Recalcitrant viral warts treated by diphencyproneimmunotherapy

D.A.BUCKLEY, F.M.KEANE, S.E.MUNN, L.C.FULLER, E.M.HIGGINS AND

A.W.P.DU VIVIER

Department of Dermatology, King's College Hospital, Denmark Hill, London SE5 9RS, U.K.

Accepted for publication 18 February 1999

Summary Recalcitrant viral warts are a troublesome therapeutic problem. Immunotherapy with the universal

allergic contact sensitizer diphencyprone (DCP) has been used successfully in such cases. We havereviewed our experience of the use of DCP in the treatment of resistant hand and foot warts during an

8-year period. Sixty patients were sensitized to DCP during this time; the median duration of warts

was 3 years. Twelve patients defaulted from treatment. Of the remaining 48 individuals, 42 (88%)cleared of all warts. The median number of treatments to clear was ®ve (range one to 22) and the

median time to clear was 5 months (range 0´5±14). Adverse effects occurred in 27 of 48 patients

(56%), most commonly painful local blistering (n�11), blistering at the sensitization site (n�9),pompholyx-like reactions (n�7) and eczematous eruptions (n�4). Three of those who defaulted did

so due to side-effects, one became pregnant and eight dropped out for unknown reasons. Three of the

48 patients who cleared or had at least six treatments also discontinued DCP therapy due to side-effects, but most tolerated treatment well. Twenty-®ve patients were followed up for periods of

1 month to 8 years (median 2 years) and none had a recurrence. DCP immunotherapy is an effective

option for the treatment of recalcitrant viral warts but patients must be motivated to attend forsequential applications and must be warned about potential uncomfortable side-effects.

Key words: contact sensitivity, diphencyprone, immunotherapy, viral warts

Recalcitrant viral warts are one of the most common

therapeutic problems presenting to the dermatologist.

Such patients have been unsuccessfully treated withparing, keratolytics and cryotherapy and may

previously have consulted chiropodists or undergone

surgery. A variety of additional treatments may be usedin the dermatology clinic such as intralesional

bleomycin,1 topical retinoids,2 laser destruction3 and

oral cimetidine4 but all are limited by practicaldrawbacks or lack of ef®cacy. Since 1990 we have

been treating patients with resistant warts using the

universal contact sensitizer diphencyprone (DCP) with aremarkable degree of success. We have reviewed our

experience with this method over an 8-year period to

assess the usefulness of DCP in the treatment of recalci-trant warts and the incidence of associated side-effects.

Subjects and methods

Sixty patients were sensitized to DCP between July 1990and June 1998. All had severe digital or plantar warts

which had failed to respond to at least two forms of

conventional treatment such as keratolytics and

cryotherapy. Exclusion criteria were inability to attendregularly for repeated treatments, age less than 10 or

greater than 70 years, pregnancy and lactation. In the

case of 21 patients treated prior to July 1997, data wereobtained by retrospective review of case notes. Thirty-

nine patients were prospectively recruited from the

general dermatology clinic between July 1997 andJune 1998 and data were recorded during and subse-

quent to treatment. Patients were sensitized using a 2%

solution of DCP in acetone applied to a 1-cm diameterarea of inner upper arm skin with a cotton bud. This

was allowed to air dry, covered and inspected after

10±14 days. Application was repeated on up to threeoccasions until local erythema and vesiculation

occurred.

DCP was then applied to all the warts (pared downwhere possible) using a cotton bud, allowed to air dry

and carefully covered to avoid passive transfer. Patients

were instructed to leave the dressings in place for aminimum of 48 h and to begin paring and keratolytic

British Journal of Dermatology 1999; 141: 292±296.

292 q 1999 British Association of Dermatologists

Correspondence: Dr A.W.P.du Vivier. E-mail: duVSkin@aol.com

agents when any reaction to DCP had settled. Betweentreatments, ready access to telephone advice and if

necessary to clinic was available. Routine visits for exam-

ination and treatment were at 1±4-weekly intervals asdetermined by the patients' ability to attend. The dosage

schedule was tailored to each individual, according to

their response or reaction. The standard initial concen-tration used was 0´1% for digital warts and 2´0% for

plantar warts, but in some instances where the patient

had had a very severe sensitization reaction the initialdose was reduced and subsequently slowly titrated

against the patient's response. At each visit, after ques-

tioning about adverse effects and degree of improvement,the concentration of DCP was increased by one step (if no

response), kept constant (if adequate response) or lowered

by one step (if severe blistering occurred). Stepwise con-centrations used were 0´01, 0´05, 0´1, 0´25, 0´5, 1´0,

1´5, 2´0, 3´0, 4´0 and 6´0%.

