A Study on the Efficacy of Immunotherapy with Purified Protein Derivative for the Treatment of Recalcitrant Warts

Introduction: There are many treatment modalities of warts, but most of them are destructive therapies which have propensity to cause scarring. Many antigens especially purified protein derivative (PPD) of tuberculin bacilli are being used for the regression of warts. Objective: To study the efficacy of purified protein derivative of tuberculin bacilli in the treatment of warts. Material and Methods: A randomized controlled trial was done in which 25 patients of recalcitrant warts were taken up for the study. In all the patients, 2.5 units of PPD was injected in each wart and upto maximum of 25 units PPD was given and the injections were given every 3 weeks for a total of 3 sessions. Results: Commonest type of wart seen in our study was verruca vulgaris in 15(60%) patients, verruca plana in 5(20%) patients, palmoplantar warts in 3 (12%) patients and genital warts in 2 (8%) patients. Regarding the number of warts 15 (60%) patients had more than 20 warts, 5 (20%) patients had number of lesions between 11 – 20 and another 5(20%) patients had lesions between 1 – 10. Complete clearance of lesions after 3 sessions was seen in 18 (72%) patients, partial clearance of lesions was seen in 4 (16%) patients and no response was seen in 3 (12%) patients. Conclusion: Immunotherapy with PPD causes boosting up of the cell mediated immunity of the patients which causes spontaneous regression of the warts.


Introduction
P urifi ed protein deriva ve of tuberculin bacilli has been used to boost cell mediated immunity in pa ent with warts. 1 The course of warts is quite variable in various individuals.In some pa ents, warts regress spontaneously by themselves within a period of few months to few years.This is due to the cell mediated immunity of the person, which helps in spontaneous regression of warts. 2,3There are various modali es for the treatment of warts including various physical and chemical modali es.But the main problem with most of the destruc ve modali es is the high incidence of scarring with their use.The main advantage of immunotherapy is the lower rate of recurrence of warts and also less chance of scarring.There are various an gens used for immunotherapy including candida an gen, mumps an gen and trichophy n an gen. 4,5

Objective
To study the effi cacy of purifi ed protein deriva ve of tuberculin bacili in the treatment of warts.

Material and Methods
A randomized controlled trial was done in a district hospital in North India in which 25 pa ents of recalcitrant warts were included in the study.In all the pa ents, 2.5 units of PPD was injected in each wart and upto maximum of 25 units PPD was given.The injec ons were given every 3 weeks for a total of 3 sessions.Adrenaline was kept ready in the emergency tray for any untoward anaphylac c or hypersensi vity reac ons.Clinical response was assessed by physician global assessment score and also by photographic record which was done at every visit.

Inclusion Criteria
The following pa ents were included in our study: • Pa ents with recalcitrant warts • