Update: Treatment of Cutaneous Viral Warts in Children REVIEW

REVIEW
Pediatric Dermatology Vol. 28 No. 3 217–229, 2011
Update: Treatment of Cutaneous Viral
Warts in Children
Christina Boull, M.D.,* and David Groth, M.D. *Department of Medicine-Pediatrics, University of Minnesota, Minneapolis, Minnesota,
Department of Dermatology, University of Minnesota, Minneapolis, Minnesota
Abstract: Warts remain one of the most common reasons for dermatology and primary care visits, yet no definitive therapy is available. Treatment of pediatric patients adds additional challenges, as the adept provider
must effectively manage parents’ expectations and patients’ fears. This
article provides an update on research in the field of viral cutaneous wart
therapies with a focus on pediatric patients. Safety issues and potential
complications of therapy are also addressed.
Despite rigorous investigation, a definitive treatment
for viral warts remains elusive. No single therapy cures
all warts, and so potential treatment modalities proliferate. Up to one-third of primary schoolchildren have
warts (1), and an estimated 9.1% to 21.7% of dermatology referrals are for cutaneous wart treatment (2).
Therapies for children must be safe and preferably
painless. This is especially important, as up to two-thirds
of warts clear without treatment within 2 years (3), and
therapies should not increase morbidity. Many warts,
however, do not quickly self-resolve and are associated
with decreased quality of life, embarrassment, and
physical discomfort (4).
Treatment of warts, particularly in children, relies on
both the art and science of medicine. In practice, many
warts will require treatment with a combination of
therapies. Also, as most modalities are user-dependent,
individual practitioners may experience higher or lower
success rates compared to what is reported in the literature. Whatever the method, the importance of having a
calm physician and supportive parent at the bedside
cannot be overemphasized.
Since the last pediatric review (5) in 2002, additional
research has added to our understanding of wart therapies. Randomized controlled trials are still lacking, but
this update will highlight the most recent and highest
quality studies that have potential relevance to treating
the child with warts. Studies pertaining exclusively to
immunocompromised patients will not be a focus of this
article, as this group has unique treatment needs. Referenced studies include pediatric patients or a combination of pediatric and adult patients unless otherwise
noted.
DESTRUCTIVE METHODS
Destructive methods cause nonselective damage to infected keratinocytes and surrounding cells. Electrodesiccation and curettage in particular leads to wider zones of
injury. Although very useful in the treatment of filiform
warts or small individual lesions, it should not be considered a mainstay of therapy in children. Destructive
methods tend to have high recurrence rates, and parents’
expectations should be set accordingly.
Address correspondence to Christina Boull, M.D., Department
of Medicine-Pediatrics, University of Minnesota, 420 Delaware
Street SE, Minneapolis, MN 55455, or e-mail: [email protected]
DOI: 10.1111/j.1525-1470.2010.01378.x
2011 Wiley Periodicals, Inc.
217
218 Pediatric Dermatology Vol. 28 No. 3 May ⁄ June 2011
Salicylic Acid
Duct Tape
Salicylic acid remains the best tested wart therapy.
A systematic review pooling data from six placebo controlled trials of salicylic acid for warts in adults and
children showed a cure rate of 75% compared with 48%
in controls (odds ratio 3.91, 95% confidence interval 2.4–
6.36) (6). A Cochrane Review (7) comments that ‘‘there is
certainly evidence that simple treatments containing
salicylic acid have a therapeutic effect.’’
For optimal effect, warts may be pared down with an
emery board or pumice stone and covered with a patch to
maintain good contact. Salicylic acid should be used very
cautiously on facial warts due to risk of scarring.
In addition to the variety of over-the-counter products available, pharmacists can be directed to compound
higher concentration formulations. We find that Aquaphor compounded with 30% to 40% salicylic acid can be
quite effective for multiple and hyperkeratotic warts.
Duct tape gained interest in 2002 when Focht et al (11)
reported that in 60 children, wart treatment with silver
duct tape was significantly more effective than cryotherapy. Eighty-five percent (22 ⁄ 26) of the patients using
duct-tape therapy had complete resolution of their warts
compared to 60% (15 ⁄ 25) of patients receiving cryotherapy after 2 months of therapy (p = 0.05). More
rigorous blinded controlled follow-up studies by de Haen
et al (12) and Wenner et al (13) of children and adults,
respectively, found no statistical benefit of duct tape over
placebo. Notably, silver duct tape was used by Focht,
and clear duct tape was used by the de Hean and Wenner
groups. This difference may be a factor in the discrepancy
among outcomes.
Success of home-applied wart therapies depends on
the motivation of both the family and the patient.
Treatments are frequent and can be time-intensive, but
the benefit of therapy may rely as much on the ritual as
on the medicinal value. Successful use, however, will
prevent the necessity for more painful second-line
treatments.
Cantharidin
Cantharidin, a blistering agent derived from beetles,
triggers the release of proteases, which degrade desmosomal attachments leading to acantholysis. Due to the
intraepidermal location of the lysis, lesions heal without
scarring (8). Cantharidin 0.7% preparation is applied to
the lesion topically in the office, covered, and washed off
anywhere from 2 to 12 hours later. Patients experience
blistering within 24 to 48 hours, and longer application
time leads to more blistering. One case of lymphangitis
has been reported following treatment. Cantharidin
should only be applied in the office, as ingestion has led to
severe toxicity and death. In a recent case series, 15 of 15
patients with recalcitrant facial flat warts treated with
cantharidin had complete resolution after a mean of 2.6
treatments, and no significant complications or scarring
were reported (9).