Treatment was continued until neither patient nordoctor could detect any clinical sign of residual wart at

any site. Patients who failed to attend were contacted by

letter (and telephone where possible) and offered furtherappointments. Fewer than six applications was not

considered an adequate trial of treatment, so patients

who had not cleared and who stopped attending beforethey had had six applications were considered to have

defaulted. Patients who had had six or moreapplications and failed to improve, or experienced

adverse effects they found intolerable, were withdrawn

from the study. Patients who cleared of all warts,irrespective of the number of applications (many

patients cleared with ®ve or fewer), were considered

therapeutic successes. Localized itching and/or mildvesiculation were an expected result of the treatment

and were not considered adverse effects.

Results

Sensitization to DCP was attempted in 60 patients, andwas successful in all. Thirty-nine sensitized after one

application of 2% DCP, 20 after two applications and

one after three. Twelve patients who were not clear attheir most recent clinic visit defaulted after between no

and ®ve treatments with DCP. One had had localized

blistering, one in¯uenza-like symptoms and one areaction at the sensitization site; these were considered

to have defaulted due to adverse effects. One patient had

become pregnant. The other eight were presumed tohave defaulted due to dif®culty in attending, although

as they were not contactable by letter or telephone,

exact details were unavailable.

Of the remaining 48 patients, there were 23 malesand 25 females. The mean age of patients was 34 years

(range 11±65). The median duration of warts was

3 years (range 3 months to 20 years). Warts werelocated on the sole in 28 patients, on the hands in 12

and at both sites in eight. All patients had previously

received prolonged conventional treatment: keratolyticsin 47 patients, cryotherapy in 31 and surgery or

electrocautery in 13. Five had attended chiropodists,

11 had attended or been referred by other dermatologydepartments and three had had intralesional bleomycin.

Forty-two of the 48 patients who persisted with

treatment (88%) cleared completely of all warts after amedian of ®ve applications (range one to 22). The mean

age of patients who cleared was 32 years (range 11±65)

and the median duration of warts 3 years (range3 months±14 years). The median interval between

treatments in these patients was 3 weeks (range 1±4)

and the median time to clear 5 months (range 0´5±14).The median concentration of DCP used for digital warts

(n�18) at the beginning of treatment in patients who

cleared was 0´1% (range 0´05±2´0) and at the ®naltreatment 1´0% (range 0´1±2´0); for plantar warts

(n�32) the corresponding concentrations were 2´0%

(range 0´05±2´0) and 2´0% (range 0´01±6´0),respectively. Side-effects occurred in 24 (57%) of those

who cleared. Follow-up data are available for 25patients who cleared, for periods ranging from

1 month to 8 years (median 2 years; total person years

of follow-up 54), and none had a recurrence.For the six patients who failed to clear, the mean age

was 35 years (range 21±55), the median duration of

warts 5´5 years (range 11 months to 20 years) and themedian interval between treatments 3´5 weeks (range

1±4). In the two patients with digital warts who failed

to clear, the concentrations of DCP used were 0´1%initially in both and 1´0% and 6´0%, respectively, at the

®nal treatment. In the four patients with plantar warts

who failed to clear, the median concentrations of DCPused were 2´0% at the initial treatment (range 0´5±2´0)

and 6´0% at the ®nal treatment (range 2´0±6´0). Side-

effects occurred in three of these patients (50%).Three of the patients who failed to clear had no

reaction to DCP applied to the warts at concentrations

of up to 6% on the sole and 1% on the ®ngers, despitehaving had weak sensitization reactions. One

subsequently underwent investigations of cell-mediated

immunity which were normal and in another the wartcleared after it was biopsied. The other three patients

who failed to clear had strong reactions to DCP applied

on at least six occasions without improvement, and

IMMUNOTHERAPY OF VIRAL WARTS 293

q 1999 British Association of Dermatologists, British Journal of Dermatology, 141, 292±296

eventually withdrew due to side-effects. The ®rst, a 55-year-old man with a plantar wart who had a severe

eczematous eruption on the ipsilateral lower leg follow-

ing the sixth application of 2% DCP, refused furtherimmunotherapy and his wart eventually cleared with

intralesional bleomycin. A 32-year-old woman with a

plantar wart had eight applications of DCP at concen-trations of up to 6% with moderate improvement, but

