Treatment of viral warts with intralesional bleomycin

Viral warts are one of the most prevalent dermatoses. The clinical picture varies from a single lesion with spontaneous cure to multiple recalcitrant lesions. Bleomycin sulfate is a cytotoxic action drug approved for the chemotherapeutic treatment of some malignancies. There are a number of studies that have been carried out during the last 45 years demonstrating its usefulness in dermatology, especially in intralesional therapy for viral warts, meaning it is an excellent option for lesions in difficult-to-handle topographies and for cases that do not respond to other approaches.


INTRODUCTION
Bleomycin was originally isolated from the fungus Streptomyces verticillus, in 1962, by Umezawa et al. 1 This glycopeptide has antibacterial and antiviral effects, however, it is very useful because of its cytotoxic effect.It was approved by the Food and Drug Administration (FDA) for systemic treatment of testicular carcinoma, malignant pleural effusion, Hodgkin and non-Hodgkin lymphoma.][4] Despite not being approved for intralesional treatment, there are many case reports and studies in dermatology demonstrating efficacy and safety for the treatment of many conditions, such as viral warts, keloids, hemangiomas, vascular malformations and some malignant neoplasms (basal cell carcinoma, keratoacanthoma, squamous cell carcinoma and Kaposi sarcoma), for example. 3,5,6

Pharmacodynamics
Knowing its low absorption when administered orally, intravenous, intramuscular or subcutaneous administration should be used in cases of systemic treatment, according to the approach protocol. 3ue to its low transepidermal absorption, a very high dose is required to achieve minimum tissue concentration when applied topically. 3Therefore, intralesional injection becomes an option for the treatment of localized lesions.It is considered that systemic absorption is minimal after one intralesional injection. 7,8ames et al. 9 dosed the serum level of bleomycin in seven patients with palmar viral warts after injection of one unit (U) of the drug.Serum concentration ranged from 7.5 to 113.5ng/ ml and from 4.9 to 34.8ng/ml after 45 and 120 minutes, respectively.
It is mainly excreted through the kidneys, but liver participation is suggested. 3,10There is also enzymatic destruction with bleomycin hydrolase, enzyme found in many tissues, in varying concnetrations. 3

Mechanism of action
It acts mainly via cleavage of the DNA strand.In the presence of oxygen, Fe 2+ and a reducing agent, bleomycin transfer electrons from Fe 2+ to oxygen, generating reactive oxygen species.The free radical causes oxidative damage to the nucleotides, cleaving the DNA strand. 3There is also degradation of cellular RNA. 11Another mechanism of action related to a good therapeutic response in viral warts is endothelial damage. 11Direct effect of bleomycin on human papillomavirus (HPV) was not described.
Because it is a hydrophilic substance, its permeability through the cell membrane is low.Mizuno e Ishida 12 demonstrated that the association of bleomycin with lidocaine, procaine, tetracaine, dibucaine, butacaine or ethanol generates an increased cytotoxic effect.These substances would cause a disorganization of the cell membrane and, therefore, increased transmembrane permeability. 3,12

Pharmaceutical form
The preparation commercially available is bleomycin sulfate, lyophilized powder, in vial/ampoule with 15U. 3,4

Viral warts
Cutaneous viral warts are a common, benign skin infection, caused by HPV, that most frequently affects hands and feet (Figure 1). 13,14The presentation and severity can vary from a single lesion with spontaneous resolution to multiple, chronic lesions.][15] Immunosuppressed individuals are highly susceptible, with long standing lesions and reduced response to treatment. 13,15esides aesthetic and functional limitations, we should bear in mind the association between HPV and cutaneous squamous cell carcinoma. 15Therefore, it is important to biopsy chronic verrucous lesions in adults, since they can represent malignant epithelial neoplasms.

Intralesional bleomycin for the treatment of viral warts
The first description of intralesional bleomycin for the treatment of viral warts was in the 1970s, and since then many studies have confirmed its efficacy and safety.For many authors, this is an excellent therapeutic option for difficult-to-approach sites, particularly the periungual region (Figures 2 and 3), and for recalcitrant lesions, even in immunosuppressed individuals. 3,8,9,11,13,14,16,17har et al. 18 assessed 73 patients between 5 and 50 years of age, with a total of 155 warts, comparing cryotherapy with intralesional bleomycin.The cure rate in the bleomycin group was of 94.9%; in the group treated with cryotherapy, 76.5%.
In a similar study, Adalatkhah et al. 19 demonstrated cure in 86% and 68% of the cases treated with bleomycin and cryotherapy, respectively.Rossi et al. 20 demonstrated a cure rate of 82%, 2.5-fold higher than in the placebo group.
Besides common and palmoplantar warts, there are studies showing efficacy for the treatment of anogenital warts, with a cure rate of up to 70%. 21ince intralesional bleomycin is a modality considered to be off-label, there is no standardized dilution.Most authors describe the use of this drug in varying concentrations, from 1 to 1.5U/ml: 15ml saline 0.9% for 15U bleomycin = 1U/ml. 25ml distilled water for 15U bleomycin.Mix 1/3 of this solution with 2/3 2% lidocaine = 1U/ml. 18,22 ml saline 0,9% + 6ml 2% lidocaine for 15U bleomycin = 1.5U/ml. 21he needle should be inserted at the base of the lesion and the injection continued until the local blanching is achieved. 18,21This is an important sign that the medication was correctly injected. 3ost articles mention that the ideal dose should range between 0.1 and 0.3U/lesion, and 3U is the maximum dose recommended per treatment.Usually, 2 or 3 treatments are required, every 3 or 4 weeks. 3,18,21,23

B C B
For lesions on the hands and/or feet, in the first week after the procedure, the formation of hematic and darkened crusts is expected.This is due to the absolute reduction in blood flow, which results in necrosis and subsequent disappearance of the lesion (Figure 4).In general, there is resolution in 2 to 4 weeks.Facial warts regress gradually and the lesions disappear without crust formation. 3,11Blood flow is probably reduced after injection; however, it is not completely blocked due to the rich vasculature of this area.Induction of endothelial apoptosis and direct keratinocyte injury can result in wart regression without necrosis or eschar. 11pplication of a drop of bleomycin solution on the surface of the lesion, followed by multiple punctures is an alternative to intralesional therapy that was described as translesional multipuncture. 4,15Khalid et al. 15 used this technique in 15 patients, using 0.1U/ml bleomycin solution and a 27G needle.The dose used ranged between 0.3 and 0.6ml per treatment.After 4 weeks, another treatment was performed in cases that persisted or recurred.They observed that 46.6%, 73.3% and 86.6% had a good response after 1, 3 and 6 months after the procedure, respectively.

Side effects
Pain is one of the main limiting factors of this treatment, which can last up to 72 hours, with a peak at the time of injection. 3This would be one of the reasons why some authors use lidocaine as diluent, reducing pain during and immediately after the procedure.Other common side effects of the intralesional therapy with bleomycin are: erythema, edema, ulceration, hematic crust formation and eschars. 2,3,16ransient hypopigmentation or hyperpigmentation can occur (particularly in phototype IV, V or VI patients), atrophic or hypertrophic scars and hematomas.[4]8 Although rare, flagellate dermatitis can also occur with intralesional therapy. 3,24here are no reports of systemic complications with the use of intralesional bleomycin, except for flu-like symptoms, only described in the treatment of hemangiomas or vascular malformations. 7,21,25ptions to reduce pain during intralesional injection

Contraindication
Hypersensitivity or idiosyncratic reaction to the medication, Raynaud phenomenon, peripheral vascular disease, pregnancy (category D) and breastfeeding. 3,27here are no safety studies regarding intralesional use in the pediatric age group. 3

CONCLUSION
Despite being described for many years as an effective and safe therapeutic approach for viral warts, intralesional injection of bleomycin remains an off-label option.Studies revealed a high cure rate even in cases refractory to other therapies, in lesions on difficult-to-handle sites and in immunosuppressed patients.Pain is the main limiting factor of this procedure.
We highlight the importance of histopathology in the evaluation of long standing verrucous lesions in adults, because they can represent a squamous cell carcinoma and not only a plain viral wart.l

Figure 1 :
Figure 1: Periungual viral wart, affecting the lateral nail fold of the right thumb

Figure 2 :
Figure 2: A -Periungual viral wart B -After 4 weeks of intralesional bleomycin C -Seven months after a single treatment with intralesional bleomycin, complete resolution of the lesions

Figure 3 :
Figure 3: A -Periungual viral wart on the left great toe for 5 months, no response to multiple topical treatments B -Six months after a single treatment with intralesional bleomycin

Figure 4 :
Figure 4: Four days after the procedure, with its typical signs