Combination therapy with a compound of cantharidin 1%, salicylic acid 30%, and podophyllotoxin 5%
(Cantharone Plus) followed by debridement showed a
95.8% cure rate for plantar warts at 6 months in 144
adults and children (10). Most patients (86.8%) required
only one treatment. Although wart enlargement within a
few months following treatment can occur with any
destructive modality, in our experience it occurs more
frequently with this preparation. As with other cantharidin-containing products, it is painlessly applied in clinic,
but parents should be advised that significant blistering
may occur within 24 hours. Of note, cantharidin is not
FDA approved in the United States and so must be
compounded by a pharmacist or purchased online from
Canada where it is available over the counter.
Cryotherapy
Gibbs et al (6) analyzed data from 16 trials of cryotherapy published between 1976 and 2001 in a systematic review and found that studies comparing
cryotherapy to placebo showed no significant difference
in cure rates. Trials comparing cryotherapy to a myriad
of other wart treatments noted complete wart resolution
rates of 33% to 93% for cryotherapy alone, and 29% to
75% when used in conjunction with salicylic and lactic
acid. A Cochrane Review (7) concluded, ‘‘there is less
evidence for the efficacy of cryotherapy (than for salicylic acid treatments) but reasonable evidence that it is
only of equivalent efficacy to simpler and safer treatments.’’ Nevertheless, cure rates are likely operator
dependent.
Other investigations into the best techniques for
delivery of cryotherapy have found that the use of a
cryotherapy gun is not superior to cotton-wool buds for
application of liquid nitrogen (13). Longer freezing cycles
lead to higher cure rate but produce more pain and
blistering (14). Reported complications include hemorrhagic blistering, hypopigmentation, nail dystrophy in
periungual areas, and, rarely, short-term neuropathy
when used on digits.
We believe that despite no proven benefit in efficacy,
children find cotton-wool buds to be less intimidating
than spray guns. We freeze aggressively to minimize the
child’s need for additional office visits.
Case series
Cantharidin
de Bengoa
Vallejo et al (10)
Open
Open
Open
Case series
Case series
Open
Case series
Case series
Cryotherapy
Ahmed et al (14)
Connolly et al (15)
Pulsed Dye Laser
Robson et al (17)
Vargas et al (20)
Kopera (18)
Akarsu et al (23)
Park et al (22)
Schellhaas et al (19)
Sethuraman
et al (21)
Blinded
Wenner et al (13)
Recalcitrant facial
flat warts
Plantar warts
Wart description*
56 children
134 adults
and children
19 adults
and children
12 adults
40 adults
363 adults and
children
200 adults
and children
Recalcitrant hand
and foot warts
Recalcitrant warts,
any location
Anogenital
warts excluded
Non-anogenital warts
PDL
PDL
PDL
PDL versus
PDL + SA
PDL
Any location
Facial flat warts
PDL versus
cantharidin
and ⁄ or
cryotherapy
PDL
Cryo gun versus
cotton wool buds
10 s freeze versus
‘‘gentle’’ freeze
Recalcitrant and
non-recalcitrant
warts on any site
Hand and foot warts
Hand and foot warts
Outcomes 6 weeks
Cure in 8 ⁄ 51 (16%)
versus 3 ⁄ 52 (6%)
Cure in 8 ⁄ 39 (21%)
versus 9 ⁄ 41 (22%)
Cure in 46 ⁄ 61 (75%)
Cure in 18 ⁄ 56 (32%)
patients and 99 ⁄ 206
(48%) warts
Cure in 89%
Cure in 22 ⁄ 33 (67%)
versus 23 ⁄ 33 (70%) warts
Up to 12
treatments (2 wks)
Avg no. of treatments
= 3.1 (2.5–4 wks)
Up to 5
treatments (2–3 wks)
Up to 3 treatments
(3–4 wks)
3.38 avg no. of tx
(3.26 wks avg)
Up to 5
treatments (4 wks)
Cure in 12 ⁄ 12 (100%)
Cure in 63%
Up to 4
treatments (1 mo)
Cure in 66% versus 70%
Cure in 39 ⁄ 158 (44%)
3 months (2 wks)
versus 55 ⁄ 118 (47%)
Cure in 42 ⁄ 71 (59%) versus Up to 5
25 ⁄ 75 (33%)
treaments (2 wks)
8 weeks
8 weeks
16 weeks (3 wks)
Up to 4 treatments
(15–20 days)
Duration of treatment
and (time between
treatments)
Cure in 22 ⁄ 26 (85%)
versus 15 ⁄ 25 (60%)
Topical
138 ⁄ 144 (96%)
cantharidin 1%,
SA 30%, and
podophyllotoxin 5%.
