Successful treatment of disseminated facial verrucae with contact immunotherapy

ARTICLE

Verrucae planae (flat warts) are small, skin coloured or light brown and slightly elevated, flat-topped, grouped papules with minimal scale, sometimes occurring in a filiforme pattern. They are most frequently located on the face, hands and lower legs. Young children of both sexes but also adults, preferentially women, are affected. Their etiology is associated with human papilloma viruses, usually types 1-3, 5, 7, 10, 26-29 and 41 [1]. The therapeutic management depends on the age of the patient, the extent and duration of the lesions, the individual immunological status and the patient's desire for therapy. Therapeutic options include chemical peeling, electrodissication, curettage, cryotherapy, CO₂-laser and topical immunotherapy. We report on a 14-year-old girl with verrucae planae juveniles of the face, refractory to common therapeutic procedures. The facial localization, the high cosmetic impairment and a psychoreactive distress led the girl to ask for therapy. After 6 weeks of topical immunotherapy with diphenylcyclopropenone the patient was in complete remission.

Case report

When admitted to our department, the 14-year-old girl reported increasing eruptions of multiple, skin-coloured to grey-brown, 2-5 mm papules on the whole face (Figs. 1A, 3A). The first papules had developed on the forehead 18 months earlier and had been treated by curettage several times (Fig. 2A). A few months later, the whole face was covered by multiple filiforme warts. No history of any severe disease, immune defect, atopy or consumption of any medication could be found. Blood tests were normal except for a borderline white blood count (10.5/µl, normal range: 4.00-10.0/µl), lowered serum transaminase (0.06 umol/s.l, normal range < 0,52 umol/s.l), hyperalbuminemia and lowered beta globulins. Peripheral immunophenotyping of lymphomononuclear cells and of immunoglobulins in the blood were normal. Prick tests for atopy screening were negative. An intracutaneous recall antigen test revealed a slightly diminished activity. Dermatopathological examination confirmed an acanthotic epidermis with papillomatosis, hyperkeratosis and parakeratosis in accordance with the diagnosis of verrucae planae. Because of the widespread distribution, the long clinical course of the disease and the probable risk of scarring by electrodisiccation or CO₂-laser, and, in particular the high probability of relapse, we decided to start topical immunotherapy in order to induce a longstanding T cell memory. The initial challenge was performed using a 0.5 ml solution of diphenylcyclopropenone 2% in acetone on the forehead. The patient reported 3 days of erythema and itching at the site of the first application. After a one-week break, the challenge for a successful sensitization was performed using diphenylcyclopropenone 0.01% on the forehead. After the challenge, the girl reported edema and redness of the whole face. Several verrucae became inflammed so that the treatment had to be interrupted for 2 weeks. Thereafter, the challenge was continued weekly with a concentration of 0.01%. Except for slight itching and redness no adverse events were observed. After the 4th challenge, the first warts peeled off and six weeks after initial treatment, most of the warts had disappeared (Figs. 1B, 2B, 3B). DCP application was continued at the same concentration and quantity on the remaining verrucae of the face. After nine applications the topical contact immunotherapy was discontinued as there were no signs of any remaining verrucae planae. So far, the patient remains free of relapse.

Discussion

Disseminated flat warts are a therapeutic problem in particular if affecting the face. Characteristically, they easily become irritated and the chance of further autoinocculation of the HPV-virus and dissemination is increased. In our patient, curettage had been performed but with no success and, in addition, self-manipulation by the girl had led to massive spreading of the warts. Considering that the whole face was covered with the lesions, treatments such as cryotherapy, CO₂-laser and curettage would have incurred a high risk of scarring and further inoculation of virus. Verrucae are known to have a high frequency of spontaneous remission but due to the severe course and the severe psychological suffering of the young girl some sort of therapy was urgently required.

Immunotherapy with potent contact allergens such as dinitrochlorobenzene (DNCB) or diphenylcyclopropenone (DCP) has already been used in the treatment of alopecia areata and resistant warts [2]. In 1973, Lewis [3] and Greenberg [4] first described a success in therapeutically refractory verrucae vulgares by application of DNCB, with a cure rate of 91% in compliant patients [3]. The good results were later confirmed by Wiesner-Mentzel et al. [5] and Erikson [6]: 86% of the patients were successfully sensitized and 80% out of these were cured [6]. A clear dose and time relationship however does not exist. There are several studies reporting successful treatment with DCP that are characterized by different application modalities [7-11]. Whereas, for example, Wiesner-Mentzel applied the contact allergen twice a week in an increasing dosage over a period of two to three months [5], Rampen et al. used a weekly application over eight weeks [8] while Larsen every three weeks over an average time of six months [7]. The rate of positive responders for the treatment of warts varies from 60% [8, 11] to 85% [7]. The relapse rates range from 1% to 22% [7]. We applied DCP once a week over nine weeks and confirmed the results of Rampen [8]. In addition, we observed that this procedure has a low frequency of adverse events. Those reported for DCP in the literature include urticarial reactions, generalized rashes, severe local reactions, contact allergy to acetone, pigmentary incontinence such as vitiligo [12], even erythema multiforme-like eruptions [13] and finally extrasystoles [9] and the Renbök phenomen, an inverse Köbner reaction [14]. On the other hand, it must be emphasized that topical immunotherapy is less painful, has a minimal risk of scarring, is easy to handle and does not interfere with physical activities such as sports, not forgetting the low degree of disablement, especially in the case of plantar wart treatment.

The mechanism of wart destruction by the host's own self-defense mechanisms has become more and more clear. Contact immunotherapy may work via the induction of a type IV hypersensitivity response in virus-infected tissue. An additional role of humoral factors as a second step is suggested by data of Erikson, as he found an incidence of complement-binding virus antibodies increasing from 15% before to 48% after contact immunotherapy [6]. We think that this is an epiphenomenon after the virus is exposed to the immune system again. Naylor et al. proposed wart-antigen-specific T cell cytotoxicity to be less likely as the primary mechanism of action because he observed a lack of resolution in non-treated warts [11]. It is well known that viral particles can grow in an immunological niche, for example a wart. Patrolling T cells may not reach or may not even recognize the viral DNA or the infected cell. MHC I and MHC II expression can be minimized in the keratinocytes of warts. It has been reported that ICAM-1 expression preceeds re-recognition and cell trafficking into the wart. Our case report demonstrates that the observation of Naylor et al. [11] must not be generalized as we applied DCP on the forehead only. As there were remaining warts on the left side of the perioral skin after six treatments we included this region successfully during the last three applications. Regarding the efficiacy of this method it needs to be considered that reinfection can occur. Naylor pointed out that the long-lasting immunity typical of antigen-specific cell-mediated immunity is not conferred by DCP/DNCB therapy [11]. One may speculate whether there are different immunological mechanisms also including a specific effector lymphocyte response leading to the release of interleukin-2 and interferon-gamma that augment the function of nonspecific cell-mediated defense such as phagocytes and natural killer cells [15]. Others claimed that a type III immunoreaction occurs when the fast regression of warts is observed in the presence of antibodies [16].

In summary, we have been able to clearly demonstrate that contact immunotherapy with DCP is a very effective and practical method for the treatment of refractory warts. We have additionally shown that it is effective in difficult locations such as the face, without major complications.

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