Topical and intralesional immunotherapy in cutaneous infections

INTRODUCTION

Agents used for immunotherapy act by enhancing or suppressing the immune system.^[1] Immune enhancing or immune-modulating agents are found to be effective in the management of recalcitrant warts.^[1] Molluscum contagiosum, recurrent herpes labialis, and genitalis and cutaneous leishmaniasis are the other cutaneous infections where immunotherapy is found effective.^[2-10]

This review focuses on the topical/intralesional agents used in cutaneous infections. The common topical agents used are imiquimod 5% cream, diphenylcyclopropenone (DPCP) (diphencyprone), squaric acid dibutyl ester (SADBE), 15% sinecatechins ointment, Bacillus Calmette–Guerin (BCG) vaccine in normal saline or salicylic acid, and 15% zinc ointment.^[1,11-13] Intralesional agents found effective are Mycobacterium indicus pranii vaccine, BCG vaccine, tuberculin purified protein derivative (PPD), measles-mumps-rubella (MMR) vaccine, Candida extract, Trichophyton antigen, vitamin D3, zinc sulfate, and interferon alfa (IFN α)-2b.^[1,14] Autoinoculation (autoimplantation) is another promising therapy that has achieved clearance of warts by stimulating the immune response.^[1,14]

IMMUNOTHERAPY FOR WARTS

Recalcitrant, recurrent, or extensive warts as well as warts affecting periungual and palmoplantar sites (difficult to treat areas) are considered for immunotherapy.^[1] The first contact allergen that was used in the treatment of resistant warts was dinitrochlorobenzene (DNCB) in 1973.^[18] DNCB is no longer used widely due to its mutagenic potential.^[11]

Autoimplantation (harvesting of wart tissue followed by autoimplantation) and Falknors needling method (index wart is punctured several times with a 26-gauge needle to produce a “beefy” red wound) are the other methods that act by modulating the immune system.^[19]

The various topical and intralesional immunotherapy agents used in warts and the dose and frequency of administration are shown in Table 1.^{[1,12,13,16-18,20,21]}

Among topical agents, an evidence-based review done by Ahn and Huang noted that clinical improvement was seen in 33–50% of patients who received 5% imiquimod cream, although none of the patients experienced complete clinical clearance.^[22] A quantitative systematic review on genital warts reported that imiquimod achieved complete clearance in 51% of patients, but was not effective in human immunodeficiency virus (HIV) positive patients.^[23]

Among immune sensitizers, SADBE is considered the safest – with complete clearance in 58% of patients.^[24]

Sinecatechins are FDA approved for genital warts.^[25] It is prepared from green tea leaves from the plant Camellia sinensis. A blend of eight different catechins and other green tea components constitute the ointment. Epigallocatechin-3-gallate is the main catechin in the preparation.^[26] The clearance rate of genital warts documented following application of 15% sinecatechins ointment varied from 46% to 52% and recurrence rate was low at 6.5%.^[27]

Topically applied BCG was effective in children with common warts and plane warts with 65% and 45% resolution, respectively.^[28] In a placebo-controlled study, 80% of the patients had complete resolution of genital warts after a maximum of six BCG applications.^[29] Songsantiphap and Asawanonda, after assessing the efficacy of 15% zinc oxide ointment in 16 patients, found that the ointment applied three times a day for 4 weeks attained reduction in size of warts in comparison to placebo. The authors concluded that zinc oxide ointment can serve as adjunctive therapy to increase the efficacy of other modalities of treatment.^[13]

A case series on recalcitrant cutaneous warts treated with intralesional MMR vaccine reported complete response in nine of the eleven treated (81.9%), which was comparable to the 82% complete clearance reported by Chauhan et al.^[30,31] In an open, uncontrolled trial with intralesional vitamin D3 therapy in cutaneous warts, 78.5% of patients had complete resolution.^[32] In a 2 year study of cutaneous warts treated with intralesional Candida antigen, 80% of patients showed complete clearance of lesions. Six out of the seven immunocompromised patients who were treated also demonstrated either a partial or complete response.^[33] Hypersensitivity to Candida antigen is an absolute contraindication for this treatment modality.^[1] In a randomized controlled study, 62% of the patients responded to Trichophyton when used as a single agent.^[34] Mycobacterium w vaccine was found to have comparable efficacy to cryotherapy with 66.7% clearance in a study by Dhakar et al.^[35] Sharquie et al. demonstrated 39.7% clearance of cutaneous warts in a single-blinded placebo-controlled trial using BCG vaccine.^[36] Podder et al. in a double-blind, randomized controlled trial that assessed the effectiveness and safety of intradermal BCG vaccine in comparison to intradermal tuberculin PPD, observed both agents to be useful with better response in the BCG treated group (complete clearance in 48.5% of the BCG treated group and in 18.5% of the tuberculin PPD treated group).^[37]

A randomized controlled trial reported the usefulness of Propionium bacterium parvum (0.1 ml injected intralesionally once a month for 3–5 months) in cutaneous warts.^[21]

Another method attempted for warts is autoimplantation. In autoimplantation, a full-depth nick up to subcutis level (under local anesthesia and aseptic precautions) is made with an 18-gauge needle in a selected wart which serves as the donor wart. A chunk of wart tissue is removed and introduced in a subcutaneous pocket created with the same 18-gauge needle on the flexor aspect of the left forearm about 2 inches below the antecubital crease and secured in place by band-aid plaster. The dressings are removed after 5 days.^[38] Autoimplantation achieved clearance of lesions in 91% of patients at 2 months.^[38] ElGhareeb compared autoimplantation with MMR vaccine and noted that autoimplantation showed better efficacy in achieving clearance of distant warts (warts that were situated away from the treated wart).^[39] Complete resolution was noted in 70.7% patients with palmoplantar warts treated with Falknors needling method.^[19]

A network meta-analysis on intralesional immunotherapy for warts concluded that PPD and MMR showed superior efficacy in achieving complete primary and distant recovery and showed reduced recurrence rate at the same site in comparison to cryotherapy and other immunotherapeutic modalities.^[14] Autoinoculation showed efficacy comparable to MMR and PPD in attaining distant recovery.^[14]

Unlike PPD, intralesional MMR vaccine is not recommended in pregnancy.^[40]

RECURRENT HERPES SIMPLEX INFECTION

A double-blind, randomized placebo-controlled study in patients who had six or more self-reported episodes of herpes labialis in the preceding 12 months suggested that topical sensitization dose of SADBE (2%) on the arm may prevent herpes simplex virus (HSV) outbreaks and this was supported by another multicentre study.^[8,9]

Bernstein et al. after evaluation of subunit vaccines and imiquimod in guinea pig model of recurrent HSV type-2 infection concluded that the strategy of prime (subunit HSV vaccine) and topical pull (intravaginal/topical imiquimod) decreased recurrent HSV more effectively than vaccine alone.^[43]

CUTANEOUS LEISHMANIASIS

Nahidi et al. found a combination of topical diphencyprone and intralesional meglumine antimoniate to be more effective in acute urban cutaneous leishmaniasis than meglumine antimoniate administered alone.^[44] Topical imiquimod (5–7.5%) in combination with meglumine antimoniate was able to cure cutaneous leishmaniasis in patients who did not respond to meglumine antimoniate alone.^[10,15,45]

CONCLUSION

With the emergence of pathogens resistant to commonly used antimicrobials, immunotherapy alone or in combination with other modalities appears to be the need of the hour. Immunotherapy could be the key to treatment-resistant infections and focused research in this area may uncover lasting solutions.