0.7% cantharidin
Cure in 12 ⁄ 12 (100%)
applications
Intervention
60 children and Facial, anogenital, and Duct tape versus
adolescents
periungual
cryotherapy
warts excluded
103 children
Facial and anogenital Duct tape versus
warts excluded
placebo patch
90 adults
Anogenital
Duct tape versus
warts excluded
placebo patch
15 adults
144 adults
and children
Participants
73 adults
and children
Retrospective 61 adults
case series
and children
Blinded
de Haen et al (12)
Kartal
Case series
Durmazlar et al (9)
Duct Tape
Focht et al (11)
Open
Design
Reference
TABLE 1. Details of Referenced Trials
Absolute numbers
not reported
Less treatments
needed for face
and perineal warts
Absolute numbers
not reported
Less laser
treatments
required in SA group
Absolute numbers
not reported
43% default rate
Clear duct tape
Clear duct tape
9 patients lost
to follow-up
Notes
Boull and Groth: Update: Treatment of Warts
219
Blinded
Grussendorf-Conen
and Jacobs (44)
Micali et al (45)
Case series
Case series
5% imiquimod
5% imiquimod
5% imiquimod
Imiquimod
Hengge et al (43)
50 adults
Anogenital
and children warts excluded
18 children
Recalcitrant,
non-anogenital warts
15 adults
Recalcitrant sub
and children and periungual warts
Case series
Gamil et al (39)
Injections
Single blinded 233 adults
Mostly recalcitrant warts, Antigen ±
and children location not reported
interferon
versus interferon
or saline
Case series
23 adults
Plantar warts
MMR injection
Recalcitrant acral warts
Horn et al (38)
47 children
3 months
Cure in 9 ⁄ 28 (32%)
versus 8 ⁄ 26 (31%)
Cure in 10 ⁄ 27 (37%)
versus 4 ⁄ 16 (25%)
2 months
Cure in 25 ⁄ 32 (78%)
versus 3 ⁄ 23 (13%)
Up to 16 weeks
Up to 12 months
Up to 16 weeks
Cure in 16 ⁄ 18 (89%)
Cure in 12 ⁄ 15 (80%)
Up to 3 treatments
(3 wks)
Cure in 15 ⁄ 50 (30%)
Cure in 20 ⁄ 23 (87%)
Cure in 56% versus 23%
Cure in 22 ⁄ 47 (47%)
46% drop out rate;
all patients
zinc deficient
Better clearance
in younger patients
12 patients with
transient pigment
changes
16 patients were
immunosuppressed
43% drop out rate
Unspecified no. of
Higher distant
injections (3 wks) ⁄ Up cure rate with
to 10 treatments
antigen treated warts
of cryo (3 wks)
3.78 avg no. of
treatments (3 wks)
Up to 5
Absolute values
treatments (3 wks)
not given; intention
to treat analysis
2 months
Cure in 20 ⁄ 23 (87%)
versus 0 ⁄ 20 (0%)
12 weeks
2 months
Cure in 26 ⁄ 32 (81%)
(15 days)
(2–4 wks)
(1 wks)
(1 wks)
Duration of treatment
and (time between
treatments)
Notes
Cure in 64 ⁄ 114 (56%)
Up to 6
versus 47 ⁄ 113 (42%) warts treatments
Cure in 48 ⁄ 64 (75%) versus Up to 3
13 ⁄ 57 (23%)
treatments
Cure in 42 ⁄ 48 (88%) warts Up to 7
treatments
Cure in 17 ⁄ 18 (94%)
Up to 3
treatments
Outcomes Injection
Cure in 29 ⁄ 55 (52%)
versus cryotherapy versus 26 ⁄ 60 (43%)
Zinc sulfate
versus placebo
Zinc sulfate
versus placebo
Case series
115 adults
Non-genital, mainly
and children hand and foot warts
55 adults
Multiple recalcitrant
and children hand, foot,
and facial warts
80 adults
Recalcitrant trunk
and children and extremity warts
Clifton et al (40)
Imm. Therapy Injections
Johnson et al (37)
Open
Yaghoobi et al (36)
Zinc Sulfate
Al-Gurairi et al (35) Blinded
Karabulut et al (32) Blinded
Blinded
ALA PDT
ALA PDT versus
placebo PDT
ALA PDT versus
placebo PDT
ALA PDT
Intervention
Multiple recalcitrant
Cimetidine
common and foot warts
70 adults
Multiple warts,
Cimetidine
and children all locations
versus placebo
54 adults
Recalcitrant
Cimetidine
and children non-genital warts
versus placebo
34 children
Case series
Lu et al (28)
Case series
31 adults
Recalcitrant
and children plantar warts
18 adults
Facial flat warts
Case series
Schroeter et al (25)
Cimetidine
Orlow and
Paller (30)
Yilmez et al (31)
121 adults
Recalcitrant hand
and foot warts
Plantar warts
Wart description*
Fabbrocini et al (27) Blinded
Participants
45 adults
Design
Photodynamic Therapy
Stender et al (26)
Blinded
Reference
TABLE 1. Continued
220 Pediatric Dermatology Vol. 28 No. 3 May ⁄ June 2011
Case series
Case series
Case series
Open
Squaric Acid
Lee (46)
Micali et al (47)
DCP
Buckley et al (48)
Choi et al (49)
Open
Case series
Case control 50 children
Podofilox
Bunney et al (53)
Retinoids
Gelmetti et al (61)
Kubeyinje (60)
Recalcitrant,
any location
Flat warts
Plantar warts
Recalcitrant hand
and foot warts
Hand warts
Plantar and periungual
warts excluded
*As per author report.