then developed generalized eczema and declined further

treatment. The third patient, a 23-year-old woman witha plantar wart, withdrew after seven applications of DCP

at concentrations of up to 6% resulting in only mild

improvement and a pompholyx-like eruption on the sole.A total of 36 adverse effects occurred in 27 of 48

patients (56%): painful blistering near the wart (n�11),

blistering at the sensitization site (n�9), a pompholyx-like(n�7) or more generalized (n�4) eczematous eruption,

in¯uenza-like symptoms (n�2), vesiculation elsewhere

due to passive transfer of DCP (n�2) and inguinallymphadenopathy (n�1). The mean age of patients

who experienced side-effects (n�27) was 33 years

(range 15±57), the median duration of warts 3 years(range 3 months±20 years) and the median interval

between treatments 4 weeks (range 1±4). Similarly, in

patients who experienced no side-effects (n�21), themean age was 32 years (range 11±65), the median

duration of warts 3 years (range 3 months±14 years)and the median interval between treatments 3 weeks

(range 1±4). In patients with side-effects, the median

concentration of DCP used at the ®nal treatment for digitalwarts (n�10) was 1´0% (range 0´01±2´0) and for

plantar warts (n�23) 2´0% (range 0´01±6´0). The

results were similar in those without side-effects, themedian concentration of DCP used at the ®nal treatment

for digital warts (n�9) being 1´0% (range 0´1±6´0) and

for plantar warts (n�14) being 2´0% (range 0´5±6´0).

Discussion

Immunotherapy of warts was ®rst described 25 yearsago when it was noted that application of the universal

allergic contact sensitizer dinitrochlorobenzene (DNCB)

to warts resulted in their clearing as a bystander effect inpreviously sensitized individuals.5 An alternative

sensitizer, squaric acid dibutyl ester (SADBE), was

subsequently used in the same way.6 In 1984, aGerman group was the ®rst to report the successful

treatment of patients with resistant plantar warts using

DCP and since then there have been several otherpublications from Europe and America7±12 (Table 1).

In the U.K., DCP is used to treat alopecia areata but

there is no record of its use for viral warts. DCP was ®rstsynthesized in 1959 and ®rst used for alopecia areata in

1983.13 In view of its degradation by ultraviolet (UV)

radiation, it is prepared as dilutions in acetone andmarketed in brown UV-opaque bottles. Its shelf life is

3 months and it is commercially available in the U.K. at

concentrations of 0´001±6´0% (Nova Laboratories Ltd,Wigston, U.K.). There has been a single case report of its

successful use in cutaneous malignant melanomametastases.14

Our clearance rate of 88% with DCP is similar to that

reported with DNCB (69±91%)15±20 and better than thatwith SADBE (11%).6 However, DCP may be a safer option,

as unlike DNCB, it is not mutagenic in the Ames assay9

and not detectable in serum or urine after topical applica-tion.21 A precursor and potential contaminant of DCP,

a,a0-dibromodibenzyl ketone, has been found to be muta-

genic in vitro.22 DCP is a more potent contact sensitizerthan DNCB for the same concentration.9 SADBE is an

unstable and considerably more expensive alternative.9

We achieved a higher clearance rate in our studythan did others with DCP (8±75%).7±12 One reason for

294 D.A.BUCKLEY et al.

q 1999 British Association of Dermatologists, British Journal of Dermatology, 141, 292±296

Table 1. Comparison of outcomes in studies using diphencyprone (DCP) to treat viral warts

First author, year No. of No. of Concentration

and reference patients Wart type treatments (%) of DCP % clear % side-effects Comments

Wiesner±Menzel (1984)7 8 Plantar 8±12 1´0±3´0 75 12´5 Sensitized on 10 ´ 10 cm

area of skinLane (1988)8 10 Hand, plantar Unknown 0´1±1´0 50 20 Allowed to self-treat

Naylor (1988)9 45 Plantar, hand, Unknown 0´01±1´0 62 49 Allowed to self-treat on a

glabrous, genital daily basis

Orecchia (1988)10 44 Plantar, hand, face 3±10 0´2±2´0 45 25 Best results in hand andfacial warts

Rampen (1996)11 111 Plantar, hand 8 0´001±3´0 8 4´3 44% clear at 4 months follow-up

Buckley (present study) 48 Plantar, hand 1±22 0´01±6´0 88 56 12 of original 60 patients

defaulted

this may be the fact that we did not discontinuetreatment after an arbitrary number of applications,

but rather continued until all warts were clear. We also

increased the concentration of DCP after eachtreatment, if the patient had had no symptoms and

the warts had not improved, up to a maximum of 6%.

