Journal of Dermatological Treatment

ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: https://www.tandfonline.com/loi/ijdt20

Efficacy of Bleomycin Application on Periungual

Warts after Treatment with Ablative Carbon
Dioxide Fractional Laser: A Pilot Study

Joong Heon Suh, Soo Kyung Lee, Myoung Shin Kim & Un Ha Lee

To cite this article: Joong Heon Suh, Soo Kyung Lee, Myoung Shin Kim & Un Ha Lee
(2019): Efficacy of Bleomycin Application on Periungual Warts after Treatment with Ablative
Carbon Dioxide Fractional Laser: A Pilot Study, Journal of Dermatological Treatment, DOI:
10.1080/09546634.2019.1605136

To link to this article: https://doi.org/10.1080/09546634.2019.1605136

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Original Article

Efficacy of Bleomycin Application on Periungual Warts after Treatment with

Ablative Carbon Dioxide Fractional Laser: A Pilot Study

Joong Heon Suh*, M.D., Soo Kyung Lee*, M.D., Myoung Shin Kim*, M.D., Un

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Ha Lee*, M.D.

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*
Department of Dermatology, Sanggye Paik Hospital, Inje University College of

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Medicine, Seoul, Republic of Korea
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Short title: Bleomycin for periungual warts
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Corresponding author: Un Ha Lee, Department of Dermatology, Sanggye Paik Hospital,

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Inje University College of Medicine, 1342 Dongil-ro, Nowon-gu, Seoul, Korea.

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E-mail: woods75@hanmail.net
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Post Code: 01757

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Phone Number: 82)+2 950 1131

Fax Number: 82)+2 931 8720

Word Count: 3530 words

Figure Count: 3 figures

Table Count: 2 tables

ABSTRACT

Background: Treating periungual warts is a therapeutic challenge. Treatments are often

ineffective and may cause complications including permanent nail changes, pain, and

scaring. Translesional bleomycin delivery via the multipuncture technique is now

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reported.

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Objective: To investigate the efficacy and safety of bleomycin solution (1 U/mL) after

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ablative fractional carbon dioxide laser for treating periungual warts.
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Methods: Warts were treated with ablative carbon dioxide fractional laser, after which

bleomycin was applied. Patients were treated every 2 weeks until the lesions
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disappeared. Treatment was discontinued if adverse events occurred or the patient

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wanted to stop.
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Result: Seventeen patients (11 women, mean age 16.23 years) with a total of 38 warts
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were enrolled from May 2017 to Aug 2018. Twenty-six lesions (68.4%) achieved
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complete clearance; 3 (7.8%) had excellent partial response (>75% improvement). The

warts clearing completely did not recur over the follow-up period of 6 months. No

significant long-term adverse effects occurred. One lesion showed postinflammatory

hyperpigmentation, resolving within 1 month; five patients (29%) had short-term

localized moderate pain after treatment.

Conclusion: Bleomycin solution after ablative fractional carbon dioxide laser is

effective and safe to treat periungual warts. Further large controlled studies are

necessary to validate effectiveness and find an optimal regimen.

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Keywords: Periungual warts, Bleomycin, Fractional Ablative Carbon Dioxide Laser.

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INTRODUCTION
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Viral warts are a cutaneous infection caused by the human papilloma virus (HPV).

Some viral warts may resolve spontaneously without complications, but most usually
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spread or gradually increase in size and volume, resulting in not only cosmetic problems
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but also bleeding and pain.1

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When HPV infection occurs adjacent to the nail plates, it may infiltrate underneath the
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nail plate or into the nail matrix. The commonly used therapeutic modalities such as
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liquid nitrogen cryotherapy or intralesional bleomycin injection can irreversibly damage

the nail matrix, resulting in permanent nail dystrophy and cosmetic problems.2 Till date,

the variety in the existing clinical treatment regimens demonstrates that no single

treatment modality has been fully satisfactory; therefore, investigations into additional
methods are required.

Bleomycin has been used as one of the chief methods to treat viral warts since the

1970s, due to its cytotoxic effect by inhibiting DNA and protein synthesis.3 However,

direct injection of bleomycin into the lesion adjacent to the nail poses the risk of not

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only functional and cosmetic nail damage but also severe adverse complications such as

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Raynaud phenomenon and gangrene.4,5 Therefore, a multi-puncture technique enabling

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delivery of the bleomycin into the wart less invasively has been introduced to enable a
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good response to treatment without safety risks.6

The objective of this pilot study was to evaluate the efficacy and complication profile
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of treating periungual warts by delivering bleomycin into the lesion along with ablative
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carbon dioxide (CO2) fractional laser.

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METHODS

Patients

Patients visiting the department of dermatology in the Inje University Sanggye Paik

hospital from May 2017 to August 2018 were enrolled to participate in this study.

Thirty-eight periungual warts from 17 patients were enrolled. The inclusion criteria

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were patients having least 1 periungual wart with or without previous treatment.

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Patients having onychodystrophy due to other previous wart treatment or other diseases

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that may cause nail dystrophy (onychomycosis, psoriasis, lichen planus, atopic
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dermatitis, hand or foot eczema, traumatic hematoma, and bacterial infection) were

excluded. Pregnant and lactating women and those with hypersensitivity to lidocaine or
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topical analgesics were also excluded. The institutional review board of Inje University
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Sanggye Paik Hospital approved this study.

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Therapeutic Procedures
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The skin was cleaned with an alcohol swab, and the hyperkeratotic part of the lesion
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was trimmed with a scalpel blade to the depth of inducing pinpoint bleeding or

revealing black dots. The part of the nail plate covering the subungal wart was trimmed

if necessary to reveal the wart tissue to be treated. Topical analgesic cream (LMX4,

Ferndale Laboratories, Ferndale, MI, USA) was applied to the top of the lesions for 30
minutes. After cleansing the topical analgesics, the periungual wart area was treated

with three passes of ablative carbon dioxide fractional laser (eCO2 laser, Lutronic corp,

Goyang, Korea). Single-pulse treatment parameters were 180 mJ pulse energy, 100

spots/cm2 density in the static mode. Immediately after the fractional treatment, 1 U/mL

bleomycin solution was applied on the surface of the wart with a sterile cotton swab to

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allow the solution to infiltrate into the warts. At the end of the procedure, topical

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mupirocin was applied with a simple dressing. Patients were instructed to treat the

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lesion with topical mupirocin twice daily. Treatment was repeated every 2 weeks. We
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designated a standard scheduled treatment as 6 consecutive sessions of this protocol

therapy. If a patient wanted to maintain the treatment even after the standard 6 sessions,
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we continued the treatment every 2 weeks until the lesions cleared or patients wished to
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stop. All the patients were informed that they could quit or change to other alternative
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methods at any time they wished. All patients filled out an informed consent form
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before beginning the treatment.

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Bleomycin solution

Bleomycin was obtained in vials containing 15 mg (15 U) powder (Bleocin: Nippon

Kayaku Co. Ltd., Tokyo, Japan). The bleomycin was dissolved in 15 mL of 2%

lidocaine to achieve a concentration of 1 U/mL. The solution was soaked into sterile
cotton swabs using a syringe.

Assessment and Follow-Up

At the initial visit, the warts were photographed. Each wart was evaluated and

meticulously tracked throughout this study with successive photographs. The clinical

efficacy of the treatment was determined by three independent dermatologists. The

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lesions that were free of hyperkeratotic tissue and appeared to have a smooth surface

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texture were classified as complete clearance (100% clearance of wart area, CC). Partial

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response was classified into 4 groups. Excellent, Good, Fair, and Poor partial response
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were designated to imply 75-99%, 50-74%, 25-49%, and 0-24% improvement,

respectively, by the lesion surface area (Table 2). All possible side effects including pain,
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bleeding, nail dystrophy, Raynaud’s phenomenon, gangrene, and hyperpigmentation

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were recorded. Patients who achieved CC were re-evaluated 4 weeks after the final visit
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to check their recurrence. The visual analogue scale (VAS) score was also measured
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after every treatment.

