Int J Biol Med Res.2017;8(1):5820-5826 Int J Biol Med Res www.biomedscidirect.com Volume 6, Issue 2, April 2015 Contents lists available at BioMedSciDirect Publications International Journal of Biological & Medical Research BioMedSciDirect Publications Journal homepage: www.biomedscidirect.com International Journal of BIOLOGICAL AND MEDICAL RESEARCH Case report Intralesional immunotherapy with Bacille Calmette-Guerin (BCG) vaccine for the treatment of warts: case report and systematic review Sahar Alsharif a,*, Hanadi Alzanbagia, Dania Melebarib, Norah Firaqb a b PGY at the Dermatology Residency Program, Western region, Saudi Arabia. General physician at ministry of health, Saudi Arabia ARTICLE INFO ABSTRACT Keywords: Intralesional immunotherapy BCG wart Abstract Warts are viral infection caused by human papillomaviruses (HPV). It consider one of the common dermatological diseases. The treatment options of warts include topical therapies, and destructive methods. Many of these options are destructive that may result in scarring and all of them are not practical for patients with a large number of warts because they need individual treatment of each wart. New modality of treatment developed that uses intralesional immunotherapy approaches. We present a case of a 21-year-old male who presented with multiple warts over both hands and neck for 1 year duration and not responding to different types of therapy. Intralesional (BCG) vaccine 0.1 ml was injected into the largest and first wart that appeared over the right thumb for three sessions with a two weeks interval. He reached complete clearance at one week after the third session. Follow-up was made every week during the treatment course then every month for 6 months. No significant side effects or recurrence were observed until the time of writing this paper. Our case and review support the use of intralesional immunotherapy with BCG vaccine in the treatment of different types of warts. c Copyright 2010 BioMedSciDirect Publications IJBMR - ISSN: 0976:6685. All rights reserved. 1. Introduction Warts are viral infection caused by Papilloma viruses which are epitheliotropic nonenveloped small double-stranded DNA viruses. Many modalities are available for treatment of cutaneous warts with different effectiveness and recurrent rate. Treatment options include topical treatment which takes longer time but less pain comparing to invasive therapy. Examples of topical treatments include topical salicylic acid, topical imiquimod, and bleomycin injections. On the other hand, invasive therapy which includes cryotherapy, excision, electrocautery, and laser vaporization. It is worth to mention that laser vaporization achieves rapid clearance but results in scaring. Various immunotherapeutic modalities have been utilized in the treatment of warts, including candida albicans trichophyton; and tuberculin antigens such as purified protein derivative (PPD), Mycobacterium w vaccine, vaccines such as measles, mumps, and rubella (MMR), and most recently Bacillus Calmette Guérin (BCG) vaccine. The use of these modalities was based on the assumption that they could provoke a host immune response * Corresponding Author : Sahar Alsharif P.O. Box 16688 Makkah 21955 Saudi Arabia Tel.: +966 555539141. E-mail address:s.h.alsharif@hotmail.com c Copyright 2011. CurrentSciDirect Publications. IJBMR - All rights reserved. resulting in clearance of the treated wart, and even warts at distant sites. We present a case of a common wart treated by Intralesional (BCG) vaccine that results in a complete clearance with no recurrent up to the date of writing this paper. Case Report: A 21-year-old male patient, not known to have any medical illness, presented to dermatology clinic with multiple warts over both hands and neck for 1 year duration. The warts started at the dorsal surface of the right thumb, then increased to involve both surfaces of both hands. (Figure 1) The most recent warts appeared over the neck (Figure 3 A). The patient has been treated with cryotherapy, topical salicylic acid 16.7% w/w and lactic acid 16.7% w/w without significant improvement. The patient was upset because the wart over both hands were interfere with his daily activity. Treatment by intralesional Bacillus Calmette Guérin (BCG) vaccine was discussed with the patient, and informed consent was obtained.
5821 Intralesional (BCG) vaccine 0.1 ml was injected into the largest and first wart that appeared over the right thumb for three sessions with 2-weeks interval. Warts over the neck -the most recent ones- were first to completely disappear within one week of the first injection. (Figure 3 B) Then, a gradual decrease in the size of all warts were observed until reaching complete clearance at one week after the third session. (Figure 2) Patient complained of pain at the site of injection with each session of treatment. He also developed flu-like symptoms at the night of the first injection that lasted for one day. No other side effects were observed during, or after, the treatment course. Follow-up was made every week during the treatment course then every month for 6 months. No side effects or recurrence were observed until the time of writing this paper. Figure 1 Multiple common warts over both surfaces of both hands before treatment; Note the largest and first wart that appeared over the dorsal surface of right thumb Figure 2 Complete clearance of the warts at one week after the third session Figure 3 (A) Multiple common warts over the neck; (B) Complete clearance of the warts at one week after the first session
5822 Table 1 : main characteristics of the all published studies that use intralesional BCG vaccine in the treatment of wart
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5825 Discussion: Cutaneous warts are viral infection caused by a specific types of human papillomaviruses (HPV). Classification of warts is based on morphology (e.g., filiform or mosaic warts), and anatomic location (e.g., periungual warts). The warts can be also classified into three main types: common warts (verruca vulgaris), plantar warts (verruca plantaris), and flat warts (verruca plana). The prevalence of the cutaneous and anogenital warts in the United States is range from 2 to 20%. Warts can affect both males and females of all ages, racial, and ethnic groups. However, warts occur most commonly in children and young adults, immunosuppressed patients and patients with defective skin barrier. Although spontaneous resolution of warts can occur in around 66% of children within two years; spontaneous remission in adults tends to be more slower course and may take up to several years or longer with high recurrence rate in both populations. However, warts can cause discomfort, destructive (as in the case of periungual warts) and cosmetically unacceptable that may lead to significant impact on quality of the patients' life. So, most of the physicians tend to treat the warts. The treatment options of warts include topical therapies (e.g. topical salicylic acid, topical lactic acid, topical imiquimod or topical cidofovir), and destructive methods which include medical agents (e.g., bleomycin, trichloroacetic acid in high concentrations, podophyllotoxin, cantharidin and 5-flurouracil ) and surgical (e.g., curettage, cryotherapy, electrocautery, aggressive cryosurgery, surgical excision, laser vaporization, and photodynamic therapy). Each of these modalities has its own side effects that may limit the treatment. For example, topical therapies usually require frequent treatment applications, long treatment course and often associated with variable efficacy and high recurrence rate. The destructive approaches are typically painful which are intolerable by children and are often associated with significant adverse effects such as scarring. In addition, all of these local modalities are not practical for patients with a large number of warts because they need individual treatment of each wart. There are also many systemic therapy that have been reported effective in small numbers of patients include oral cimetidine, interferon, oral acitretin, and oral zinc sulfate. Cell mediated immunity appear to be a key effector in development of warts. However, the exact mechanisms are not yet fully understood. In condition with persistent decrease of cell mediated immunity such as AIDS, the prevalence and severity of the warts increase. In contrast, when the immune response stimulated, the warts disappear. This directed the attention towards stimulation of the patient's cell mediated immunity to eradicate the HPV. From this point of view, new modality of treatment developed that uses intralesional immunotherapy approaches. Antigens studies include Candida albicans; measles, mumps, and rubella (MMR); Trichophyton; and tuberculin antigens such as purified protein derivative (PPD), Mycobacterium w vaccine, and most recently Bacillus CalmetteGuerin (BCG). Intralesional immunotherapy is relatively cost effective in comparison with traditional treatment modalities. Aldahan demonstrated in his review that the treatments with Intralesional BCG vaccine are considered to be cheaper one. In addition, intralesional immunotherapy in general can potentially lead to significant improvement in the treatment of warts, not only at the treated wart but also at distant untreated warts. In literature, we found seven published studies that use intralesional BCG vaccine in the treatment of wart. (Table 1) The total number of patients who received intralesional BCG vaccine as a treatment of wart from all studies was 122 patients. Only one study was a single blind placebo controlled study conducted on 154 patients divided by equal matched into 81 patients in group I who received 0.1 ml BCG vaccine in 1-3 doses with a one-month interval, and 73 patients in group II who were injected with distilled water. Sharquie concluded that the BCG vaccine was an effective and safe modality of treatment of viral warts. However, rest of the studies were case reports and case series. First published study was reported in 1977 by D'Alessandria. All the studies had used BCG vaccine dose range from 0.025 ml to 0.5 ml. In view of all that has been mentioned so far, in our case, we preferred to use the most frequent dose in previous studies which was 0.1 ml BCG vaccine in 1 to 3 doses with a two weeks interval. Most of the studies showed significant improvement with complete clearance of the wart within duration range from 6 weeks to 2.5 months. In contrast to earlier findings, Malison in his study that conducted in 1981 completely failed to demonstrate any improvement of the wart. His explanation was due to the presence of blocking factor within wart tissue that suppress a normal cell mediated immunity is an immune response. From our point of view, a possible explanation for these results may be the lack of adequate intralesional injection technique in his study. Because they attempted to inject BCG intralesional but they faced difficulty in that, so they injected the BCG adjacent to large clusters of lesions. Frequent few side effects of intralesional BCG vaccine were reported in the literature include local pain, erythema, edema, pustules, at the site of injection and flu-like symptoms that rapidly subsides. Granulomatous hepatitis following BCG Injection of wart is a very rare serious side effect that reported in one case only. In general, previous studies did not recommend the use of BCG vaccine in immunosuppressed patients. In addition, it is important to take caution when use BCG vaccine in patients on beta blockers as they may become unresponsive to epinephrine in the event of anaphylaxis. Conclusion: In conclusion, our case and review support the use of intralesional immunotherapy with BCG vaccine in the treatment of different types of warts single or multiple, recalcitrant or nonrecalcitrant, and cutaneous or mucocutaneous wart. By using this effective, safe, inexpensive, and available modality for treatment of warts, the aggressive destructive methods could be avoided. More research using controlled trials is needed to compare the efficacy of intralesional immunotherapy with BCG vaccine and other intralesional immunotherapy for the treatment of warts.
5825 Conflict of interest 12. The authors have no conflicts of interest that are directly relevant to the content of this case report. No sources of funding were used to assist in preparation of this manuscript. D Alessandria RM, Khakoo RA. Granulomatous hepatitis in a healthy adult following BCG injection into a plantar wart. Am J Gastroenterol [Internet]. 1977 Oct [cited 2017 Jan 18];68(4):392 5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/605897 13. Malison MD, Salkin D. Attempted BCG immunotherapy for condylomata acuminata. Br J Vener Dis [Internet]. BMJ Group; 1981 Apr [cited 2017 Jan 1 8 ] ; 5 7 ( 2 ) : 1 4 8. http://www.ncbi.nlm.nih.gov/pubmed/7214125 14. Fayed ST, Amer M, Ammar E, Salam MA. Local BCG injection administered to patients with flat condyloma of the cervix. Int J Gynecol Obstet [Internet]. 2009 Dec [cited 2017 Jan 18];107(3):253 4. Available from: http://doi.wiley.com/10.1016/j.ijgo.2009.06.016 15. Kumar P, Das A. Excellent response to intralesional bacillus calmetteguérin vaccine in a recalcitrant periungual wart. J Cutan Aesthet Surg [Internet]. Medknow Publications; 2014 [cited 2017 Jan 18];7(4):234 5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25722606 16. Gupta SK. Single dose intralesional immunotherapy with BCG of medically resistant condylomata acuminata of the penis: report of two cases. Int J Dermatol [Internet]. 2016 May [cited 2017 Jan 18];55(5):583 6. Available from: http://doi.wiley.com/10.1111/ijd.12900 References 1. 2. Shaheen MA, Salem SAM, Fouad DA, El-Fatah AAA. Intralesional tuberculin (PPD) versus measles, mumps, rubella (MMR) vaccine in treatment of multiple warts: a comparative clinical and immunological study. Dermatol Ther [Internet]. 2015 Jul [cited 2017 Jan 1 8 ] ; 2 8 ( 4 ) : 1 9 4 2 0 0. http://doi.wiley.com/10.1111/dth.12230 Aldahan AS, Mlacker S, Shah V V., Kamath P, Alsaidan M, Samarkandy S, et al. Efficacy of intralesional immunotherapy for the treatment of warts: A review of the literature. Dermatol Ther [Internet]. 2016 May [cited 2017 Jan 18];29(3):197 207. Available from: http://doi.wiley.com/10.1111/dth.12352 3. Nofal A, Yosef A, Salah E. Treatment of recalcitrant warts with Bacillus Calmette-Guérin: a promising new approach. Dermatol Ther [Internet]. 2013 Nov [cited 2017 Jan 18];26(6):481 5. Available from: http://doi.wiley.com/10.1111/dth.12019 4. Sterling JC, Gibbs S, Haque Hussain SS, Mohd Mustapa MF, Handfield-Jones SE. British Association of Dermatologists guidelines for the management of cutaneous warts 2014. Br J Dermatol [Internet]. 2014 Oct [cited 2017 Jan 18];171(4):696 712. Available from: http://doi.wiley.com/10.1111/bjd.13310 5. Nofal A, Nofal E, Yosef A, Nofal H. Treatment of recalcitrant warts with intralesional measles, mumps, and rubella vaccine: a promising approach. Int J Dermatol [Internet]. 2015 Jun [cited 2017 Jan 18];54(6):667 71. Available from: http://doi.wiley.com/10.1111/ijd.12480 6. Orlow SJ, Paller A, Dunagin W, Millikan L, Abcarian H, Sharon N, et al. Cimetidine therapy for multiple viral warts in children. J Am Acad Dermatol [Internet]. Elsevier; 1993 May [cited 2017 Jan 18];28(5):794 6. http://linkinghub.elsevier.com/retrieve/pii/s0190962209802788 7. Glass AT, Solomon BA, Simon MR SDCS, Ershler WB HMBB et al, Raptopoulou GM BPVN et al, Griswold DE ASBA et al, et al. Cimetidine Therapy for Recalcitrant Warts in Adults. Arch Dermatol [Internet]. American Medical Association; 1996 Jun 1 [cited 2017 Jan 1 8 ] ; 1 3 2 ( 6 ) : 6 8 0. http://archderm.jamanetwork.com/article.aspx?doi=10.1001/archder m.1996.03890300108014 8. Mosa C, Trizzino A, Trizzino A, Di Marco F, D Angelo P, Farruggia P. Treatment of human papillomavirus infection with interferon alpha and ribavirin in a patient with acquired aplastic anemia. International Journal of Infectious Diseases. 2014. 9. Simone C De, Capizzi R, Carbone A, Fossati B, Valenzano F, Amerio P. Use of acitretin in a case of giant common warts in an HIV-infected patient. Eur J Dermatol [Internet]. [cited 2017 Jan 18];18(3):346 7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18474473 10. Stefani M, Bottino G, Fontenelle E, Azulay DR. Comparação entre a eficácia da cimetidina e do sulfato de zinco no tratamento de verrugas múltiplas e recalcitrantes. An Bras Dermatol [Internet]. Sociedade Brasileira de Dermatologia; 2009 Feb [cited 2017 Jan 18];84(1):23 9. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=s036505962009000100003&lng=pt&nrm=iso&tlng=pt 11. Sharquie KE, Al-Rawi JR, Al-Nuaimy AA, Radhy SH. Bacille CalmetteGuerin immunotherapy of viral warts. Saudi Med J [Internet]. 2008 Apr [ c i te d 2 0 1 7 J a n 1 8 ] ; 2 9 ( 4 ) : 5 8 9 9 3. Ava i l a b l e f ro m : http://www.ncbi.nlm.nih.gov/pubmed/18382805 c Copyright 2010 BioMedSciDirect Publications IJBMR - ISSN: 0976:6685. All rights reserved.