Outcomes measured in number of patients unless otherwise specified.
20 children
382 adults
and children
7 children
Case series
Cidofovir
Field et al (54)
39 children
Blinded
40 adults
and teens
SADBE
Intervention
Cure in 4 ⁄ 7 (57%)
Cure in 19%
versus 20% of warts
Topical 0.05%
tretinoin versus no
treatment
Oral etretinate
Cure in 84% versus 32%
Cure in 16 ⁄ 20 (80%)
6 weeks of daily
application
Up to 3 months
Up to 12 weeks
Up to 12 weeks
6 weeks
Cure in 22 ⁄ 34 (65%)
Up to 4 weekly
versus 12 ⁄ 34 (35%) warts treaments
Cure in 45 ⁄ 72 (63%)
versus 38 ⁄ 75 (51%)
Many patients
received adjunctive
therapies during
study period
One child dropped
out of study
Absolute numbers
and treatment
concentrations
not provided
One child dropped
out due to irritation
One child had
detectable serum
levels of 5-FU.
Absolute numbers
not reported for
wart clearance
Up to 22 treatments
over 14 months
Number of treatments Increased sustained
not reported
clearance with DCP
Up to 10 weeks
(twice weekly)
Cure in 124 ⁄ 148 (84%)
Cure in 42 ⁄ 45 (88%)
Up to 15 treatments
(2–4 wks)
Duration of treatment
and (time between
treatments)
Notes
Cure in 20 ⁄ 29 (69%)
Outcomes SA versus podophyllin Cure in 84% versus 81%
Topical 1% cidofovir
Injection with 5-FU
+ epinephrine
+ lidocaine
Once daily versus
twice daily
topical 5% 5-FU
DCP versus
cryotherapy
DCP
Facial warts excluded,
SADBE
no genital warts treated
Recalcitrant non-facial,
non-genital warts
Wart description*
60 adults
Recalcitrant digital
and children
or plantar warts
83 patients, ages Location not reported
not reported
188 children
29 adults
and children
Participants
Gladsjo et al (50)
5-FU
Yazdanfar et al (51) Blinded
Design
Reference
TABLE 1. Continued
Boull and Groth: Update: Treatment of Warts
221
222 Pediatric Dermatology Vol. 28 No. 3 May ⁄ June 2011
TABLE 2. Details of Referenced Review Articles
Therapy
Reference
Trial types
included
No. of studies
No. of studies adequate for
reviewed
analysis
Design
Salicylic acid Gibbs et al (6) Randomized
13
controlled
Cryotherapy Gibbs et al (6) Randomized
16
controlled
Cimetidine
Fit and
Open label and 21
Williams (33) randomized
controlled
Bleomycin
Saitta et al (52) Any
Interferon
Gibbs et al (6) Randomized
controlled
6
2
12
12
12
6
0
PHOTOTHERAPIES
Laser
Laser modalities abound, but carbon dioxide and pulsed
dye lasers (PDL) are the most represented in the literature for wart treatment. Despite comparable resolution
rates, CO2 laser is less favorable, producing nonselective
thermal tissue destruction with wounds left to heal by
secondary intension (16).
Pulsed dye lasers is more selective, causing thermal
damage directly to the microvasculature of the wart (16).
In a trial by Robson et al (17), 40 adults were randomized
to treatment with PDL or ‘‘conventional therapy’’ with
cantharidin, cryotherapy, or both. Complete resolution
was noted in 76% of recalcitrant and 51% of nonrecalcitrant warts treated with PDL and in 60% of recalcitrant
warts and 77% of nonrecalcitrant warts treated with
conventional therapy after up to four treatments. Differences were not statistically significant. Proximal lesions had better cure rates with PDL than acral lesions.
Two additional series of PDL for recalcitrant warts in
adults and children noted clearance rates of 63% to 89%
(18,19). Vargas et al (20) reported good cosmetic results
for PDL treatment of 12 adults with facial warts who all
had complete clearing without scarring after a maximum
of three sessions.
Sethuraman et al (21) noted a clearance rate of 75% in
61 pediatric patients with recalcitrant warts after an
average of 3.1 treatments. Complications included pigment changes, blistering, and mild scarring. Park et al
(22) treated 56 children with PDL and achieved a complete response rate in 48.1% of warts (99 ⁄ 206) after a
mean of 3.1 treatments. Park concluded that the higher
cost of individual treatments may be balanced by the
lower number of treatments needed to achieve remission.
