusion

The results of the evidence-based Cochrane review have profound implications for pharmacy. They call into question the efficacy of some physician-directed treatments but affirm the efficacy of salicylic acid, a modality available for pharmacist recommendation. It is seldom that a OTC product or device receives such a ringing endorsement, backed by the full weight of scientific evidence. The results also show that the considerable pain associated with physician-directed cryotherapy may not be necessary, since this treatment has not been proven superior to salicylic acid. Further, this raises an intriguing question. Physician-directed cryotherapy uses liquid nitrogen, at a temperature of 321°F. Some warts require as many as four widely spaced applications of liquid nitrogen, a process that can take more than two months. The home cryotherapy devices use dimethyl ether, which one manufacturer admits exists at a much higher temperature than liquid nitrogen.[10] If physician-directed cryotherapy with liquid nitrogen is not demonstrably superior to salicylic acid, it seems axiomatic that a home version using a higher temperature cryotherapy agent should be markedly inferior to salicylic acid. Until these issues are resolved, pharmacists would be well advised to continue recommending home treatment of warts with salicylic acid, unless contraindicated.

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