There was wide variation in the intensity of individualpatients' reactions to any particular concentration of

DCP, which bore no relation to the eventual likelihood of

clearing (e.g. some cleared after only one or twoapplications of 0´1% DCP with minimal or no

symptoms, while others failed to improve or to

experience symptoms as the concentration of DCP wassequentially increased up to 6%, but subsequently

slowly cleared with mild vesiculation as this concentra-

tion was repeatedly applied). The median initial and®nal concentrations of DCP used did not differ between

those who cleared and those who did not.

Our study population differed somewhat from that inother studies which included patients with genital warts

and facial plane warts.9,10 In a previous paper, none of

the small number of patients with genital wartscleared.9 We do not treat genital or facial warts with

DCP, as the risk of passive transfer is high in the genital

area, and bullous or eczematous side-effects would beless acceptable on the face. In our view, DCP

immunotherapy is particularly suitable for plantar,palmar, periungual and digital warts. As we had no

controls, we cannot exclude that some of our patients

might have cleared due to chance during the course oftreatment. Two-thirds of warts will be expected to

resolve spontaneously within 2 years.23 However, as

most of our patients had warts of longer durationthan this and previous second- and third-line

treatments had failed, it seems unlikely that the

resolution was spontaneous. We found age to have noin¯uence on the likelihood of clearance, but the

duration of warts was longer (median 5´5 vs. 3 years)

in those who failed to clear. Age and duration of wartswere unrelated to the incidence of side-effects. There

have been no controlled trials of the use of DCP vs.

placebo, although in patients in whom some warts wereleft as untreated `controls' the latter failed to clear.7,12 A

study reporting unilateral treatment with DNCB noted

clearing of warts on the untreated side.24 We have apolicy of treating all detectable warts in each individual

to maximize the likelihood of clearance.

The potential side-effects of DCP treatment are notinconsiderable. In patients treated for warts these are

mainly blistering at the sensitization site and near the

wart. Distant or more widespread eczematous eruptions

also occur,8±11 either due to passive transfer of DCP orautoeczematization. Such reactions generally respond

to a potent topical steroid, although in a small number

of patients eczema may persist for 2±3 weeks after eachapplication. Regional lymphadenopathy is a less

frequent adverse effect. Contact urticaria,8 erythema

multiforme-like reactions25 and, in patients treated foralopecia areata, in¯uenza-like symptoms26 (as

experienced by three of our patients), vitiligo27 and

`dyschromia in confetti'28 have also been reported. Wefound most patients with recalcitrant viral warts to be

very well motivated and to tolerate any side-effects well.

A number of our patients cleared without anysymptoms at all. Although the scheduled frequency of

application varied between patients, this did not

in¯uence the likelihood of side-effects as the intervalsbetween applications (minimum 7 days) were such that

any adverse reaction would have occurred prior to the

next visit, enabling deferment of a treatment ifnecessary. The concentrations of DCP used were titrated

to each individual's contact allergic response, and thus

did not in¯uence the likelihood of side-effects.Certain precautions are advisable if DCP treatment is

to be undertaken. Use in pregnancy is probably best

avoided as it remains an unlicensed treatment andthere are no data on its safe use in this situation.

Patients should be followed up regularly and haveeasy access to advice in the event of complications. In

our view, patients should not be allowed to self-treat

as the risk of adverse reactions with unsupervised useis too great. Staff should be well trained in handling of

the chemical29 and should wear protective latex or

vinyl gloves for all parts of the procedure, includingdisposal of contaminated equipment (in our depart-

ment, we place the used cotton buds into `sharps

containers').We ®nd DCP an effective therapeutic modality for the

treatment of resistant viral warts, which is popular with

patients. In view of its propensity to cause side-effects,its use is best limited to supervised application in

dermatology departments. Best results are achieved

when diligent paring and keratolytic treatment areused in conjunction with treatment. It does, however,

require repeated hospital visits and so is not a practical

option for all individuals.

Acknowledgments

Our thanks to Mr Richard Hooper, Department of Public

Health and Epidemiology, King's College School of

Medicine and Dentistry, for statistical advice.

IMMUNOTHERAPY OF VIRAL WARTS 295

q 1999 British Association of Dermatologists, British Journal of Dermatology, 141, 292±296

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