Outcomes
Notes
Cure in 144 ⁄ 191 (75%)
versus 89 ⁄ 185 (48%)
Cure in 11 ⁄ 31 (35%)
versus 13 ⁄ 38 (34%)
Cure in 48–81% in
Controlled trials
open studies; No
could not be
benefit of cimetidine
pooled due to
over placebo in
variable
controlled trials
cimetidine
dosing
Any
Cure in 0–94%
Not a systematic
review
Interferon alpha, Cure ranged from
Studies could
beta, or gamma 22% to 66% in
not be compiled
versus placebo
the interferon groups
Salicylic acid
versus placebo
Cryotherapy
versus placebo
Various designs
Pretreatment with salicylic acid may make PDL more
cost-effective by decreasing the number of laser treatments required for cure. A study of 19 patients randomized to PDL therapy with or without salicylic acid
pretreatment found no significant difference in cure rates
after five treatments (69.7% in the SA-treated group vs
66.6% in the control group), but the group pretreated
with salicylic acid required an average of 2.2 treatments
compared to 3.1 treatments in the control group
(p < 0.05) (23).
Pulsed dye lasers is an important new therapy that is
safe and generally well tolerated by children. Cooling
devices can lessen pain.
Photodynamic Therapy
In photodynamic therapy (PDT), a photosensitizing
agent, most commonly 5-aminolaevulinic acid (ALA), is
topically applied and absorbed by hyperkeratotic wart
keratinocytes. When stimulated by light, accumulated
porphyrins induce a photooxidation cascade damaging
treated cells (24).
A series of 31 children and adults with recalcitrant
plantar warts treated with ALA-PDT attained a clearance rate of 88% (42 ⁄ 48) of warts after an average of 2.3
treatments. Younger patients had better outcomes, with
100% clearance in all patients younger than 27 and no
clearance in patients older than 45. Side effects included
minor pain and itching with one case of mild hypopigmentation (25).
In a randomized controlled study, 45 adults with
recalcitrant hand and foot warts were treated with either
ALA-PDT or placebo-PDT with weekly treatments for
up to 6 weeks. Complete clearance of warts was seen in
56% of patients in the active treatment group, compared
Boull and Groth: Update: Treatment of Warts
with 42% in the placebo group (p < 0.05) (26). In a
similar study of ALA-PDT for plantar warts, 121 adults
were randomized to treatment with either ALA-PDT or
placebo-PDT. After up to three treatments, a cure rate of
75% (48 ⁄ 64) was noted in the ALA-PDT group compared to 22.8% (13 ⁄ 57) in the placebo group (p < 0.001)
(27).
Like PDL, PDT gives good cosmetic results for facial
warts. Eighteen adults treated with azone followed by
ALA-PDT had a clearance rate of 94.4% after two sessions. Twelve patients had transient pigment changes,
but no scarring resulted (28).
IMMUNOTHERAPIES
Cimetidine
Oral cimetidine, a histamine H2-receptor antagonist was
trialed as a therapy for warts due to its immunomodulatory effects (29). An initial case series of 34 children
treated with cimetidine dosing of 25 to 40 mg ⁄ kg ⁄ day by
Orlow et al (30) demonstrated promising results with an
81% (26 ⁄ 32) cure rate over 2 months. More rigorous
studies failed to show the same benefit. Two doubleblinded placebo-controlled studies in adults and children
showed no significant benefit of cimetidine over placebo
(31,32).
Despite case reports and smaller open-label studies
with higher success rates in children, a 2007 review notes
that no high-quality evidence exists to support the use of
cimetidine for warts (33). Any benefit may lie more in the
psychological aspect of treatment.
Zinc
A promising new therapy, zinc, acts as an immune
modulator. Deficiency results in lymphopenia and
treatment of cell cultures with zinc produce polyclonal
activation of lymphocytes (34).
In a randomized controlled study, 80 children and
adults with recalcitrant warts were treated with placebo
or oral zinc sulfate (10 mg ⁄ kg up to a maximum dose of
600 mg ⁄ day) for 2 months (35). Of those that completed
the study, 86.9% (20 ⁄ 23) of patients in the zinc-treated
group compared to 0% (0 ⁄ 20) of patients in the placebo
group (p < 0.001) had complete wart clearance.
Importantly, all participants were zinc deficient prior to
the study, and treatment response correlated with increase in serum zinc levels. The authors postulated that
zinc-deficient individuals may be more prone to developing warts, as a series of healthy controls had normal
zinc levels. Results are impressive, but the large drop-out
rate may have impacted outcomes. Adverse events in the
223
zinc-treated group included nausea (100%), vomiting
(12.7%), and mild epigastric pain (13%).
In 55 children and adults with recalcitrant warts, 78%
of patients randomized to treatment with zinc had
complete wart resolution in 2 months compared with
13% of patients treated with placebo. No adverse
reactions were reported. Again, a large number (68%) of
patients had low serum zinc levels prior to treatment (36).
Initial studies suggest that oral zinc sulfate is an
effective, inexpensive, and painless way to treat warts.
Additional placebo-controlled studies in zinc-replete
patients are needed to determine true therapeutic benefit.
Injected Immunotherapies
The use of injections of immune-stimulating antigens has
grown, buoyed by studies showing not only regression of
the injected wart, but also resolution of distant warts. In
a trial by Johnson et al (37), 115 patients aged 5 to 72
were treated with cryotherapy or wart injection with
Candida or mumps antigen. No significant difference
was shown between cure rates in the two groups after
three treatments, but 14 of 18 of cured antigen-treated
patients (78%; 95% confidence interval: 52–94%)
experienced clearing of all other warts despite receiving
antigen injections into only the largest wart.
