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BRIEF REPORT
Ahead of print publication  

Study of BCG immunotherapy in the management of multiple, extensive non-genital cutaneous common warts


 Department of Dermatology, SVS Medical College, Mahbubnagar, Telangana, India

Date of Web Publication24-Jan-2020

Correspondence Address:
Angoori Gnaneshwar Rao,
F12 B8 HIG-2 APHB, Baghlingampally, Hyderabad - 500 044, Telangana
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/idoj.IDOJ_461_19

   Abstract 


Background and Aims: Most of the available treatment therapeutic modalities for warts are aimed at destruction of virus. However, despite adequate treatment, the virus may persist in the surrounding tissues leading to recurrence. Owing to side effects such as pain, scarring, and risk of secondary infection, these modalities may not be suitable for multiple lesions, extensive involvement and for the treatment of warts in the paediatric age group. The aim of the study was to evaluate the efficacy and safety of intra lesional BCG vaccine in the management of patients with multiple extensive non-genital common warts. Methods: Thirty patients with multiple, extensive non-genital cutaneous common warts, with age ranging from 6 to 60 years who were not on any treatment for warts and did not have any active infections (including HIV) or past history of tuberculosis attending the department of dermatology of our hospital in a 2-year period were included. Mantoux test was performed in all patients and positive responders were taken up for study. BCG vaccine was administered into the largest wart intradermally and the injection was repeated every 3 weeks for a maximum of five injections or till the complete clearance of warts, whichever was earlier . The efficacy was assessed every 3 weeks and a final assessment was done at the end of the 12th week. Patients were followed up for another 6 months. Observations: Majority of patients were in the age group of 5-14 years. Males (63.3%) were afflicted more than females. Most patients (63.3%) exhibited partial response at the site of injected wart at the end of one month and 70% patients showed complete clearance at the end of 3 months and 36.6% responded with 3 injections and 26.6% patients required 4 for response followed 23.3% requiring 5 injections. Conclusion: Intralesional immunotherapy using by BCG vaccine appears to be is a promising treatment modality for the treatment of warts, particularly the multiple and recalcitrant ones. The advantages include the resolution of both the injected and distant warts with negligible recurrence and with minimal side effects.

Keywords: BCG vaccine, immunotherapy, multiple warts



How to cite this URL:
Rao AG, Haqqani R. Study of BCG immunotherapy in the management of multiple, extensive non-genital cutaneous common warts. Indian Dermatol Online J [Epub ahead of print] [cited 2020 May 25]. Available from: http://www.idoj.in/preprintarticle.asp?id=276588




   Introduction Top


Recalcitrant warts are defined as the warts which reappear after 4-5 sessions of selected treatment options or fail to improve. Treatment of warts especially multiple, subungual and plantar ones is difficult and painful, with a substantial risk of recurrence. Current therapies include destructive modalities and immunotherapy. Destructive techniques encompass most traditional interventions, such as monochloroacetic/trichloroacetic/bichloroacetic acid, podophyllin, podophyllotoxin, 5-fluorouracil, bleomycin, retinoids, salicylic acid, glutaraldehyde, formaldehyde and cantharidin, as well as physical modalities such as surgical excision, cautery, diathermy, cryotherapy and lasers.[1] In the recent times, topical and systemic immunotherapy owing to its non-destructive action, ease of use, and promising results has found a significant place in the treatment of warts.

Intralesional immunotherapy utilizes the ability of the immune system to mount a delayed type hypersensitivity response to various antigens as well as the wart tissue. It leads to the production of Th1 cytokines which activate cytotoxic and natural killer cells leading to and eradication of the HPV infection. This clears not only the local warts but also distant warts, unlike traditional wart therapies.[2]


   Methods Top


We carried out a prospective study amongst 30 patients of extensive, multiple non-genital common warts who were administered multiple intralesional BCG vaccines. We did not design a placebo arm in our study because the cure rate for a placebo arm was 22% in a Cochrane review.[2] Thirty patients with multiple, extensive non-genital cutaneous common warts, with age ranging from 6 to 60 years who were not on any treatment for warts and did not have any active infections (including HIV) or past history of tuberculosis attending the department of dermatology of our hospital from October 2016 to September 2018 were included in the study. Patients below 5 years and above 60 years of age and immunocompromised patients, pregnant and lactating women, and subjects currently using any other treatment modality for warts were excluded from the study. The institutional ethics committee approved the study. Detailed history and demographic data was recorded. Cutaneous examination was carried out to record the site, number, duration of warts. All the routine investigations including serology for human immune deficiency virus (HIV) was done. Under aseptic precautions, 0.1 ml of BCG vaccine was given intralesionally into the largest wart intradermally, using an insulin syringe to produce a raised, blanched bleb. The intralesional injection was repeated once every 3 weeks till complete clearance of the warts or for a maximum of 5 injections without response. The efficacy of the medications was assessed every 3 weeks, till final assessment at the end of the 12th week. Patients were followed up for another 6 months for any recurrence. All adverse events were recorded. The response was evaluated as: complete response, defined as the complete absence of clinically apparent wart; partial response as decrease in size >25 and no response as <25% decrease in size.

Statistical analysis

Data was analysed by Microsoft excel and graph pad prism software. Data was summarized by Mean ± SD for continuous data and percentages for categorical data. The comparison between two variables was done by chi square test for categorical data. All P values < 0.05 were considered as statistically significant.

Observations

Out of the 30 patients, majority (36.67%) were in the age group of 5-14 years, followed by 15-24 years (30%), 25-34 years (23.3%) 35-44 years (6.67%) and 45-54 years (3.3%). There were 19 males (63.3%) and 11 females (36.6%) with a male to female ratio of 1.72:1. Majority of them (83.3%) had warts in the range of 2-21 in number [Figure 1]a, [Figure 2]a and [Figure 3]a and 6.67% patients each had warts in the range of 22-41 and 42 to 61, respectively. Only one patient (3.33%) had warts in the range of 62-81. 63.3% patients showed partial response, 10% showed complete clearance and 26.7% showed no response to intralesional BCG at the injected wart at the end of one month. 50% patients showed partial response, 43.3% showed no response and 6.7% had complete clearance in distant non-injected wart at the end of 1 month. [Table 1] Moreover, 70% patients showed complete clearance, [Figure 1]b, [Figure 2]b and [Figure 3]b 23.3% showed partial response and 6.7% were non-responders to intralesional BCG injected warts at the end of 3 months. 60% patients showed complete clearance, 26.7% showed partial response and 13.3% did not respond at distant non-injected warts at the end of 3 months. [Table 2] There was no statistical difference between the lesional site and distant site response. 82% children with warts in our study showed complete response and maximum complete response was seen in 5-14 year age group. In the present study, majority (36.6%) responded with 3 injections. 26.6% required 4 followed by 23.3% requiring 5 injections. [Table 3] Only 13.3% patients responded with two sittings of intralesional BCG. The average number of injections for response was 3.6. In the present study, clearance of warts was seen in patients with more number of warts, ranging from 22 to 72. Moreover. 52% showed complete clearance, 40% showed partial clearance and 8% showed no response in patients with warts in the range of 2-21. Most common adverse effect encountered was pain (70%), followed by edema (40%) ulceration (36.6%) scarring (33.3%) and flu like symptoms (10%).
Table 1: Response at the end of 1 month of intralesional BCG

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Table 2: Response at the end of 3-months of intralesional BCG

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Table 3: Number of injections of intralesional BCG for resolution of warts

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   Discussion Top


There is a paucity of studies regarding the efficacy of BCG immunotherapy for the treatment of different types of warts. Bohle et al. have utilized topical BCG for condylomata acuminata with complete response in 60% of patients who remained disease free at a median follow-up period of 9.2 months.[3] Similarly, Metawea et al. have reported clearance of condylomata acuminata in 80% of their patients after 6 topical BCG applications without recurrence after a 6-month follow-up period.[4] However, our study focussed on extragenital warts that were treated with intralesional BCG vaccine into the largest wart.

In the present study, age range of patients was between 6-51 years, which is in concordance with the study by Sharquie et al.[5] However, it is lower than in the study by Jagati et al.[6] The male to female ratio in our study was 1.72:1. However, it is higher as compared to the study by Podder et al.[7] (1.53:1) Contrarily, female preponderance was reported by Kenawi et al.[8] (0.76:1) In the present study, the mean number of warts was 15.4 ± 17.4 with a range between 2-72, which is comparable to the study by Podder et al. (13.94 ± 17.02). Our study revealed complete clearance of warts in fewer number of patients at injected (10%) as well as distant sites (6.7%) at the end of 1 month (one dose of BCG). This is in concert with the study by Sharquie et al. who claimed complete clearance in 6.4% patients at the end of one month after injecting BCG in the forearm. However, their study did not differentiate between lesional and distant wart response as injection was not given in the largest wart. Our study and that by Sharquie et al. elucidate the demand for more number of BCG injections for the clearance of warts.

In our study, partial response was seen in 63.3%

at the injected wart site and amongst 50% patients at distant sites, at the end of 1 month. This therapeutic response in our study was much higher than that reported by Kus et al.[9] (29.4%), Clifton et al.[10] (47%), Signore[11] (51%), Horn et al.[12] (53%) which used other antigens like tuberculin, mumps, candida and trichophytin respectively. Thus, the BCG immunotherapy validates its supremacy over other antigens. However, further comparative studies using multiple antigens are needed to establish these findings.

The clearance of untreated warts, particularly at distant sites, strongly indicates the acquisition of a widespread CMI against HPV as a response to BCG injection.

Significant response in this study with BCG may be because of use of viable antigen (live vaccine) and antigenic power (vaccines are more antigenic than skin test antigens). From the study, it was also observed that some patients who had response at injected wart did not show response in distant warts. L1-specific T cells which are involved in wart regression might not have been produced adequately in these patients.[13]

Our study observed complete clearance in 70% patients, partial response in 23.3% and no response in 6.7% at injected warts at the end of 3 months. Similarly, 60% patients showed complete clearance, 26.7% showed partial response and 13.3% patients did not respond at distant non-injected warts at the end of 3 months. This is comparable to study by Jagati et al. which showed overall complete response in 78.2% patients, partial response in 13.04% and no response in 8.7%. However, this study did not differentiate between injected and distant wart response. The results of our study (60%) are better compared to the study of Podder et al. and Kenawi et al. which showed complete response in 48.5% and 40% patients respectively [Table 4].
Table 4: Studies involving BCG in the management of common warts

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Three intralesional BCG injections seem to be effective in clearing both injected and distant warts without recurrence in the present study. The 3-week time gap between sessions was to allow severe local inflammatory reaction to subside and to initiate immune stimulation before further stimulating it. This is in concurrence with the findings of Youn et al.[14] which states that immune-associated methods show better results than local destructive methods, as these modalities are able to prevent the recurrence of viral warts by maintaining the immune response.

Better response in clearance of warts in patients with large number of warts in our study is noteworthy. This could be explained by the fact that patients who had larger number of warts, continue to follow up for the treatment more than those with fewer warts, who may be reluctant to continue therapy, or may shift to another treatment. Greater number of cross-reacting epitopes are present on the whole bacterial antigen of M. bovis (in Bacillus Calmette–Guerin) and it has been hypothesized that larger warts have larger viral loads and hence greater epitope sharing with the cross-reacting antigen.[7] Interestingly, Choi et al. opined that numerous warts and longer treatment periods imply higher therapeutic difficulties.[15]

This study showed that the longer the wart duration better the response to therapy. This may be attributed to the patient's compliance in such cases. On the contrary, Bruggink et al. documented lower cure rates among patients whose warts had been present for six or more months than among those whose warts had been present for a shorter duration.[16] Pain, edema, ulceration and scarring, and flu like symptoms noted in our study were also observed in the study by Kenawi et al. On the other hand, Sharquie et al. have observed no side effects apart from the ordinary mild transient papule or pustule that healed with a mild scar similar to that seen after routine BCG vaccination. This may be explained by the difference in sensitivity to BCG vaccine and mode of injection where they injected BCG intradermally into the arm in contrast to our patient who had been highly sensitive to BCG vaccine and were injected intralesionally into a large wart resulting in a much more severe reaction.


   Conclusion Top


To conclude, intralesional BCG vaccine is effective and safe in the management of extensive warts. It has the advantage of not only being effective in clearing warts at the site of injection, but, also effective in clearing distant warts with no recurrence and negligible side effects. Hence, intralesional BCG should be considered as first line therapy in extensive and multiple warts.

Financial support and sponsorship

Nil.

Conflicts of interest



 
   References Top

1.
Nofal A, Nofal E. Intralesional immunotherapy of common warts: Successful treatment with mumps, measles and rubella vaccine. J Eur Acad Dermatol Venereol 2010;24:1166-70.  Back to cited text no. 1
    
2.
Gibbs S, Harvey I, Sterling JC, Stark R. Local treatments for cutaneous warts. Cochrane Database Syst Rev 2003;CD001781.  Back to cited text no. 2
    
3.
Böhle A, Büttner H, Jocham D. Primary treatment of condylomata acuminata with viable bacillus Calmette-Guerin. J Urol 2001;165:834-6.  Back to cited text no. 3
    
4.
Metawea B, El-Nashar AR, Kamel I, Kassem W, Shamloul R. Application of viable bacille Calmette–Guerin topically as a potential therapeutic modality in condylomata acuminata: A placebo-controlled study. Urology 2005;65:247-50.  Back to cited text no. 4
    
5.
Sharquie KE, Al-Rawi JR, Al-Nuaimy AA, Radhy SH. Bacille Calmette–Guerin immunotherapy of viral warts. Saudi Med J 2008;29:589-93.  Back to cited text no. 5
    
6.
Jagati A, Agarwal S, Parmar KS, Shah BJ, Tank J. A prospective interventional study of 50 patients to assess the effectiveness and safety of intralesional reconstituted bacille calmette guerin immunotherapy in treatment of warts. International J Adv Res 2017;3:37-41.  Back to cited text no. 6
    
7.
Podder I, Bhattacharya S, Mishra V, Sarkar TK, Chandra S, Sil A, et al. Immunotherapy in viral warts with intradermal Bacillus Calmette–Guerin vaccine versus intradermal tuberculin purified protein derivative: A double-blind, randomized controlled trial comparing effectiveness and safety in a tertiary care center in Eastern India. Indian J Dermatol Venereol Leprol 2017;83:411.  Back to cited text no. 7
    
8.
Kenawi MZ, EL-Rahman SH, Salam OH. Efficacy of intralesional 5-fluorouracil versus BCG vaccine in the treatment of warts. Egyptian J Dermatol Androl 2012;32:3-14.  Back to cited text no. 8
    
9.
Kus S, Ergun T, Gun D, Akin O. Intralesional tuberculin for treatment of refractory warts. J Eur Acad Dermatol Venereol 2005;19:515-6.  Back to cited text no. 9
    
10.
Clifton MM, Johnson SM, Roberson PK, Kincannon J, Horn TD. Immunotherapy for recalcitrant warts in children using intralesional mumps or Candida antigens. Pediatr Dermatol 2003;20:268-71.  Back to cited text no. 10
    
11.
Signore RJ. Candida albicans intralesional injection immune therapy of warts. Cutis 2002;70:185-92.  Back to cited text no. 11
    
12.
Horn TD, Johnson SM, Helm RM, Roberson PK. Intralesional immunotherapy of warts with mumps, Candida and trichophyton skin test antigens: A single-blinded, randomized and controlled trial. Arch Dermatol 2005;141:589-94.  Back to cited text no. 12
    
13.
Kim KH, Horn TD, Pharis J, Kincannon J, O'Bryan K, Myers J, et al. Phase 1 clinical trial of intralesional injection of Candida antigen for the treatment of warts. Arch Dermatol 2010;146:1431-3.  Back to cited text no. 13
    
14.
Youn SH, Kwon IH, Park EJ, Kim KH, Kim KJ. A two-week interval is better than a three-week interval for reducing the recurrence rate of hand-foot viral warts after cryotherapy: A retrospective review of 560 hand-foot viral warts patients. Ann Dermatol 2011;23:53-60.  Back to cited text no. 14
    
15.
Choi JW, Cho S, Lee JH. Does immunetherapy of viral warts provide beneficial effectswhen it is combined with conventional therapy? Ann Dermatol 2011;23:282-7.  Back to cited text no. 15
    
16.
Bruggink SC, Gussekloo J, Berger MY, Zaaijer K, Assendelft WJ, de Waal MW, et al. Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: Randomized controlled trial. Canadian Med Asso J 2010;182:1624-30.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

 
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