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Statistical analysis

Data analysis was performed using SPSS version 16 (SPSS, Inc., Chicago, IL). The

chi-square test was used to compare the clearance rates of the new-onset wart group and

the recalcitrant group (defined as warts that persisted despite any other treatment for 6
months or longer).

RESULTS

Demographic data

The demographic characteristics of the patients are listed in Table 1. A total of 17

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patients were enrolled in this study. The subjects ranged in age from 4 to 53 years and

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the mean age was 16.23 years. Six men and 11 women were included. The mean

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duration of illness was 6.64 months. Five patients had previously undergone
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cryotherapy without results. Two had undergone laser therapy (CO2 laser) without

results. One patient had a lesion that persisted despite CO2 laser and cryotherapy. The
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remaining 10 subjects had not received any treatment modality before. Thirty-eight
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periungual viral warts from the 18 patients were included in this study.
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Assessment and Follow-Up

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Fifteen of 17 patients finished the 6-session standard schedule. The number of

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treatment sessions patients received ranged from 3 to 16, and the mean number of

treatment sessions was 7.7. We found that 26 warts (68.4%) achieved CC, and 3 (7.8%)

had an Excellent partial response. The Good, Fair, and Poor partial responses were

observed in 1 (2.6%), 1 (2.6%), and 7 (18.4%) lesions, respectively (Table 1, 2). All the
lesions that achieved CC did not show any recurrence at the 1-month follow-up after the

final treatment.

Adverse Effects

After the treatment, five patients (29.4%) experienced mild to moderate pain for 24-36

hours. Only one patient demonstrated postinflammatory hyperpigmentation, which

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spontaneously resolved after 1 month. Eight patients (47%) had pinpoint bleeding

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during the treatment, which was relieved only with compression for a few minutes.

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None of the patients experienced nail dystrophy or loss, melanonychia, scarring,
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gangrene, infection, Raynaud’s phenomenon, or hypopigmentation.

The mean value of each patient’s VAS score was 4.88, ranging from 2 to 8.5. The age
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of three patients, whose average VAS score was over 7, was 4, 6, and 9 years.
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Successful rate comparison

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Fourteen (82.35%) of the 17 recalcitrant warts achieved CC. Twelve (57.14%) of the 21
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warts from the new onset-group demonstrated CC. There was no significant successful
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rate difference between the two groups (p-value: 0.096, Table 3).
DISCUSSION

Cutaneous viral warts can occur in any region of the human skin. Periungual warts,

lesions occurring near the nail plate or infiltrating beneath the nail plate, can induce

daily life functional impairments as well as cosmetic problems. Moreover, the specific

structure of the nail can not only be a barrier to effectiveness of adequate treatment but

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also raise the recurrence rate.1 Although there are many preexisting therapeutic methods

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for periungual warts including imiquimod, cryotherapy, bleomycin intralesional

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injection, intralesional immunotherapy, salicylic acid, Q-switch neodymium-doped
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yttrium aluminum garnet laser, pulse dye laser, and ALA-PDT described in the literature,

an established consensus about the optimal treatment for periungual warts does not
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exist.1,7 In this pilot study, we demonstrated that applying bleomycin solution through
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the multiple punctures created with fractional ablative CO2 laser can be an effective and
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safe modality to treat periungual warts.

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Over 100 serotypes of human papillomavirus have been recognized. Their affinity for
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sites in the human body differs depending on their serotypes. HPV serotypes 1, 2, and 4

are common causes for periungual warts originating from the hyponychium or the

proximal and lateral nail folds.8

Bleomycin is an antitumor, antibacterial, and antiviral agent that was originally isolated
from the actinomycotic soil fungus, Streptomyces vericillus.9 Bleomycin acts via

various pathways. Its anti-tumorous activities primarily lie in its ability to cleave DNA.