The same investigators then randomized 233 adults
and children to intralesional injection with one of four
treatments: mumps, Candida, or trichophyton antigen;
antigen plus interferon alfa 2b; alfa 2b alone; or placebo
(saline). After up to five treatments, the groups treated
with antigen alone or antigen with interferon had a
clearance rate of 56% compared to 23% in the groups
treated with placebo or interferon alone (p < 0.001).
Distant warts showed improved resolution in patients
receiving antigen (49%) compared to patients treated
with interferon or saline alone (16%) (p < 0.001).
Interferon alfa-2b did not afford a significant benefit
alone or in combination with antigen (38).
A newer trial using MMR vaccine intralesional
injections in 23 adults with plantar warts showed complete resolution in 87% of patients after up to three
treatments (39). The study, however, was flawed by a
high drop-out rate and lack of a control group.
In a pediatric series of 47 children with multiple
recalcitrant warts treated with intralesional mumps or
Candida injections, 47% of patients were cured after an
average of 3.78 treatments. Fourteen children noted
resolution of distant nontreated warts. Patients reported
itching at the injection site as the primary side-effect (40).
Other complications of immunotherapy injections
have included cases of fever and myalgias treated successfully with NSAIDs, and a single case report of a
224 Pediatric Dermatology Vol. 28 No. 3 May ⁄ June 2011
painful purple finger following a subungual wart injection. Symptoms self resolved (41).
Needles provoke anxiety in many children, and
injections into the soles of the feet are particularly painful. Care must be taken to ensure proper restraint of the
child prior to the procedure to protect both patient and
physician from accidental needle punctures. Topical
application of ice packs prior to injection may minimize
pain.
Interferon
In his review of cutaneous wart therapies, Dr. Gibbs
examined six trials testing the efficacy of intralesional
interferon injections (6). Two of these studies included
children and noted cure rates from 30% to 66%. Gibbs
noted that the quality of these studies was low, and that
interferon does not appear to be effective.
Diphencyprone is more stable in solution and less
expensive than SADBE. Buckley et al (48) documented a
75% clearance rate in 48 children and adults treated with
DCP. Fifty-six percent of patients, however, experienced
adverse events including blistering, generalized eczematous eruptions, influenza-like symptoms, and inguinal
lymphadenopathy. A randomized controlled study of
147 patients found no significant benefit of DCP over
cryotherapy for wart resolution, but noted increased
sustained clearance as 93.3% of patients with complete
resolution treated with DCP versus 76.3% treated
with cryotherapy maintained clearance at 12 months
(p < 0.05) (49).
ANTIMITOTIC THERAPIES
5-FU
Trials of imiquimod as a treatment for genital warts
propose that it acts as an immune response modifier,
stimulating the production of interferon alpha and
cytokines (42).
A case series of 50 children and adults with refractory
warts treated nightly with application of 5% imiquimod
cream on five nights per week over an average of
9.2 weeks noted a complete clearance rate of 30%
(15 ⁄ 50) (43). Warts located on the trunk and face had
higher response rates than warts on the feet.
However, 18 children with mainly acral recalcitrant
warts treated with twice daily 5% imiquimod cream and
intermittent wart paring for an average of 5.8 months
had a higher clearance rate of 88.9% (16 ⁄ 18) (44). In a
trial of imiquimod for recalcitrant sub and periungual
warts, 15 adults and children were pretreated with a
salicylic acid preparation followed with imiquimod 5%
cream under an occlusive dressing five nights per week
for up to 16 weeks (45). Eighty percent of patients had
total clearance of their warts. Local erythema, pruritis,
and burning sensation were noted. Imiquimod is well
suited to use in children and has the benefit of home use.
5-Fluorouracil (5-FU), a chemotherapeutic agent, is
thought to cause wart resolution by interfering with the
synthesis of DNA and RNA in infected cells (50). To
investigate both efficacy and systemic effects of topical
5-FU in the pediatric population, Gladsjo et al (50)
randomized 39 children to treatment with either once or
twice daily application of 5% 5-FU cream plus daily
filing, soaking, and occlusion with duct tape. After
6 weeks of treatment, 19% of the once daily and 20% of
the twice daily treated warts demonstrated complete
resolution (no significant difference). One child out of 39
had a detectable serum 5-FU level at the end of treatment
and had been in the once-a-day treatment group.
Complications included erythema, ulceration, crusting,
and occasional hypopigmentation.
A 2008 study of 40 adults and teens treated with either
once weekly intralesional injection of 5-FU mixed with
epinephrine and lidocaine or saline for up to 4 weeks
showed complete resolution of 65% (22 ⁄ 34) of 5-FU
injected warts compared to 35.3% (12 ⁄ 34) of saline injected warts (p £ 0.05) (51). Authors note that due to the
low doses of 5-FU injected, systemic reactions were
eliminated, but serum levels of 5-FU were not documented. This therapy needs more investigation before its
use in children can be advised.
Squaric Acid and Diphencyprone
Bleomycin
Both squaric acid dibutylester (SADBE) and diphencyprone (DCP) act to induce a type IV hypersensitivity
reaction against the contact agent bound to human or
viral proteins (46). Two series of 29 and 188 mostly
pediatric patients sensitized and then treated with
SADBE applications demonstrated 69% and 84%
clearance rates, respectively (46,47).
