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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