Bleomycin blocks the cell cycle at G2.10 It creates radical oxygen species by transferring

electrons from Fe2+ to molecular oxygens. These free radicals cause oxidative damage

to the deoxyribose of thymidylate and other nucleotides, ultimately cleaving the DNA

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backbone.4 Therefore, bleomycin is commonly used to treat viral warts in

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dermatological field due to its inhibition of DNA synthesis in viruses.

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Bleomycin exhibits toxicity to the lung, kidney, and skin. Systemic administration
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requires careful monitoring to prevent pulmonary fibrosis in patients over 70 years of

age and in patients with abnormal renal function. Besides, cutaneous side-effects
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including flagellate erythema, hyperpigmentation, Raynaud’s phenomenon, gangrene,

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alopecia, nail changes, and other miscellaneous reactions have been documented.
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Regarding the treatment of recalcitrant warts, adverse effects involving the fingers and
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nails, such as those seen in Raynaud’s phenomenon and gangrene, are occasionally
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witnessed even after small intracutaneous dose injections. Therefore, it is advisable to

avoid bleomycin injections in the treatment of digital warts.5

CO2 laser transmits energy through the moisture of the skin tissue and forms cavities

through thermal damage and vaporization.11 Irradiation of fractional CO2 laser on the
hyperkeratotic surface of wart formulates numerous vertical columns within the lesion,

enabling the topical application of bleomycin to penetrate far enough to induce wart

regression. We performed the laser for 3 passes to enable bleomycin to be absorbed to

the sufficient depth.

Among the 17 patients, 76.2% patients achieved more than 75% clearance, including

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CC (68.4%) and Excellent (7.8%). If the 2 patients (No 5 and 14, Table 1) who did not

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finish the protocol are excluded, we found that 26 of 32 (81.2%) achieved CC and 1 of

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32 (3.0%) warts achieved Excellent. The mean number of treatments for patients
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achieving CC was 7.6, which means the mean treatment period was 15.2 weeks.

Due to the use of topical analgesic, we could prevent pain during procedures,
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enabling the treatment of multiple wart lesions to be more convenient. The average VAS
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score ranged from 2.0 to 8.5 (mean: 4.88). The only 3 patients with a higher (>7) VAS
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score were children, aged 4, 6, and 9 years old. This finding may have been resulted not
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only from pain but from the children's fear of the treatment. The remaining 15 patients
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had mild to moderate pain that means endurable. None of the patients experienced nail

loss, nail dystrophy, or cosmetic problems. One patient demonstrated hyperpigmentation

at the treated site, which resolved spontaneously within 1 month. We could not observe

any immediate or delayed type of Raynaud’s phenomenon in any of our patients. During
the treatment, pinpoint bleeding was observed in eight (21%) patients, but all improved

within 5 minutes after gentle compression hemostasis.

In order to minimize adverse effects and maintain efficacy of bleomycin, several new

methods have been introduced. For plantar warts, AL-Naggar et al. performed a control

study to demonstrate that microneedle-assisted topical bleomycin spraying not only had

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a higher clearance rate, but also is less painful than bleomycin injection.12 In addition, a

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bleomycin microneedle patch has been developed and introduced as a convenient and

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tolerable treatment option in contrast to cryotherapy or bleomycin intralesional
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injection.13 However, few reports concerned with less invasive methods for periungual

warts exist.
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In 1996, one study showed that a 92% clearance rate was achieved when bleomycin
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was injected directly into palmar, periungual, or plantar viral warts. Bleomycin at a
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concentration of 1 U/mL was dropped on and pricked into the wart using a Monolet
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needle.14 Recent study reported successful treatment (86% CC) of periungual warts with
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0.1 U/mL low concentrated bleomycin using the tranlesional multipuncture technique.6

The importance of bleomycin delivery method can be inferred from these two different

studies.

Meanwhile, when it comes to bleomycin concentration, it is not clear if the higher the
concentration, the higher the clearance rate. In the literature, a study of periungual warts

treated with 1 U/mL bleomycin injection showed a 76% cure rate.15 Another study with

1.5 U/mL bleomycin injection demonstrated a 96% cure rate.16 Although neither was a

well-organized comparison study, the higher concentration of bleomycin may potentiate

the efficacy of treatment.

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In both studies15, 16, several notable adverse effects were observed: local chemical

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cellulitis, sterile abscess, and post inflammatory hyperpigmentation. Moreover, one

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report demonstrated a patient with periungual warts who was treated with intralesional
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injection of bleomycin sulfate and developed fingernail loss in the involved fingers.17

These are thought to be results of cytotoxic effects caused by bleomycin spreading to

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unintended perilesional normal tissues, which inevitably occurs during the intralesional
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injection process. In this study, fractional ablative CO2 laser facilitated delivery of
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bleomycin from the surface to the inside of the warts with minimal risk. Although this
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method requires multiple repetitions every 2 weeks over several months, it can be a safe
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and beneficial option due to its less invasive nature.

Viral warts are extremely infectious, so it is very common to encounter patients having

numerous warts on their fingers, toes, and other parts of their bodies1. Treating all of the

lesions at the same time with invasive or destructive modalities (cryotherapy, bleomycin
injection) often leads to a very unpleasant experience for the patients. In this study,

patient number 6 (Table 1) underwent treatment for 6 periungual warts together only

after topical analgesic application before each treatment. The average VAS score was

3.4, which means mild-moderate pain. This result proposes that bleomycin application

after ablative CO2 fractional laser can be a useful option to treat patients with a number

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of warts.

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We believe that augmenting the bleomycin concentration or conducting extra pass

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fractional laser can achieve a higher rate of CC and shorten the time required to finish
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the treatment.

In the efficacy comparison between the new-onset group and recalcitrant group, there
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was no significant difference, implying that application of this method to the recalcitrant
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warts would be feasible (p-value: 0.096, Table 2).

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The limitations of our study are its uncontrolled nature and the small number of
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patients. Larger controlled studies to validate the efficacy of applying bleomycin after
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fractional ablative CO2 laser are needed to confirm these findings. In addition, studies to

find the optimal concentration of bleomycin and laser parameter are necessary.
 CONCLUSION

Application of bleomycin (1 U/mL) after fractional CO2 laser to periungual warts is a

safe, effective, and well-tolerable treatment modality. This therapy can also be

beneficially used to treat patients with multiple warts. In the present study, we did not

observe any serious adverse events, probably because of the less invasive principle of

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drug delivery. The low occurrence of adverse events and tolerability indicates an

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advantage of this therapy over other candidate treatment modalities.

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Reference
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1. Bacelieri R, Johnson SM. Cutaneous wart: an evidence based approach to therapy. Am

Fam Physician 2005;72:647–52

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2. Miller RA. Nail dystrophy following intralesional injections of bleomycin for a periungual
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wart. Arch Dermatol 1984;120:963–4.

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3. Umenzawa H, Maeda K, Takeuchi T. New antibiotics, bleomycin A and B. J Antibiot

1966;19:200–9.

4. Yamamoto T. Bleomycin and the skin.Br J Dermatol. 2006 Nov;155(5):869-75.

5. Gonzalez FU, Cristobal M, Martinez AA, et al. Cutaneous toxicity of intralesional

 Bleomycin administration in the treatment of periungual warts. Arch Dermatol

1986;122:974–5.

6. AlGhamdi KM, Khurram H. Successful treatment of periungual warts with diluted

bleomycin using translesional multipuncture technique: a pilot prospective study. Dermatol

Surg. 2011;37(4):486-92.

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7. Yoo KH, Kim BJ, Kim MN. Enhanced efficacy of photodynamic therapy with methyl 5-

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aminolevulinic acid in recalcitrant periungual warts after ablative carbon dioxide fractional

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laser: a pilot study. Dermatol Surg. 2009;35(12):1927-32.
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8. Tosti A, Piraccini BA. Warts of the nail unit: surgical and nonsurgical approaches.

Dermatol Surg 2001;27:235–9.

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9. Saitta P, Krishnamurthy K, Brown LH. Bleomycin in dermatology: a review of

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intralesional applications.Dermatol Surg 2008; 34: 1299–1313.

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10. Barlogie B, Drewinko B, Schumann J, et al. Pulse cytophotometric analysis of cell cycle
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perturbation with bleomycin in vitro. Cancer Res 1976; 36:1182–87

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11. Fulton JE1, Shitabata PK. CO2 laser physics and tissue interactions in skin. Lasers Surg

Med. 1999;24(2):113-21.

12. Al-Naggar MR, Al-Adl AS, Rabie AR et al. Intralesional bleomycin injection vs

microneedling-assisted topical bleomycin spraying in treatment of plantar warts. J Costmet

 Dermatol 2018;23. Doi:10.1111/jocd.12537

13. Ryu HR, Jeong HR, Seon-Woo HS et al. Efficacy of a bleomycin microneedle patch for the

treatment of warts. Drug Deliv Transl Res. 2018;8(1):273-280.

14. Munn SE, Higgins E, Marshall M, et al. A new method of intralesional bleomycin therapy

in the treatment of recalcitrant warts. Br J Dermatol 1996;135:969–71.

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15. Bunney MH, Nolan MW, Buxton PK, et al. The treatment of resistant warts with

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intralesional bleomycin: a controlled clinical trial. Br J Dermatol 1984;111:197–207.

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16. Price NM. Bleomycin treatment for Verrucae. Skinmed 2007;6:166-171.
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17. Urbina Gonzalez F, Cristobal Gil MC, Aguilar Martinez A et al. Cutaneous toxicity of

intralesional bleomycin administration in the treatment of periungual warts. Arch Dermatol.

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1986 Sep;122(9):974-5.
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 Figures & Legends

Figure 1.
(A) Periungual wart above the left index nail matrix before treatment.

(B) Complete clearance without nail dystrophy after 5 sessions of the treatment of fractional laser and
1U/mL bleomycin.

Figure 2.
(A) Subungual wart on the left greater toe before treatment.

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(B) Complete clearance of the wart after 5 sessions of the treatment of fractional laser and 1U/mL
bleomycin.

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Figure 3.

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(A) Multiple wart involvement over 6 fingers including right index, right middle, 4 th, left thumb, left
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index, left middle, left 4th finger.

(B) Complete clearance of the wart after 5 sessions of the treatment without complication.
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 Table 1. Baseline and Clinical Data of 17 periungual patients

No. Sex Age N. of Disease N. of Previous Result Therapeutic AverageV

Lesio Duration treatment Treatment Response AS score

ns (Months) session (N. of lesions)

1 F 4 3 10 16 - Finished CC(3) 8.5

2 M 7 1 3 5 Cryotherapy Finished CC(1) 2.2

3 M 14 1 12 15 - Finished Poor(1) 5.6

4 F 6 1 2 10 - Finished Excellent(1) 6.5

5 F 23 4 6 5 - F/U loss Excellent(2), 3.2

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Fair(1),Good(1)

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6 M 12 6 3 5 - Finished CC(6) 3.4

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7 F 12 2 4 3 Laser therapy Finished CC(2) 5.3

8 F 53 1 12 6 Finished CC(1) 4.5

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9 F 10 1 1 13 Laser therapy Finished CC(2) 5.7

10 M 9 2 2 4 Finished CC(2) 7.2

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11 F 34 2 1 9 Finished Poor(2) 2.4

12 F 6 1 12 3 Laser therapy, Finished Poor(1) 7.5

Cryotherapy
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13 M 16 1 3 10 Cryotherapy Finished CC(1) 2.0

14 M 20 2 24 4 Cryotherapy F/U Loss Poor(2) 4.5

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15 F 18 3 12 9 Cryotherapy Finished CC(3) 5.6

16 F 20 1 3 9 Finished Poor(1) 6.8

17 F 12 5 3 5 Cryotherapy Finished CC(5) 2.2

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Table2. Statistical analysis between patients with and without the history of previous other treatments.
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Previous Treatment history (+) Previous Treatment history (-)

Complete Clearance 12 14
Non-Complete Clearance 9 3
Chi Square d.f p-value
Pearson 2.763 1 0.096
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