Bleomycin, another chemotherapeutic agent, prevents
mitosis of HPV-infected (human papillomavirus-infected) cells by inducing cleavage of the DNA backbone
(52). A recent review article, examining 12 studies of wart
treatment with intralesional bleomycin, published
between 1976 and 2002 noted cure rates from 0% to
94% (52). The highest quality data was derived from a
Imiquimod
Boull and Groth: Update: Treatment of Warts
double-blinded placebo-controlled study of 24 adults
and teens with 59 matched pairs of hand warts. Patients
received 0.1% bleomycin injections into one of their
paired warts and saline injections into the matched
control wart for up to three injections. Bleomycininjected warts showed a cure rate of 58% (34 ⁄ 59) compared to 10% (6 ⁄ 59) in the placebo group after 6 weeks
(p < 0.001). All subjects with remaining warts received
an additional injection with bleomycin, after which the
cure rate for bleomycin-treated warts was 76% (53).
Bleomycin injections typically induce eschar formation and inflammation. Complications have included
pain with injection, urticaria, nail loss, hyperpigmentation, and very rarely Raynaud’s phenomenon. Pulmonary fibrosis is an adverse reaction seen in systemic use,
but not reported in intralesional use. As safety of intralesional bleomycin has not been studied in the pediatric
population, and because it is quite painful, we do not
recommend bleomycin for young children.
225
Cidofovir
A virucidal agent that prevents DNA synthesis, cidofovir
is most commonly used intravenously to treat cytomegalovirus retinitis in immunocompromised patients. Small
studies indicate benefit in the treatment of refractory
cutaneous warts.
In a series of seven pediatric patients with hand and
foot warts treated with topical 1% cidofovir, four patients had complete clearance (54). Treatments were
nightly for up to 12 weeks, and one child stopped treatment due to local irritation. Of the two immunocompromised children in the study, one cleared and one did
not.
Two children with refractory leg or plantar warts (55)
and a 9-year-old girl with acute lymphoblastic leukemia
and refractory plantar warts (56) were treated successfully with topical cidofovir. An 11-year-old girl with
hereditary congenital lymphadema and highly refractory
All Patients
Pediatric Wart Treatment Algorithm
Topical SA*
Refusal of Painful
Treatments?
No‡
Yes
Watchful waiting
Zinc sulfate
Cimetidine
Topical retinoid
Imiquimod
Many Warts?
No
Yes
ImmunoCompromised?
Facial?†
No
No
Yes
Yes
Flat Warts?
Highly
Keratotic?
Yes
40% SA
to
debulk
Flat Warts?
No
No
No
Periungual?
No
Cryo
Cantharone Plusφ
Injected Im Txψ
Imiquimod
5-FU
PDL
SADBE/DCP
Bleomycinαβ
Cryo
Cantharidin
PDL/PDT
EDα
Yes
Topical retinoid
Imiquimod
PDL/PDT
Injected Im Txψ
Cantharone Plusφ
Cryo
5-FU
PDL
Yes
Cryo
5-FU
Cidofovir
Injected Im Txψ
Topical retinoid
Cryo
Yes
Cryo
Imiquimod
PDL
Injected Im Txψ
Figure 1. Pediatric wart treatment algorithm.
SA, salicylic acid; Cryo, cryotherapy; Injected Im Tx, injected immunotherapy; 5-FU, 5-Fluorouracil; PDL, pulsed dye laser; PDT,
photodynamic therapy; ED, electrodesiccation; SADBE, squaric acid dibutylester; DCP, diphencyprone.
*Topical salicylic acid should always be used with soaking and filing; àZinc sulfate or cimetidine may be added to all
other treatments in this category; Increased delicacy must be used for all treatments on the face; wInjected immunotherapies
include MMR, trichophyton, and Candida; aBleomycin and electrodesiccation should only be used in older patients with high
motivation for treatment; bBleomycin should not be used on digits due to risk of necrosis; /Contains salicylic acid 30%, podophyllin
2%, and cantharidin 1%.
226 Pediatric Dermatology Vol. 28 No. 3 May ⁄ June 2011
facial, hand, and foot warts had resolution of more than
90% of her lesions after five treatments with IV cidofovir
(57). Adverse effects of IV administration include
nephrotoxicity and neutropenia. One case of acute renal
failure has been reported in an adult being treated with
topical 4% cidofovir, but confounding factors likely
played a role (58). Larger studies are needed to further
assess safety and efficacy in children.
Podophyllin Resin and Podophyllotoxin
Podophyllin resin, an extract of the mayapple plant,
contains the active ingredient podophyllotoxin, an antimitotic agent. Podophyllotoxin has been used most
successfully to treat anogenital warts, but also shows
benefit in the treatment of cutaneous warts. Bunney et al
(59) found podophyllin to be equivalent to treatment
with salicylic acid for plantar warts in 382 adults and
children. As podophyllin has been associated with
neurotoxicity, and as the concentration of the active
ingredient varies between batches, the use of podophyllotoxin is now preferred.
Sinecatechins
Sinecatechins, green tea extracts, have shown promising
results for the topical treatment of anogenital warts, but
have not been tested systematically in cutaneous warts or
in children. The mechanism of action is not well defined.
Retinoids
Both topical and oral retinoids treat warts by influencing keratinization and cellular proliferation. In a casecontrol trial of 50 pediatric patients, those treated with
daily application of 0.05% tretinoin cream showed an
85% clearance rate of warts compared to a 32%
clearance in controls (60). This modality seems well
suited for painless treatment of facial planar warts.
Treatment of 20 children with oral etretinate for up to
3 months produced complete and sustained wart clearance in 16 children (61). Due to the strict precautions that
must be taken when using oral retinoids in adolescent
girls, and minimal data to support its efficacy, we do not
recommend etretinate for treatment of warts.
Pain Management
Evaluation of the benefit of eutectic mixture of local
anesthetics cream (EMLA) prior to cryotherapy, with a
randomized placebo controlled trial in adults and children showed no significant improvement in the pain
experienced during the procedure. In subgroup analysis,
however, decreased pain was seen in children receiving
cryotherapy to the soles or palms (62).
While specific guidelines are lacking, pain control
certainly makes treatments more tolerable for the patient, parent, and physician. Icepacks applied 5 minutes
before wart injections can help to numb the site. Nerve
blocks should be considered prior to treatment of larger,
localized wart clusters. Eutectic mixture of local anesthetics cream is a useful pain-mitigating tool when placed
prior to laser therapies and nerve block injections. For
maximal effect, EMLA should be applied 1 hour prior to
the procedure under an occlusive dressing. Other topical
anesthetic preparations, such as liposomal lidocaine,
may be used similarly.
Special Pediatric Considerations
In our experience, good parent-provider communication
is the most important element in effectively treating
pediatric patients. Prior to the implementation of any of
the above-described treatments, parents’ questions and
concerns must be fully addressed. In some cases, an initial
pain-free visit to discuss wart etiology and treatment
options and to establish a rapport with the child can ease
anxiety. Therapies and complications should be described in language that both the parent and child can
understand. Instruction handouts are useful to ensure
proper technique of home therapies. A child-friendly
office can make for a more positive experience. Music or
movies in treatment rooms provide a helpful distraction
for children. Talking the child through procedures by
providing reassurance and calmly explaining what to
expect next is essential.
Summary and Recommendations
Providers face an overwhelming number of treatment
options for the management of cutaneous warts. We
have included a treatment algorithm based on the combination of our clinical experience and the evidence
available (Fig. 1). As the only therapy thoroughly tested
and proven effective is salicylic acid, we recommend
starting with this in all patients with nonfacial warts.
Parents must be specifically instructed in its proper use,
including the importance of soaking and filing lesions
between applications.
For warts that fail to respond to salicylic acid, the
practitioner must determine what intensity of therapy is
appropriate. Patient age and maturity level as well as
parent preference must be considered. In most cases,
another destructive method should be employed.
Cryotherapy for nonfacial warts, cantharidin, and
Cantharone Plus are all good options and are readily
Boull and Groth: Update: Treatment of Warts
available at most primary care offices. For parents or
patients who refuse painful therapies, ongoing use
of salicylic acid or addition of a topical retinoid or
imiquimod 5% in conjunction with oral zinc sulfate or
cimetidine is recommended.
If after multiple failed treatment attempts warts are
still present, if warts are located on the face, or if the
number of warts is extensive, referral to a dermatologist
is warranted. Immunocompromised patients should be
referred sooner, as their lesions tend to be more refractory. The dermatologist may opt to repeat simple
destructive methods in a more aggressive manner prior to
moving on to other options. Next-line treatments include
injected immunotherapies (MMR, trichophyton, Candida), topical immunotherapies (SADBE, DCP), topical
5-FU, pulsed dye laser, and photodynamic therapy. As
not all dermatology offices are equipped to perform all
procedures, the referring provider should be familiar
with the resources available in his or her area. In older,
highly motivated patients with warts refractory to all
other methods, the use of bleomycin, or electrodesiccation may be considered.
Concluding Remarks
Looking to the future of wart therapies, immune modulation seems to hold growing promise. One of the
greatest breakthroughs in the treatment of HPV has been
the quadivalent vaccine. Although it has been tested only
for prevention against subtypes responsible for cervical
cancer and anogenital warts, it may provide a broader
effect. A newly published case report documents the
clearance of 30 refractory cutaneous warts in a 31-yearold male after treatment with the HPV vaccine (63). The
author proposes a cross-protective effect that has been
previously described in the HPV vaccine literature. As
children become routinely vaccinated with the HPV
vaccine, it will be informative to follow cutaneous wart
rates.
The lack of a universally effective wart therapy has
continued to drive the search for new cures; however,
without accurate appraisal of older modalities, it is
difficult to gage the success and cost-effectiveness of the
new and more expensive treatments. The EVERT trial,
currently in progress, is a randomized controlled study
comparing wart treatment with liquid nitrogen and
salicylic acid in adults and children (64). Hopefully,
additional high quality clinical investigations of our
more widely used modalities will follow. For the time
being, we must thoughtfully apply the data available to
provide safe and effective care to our patients with
warts.
227
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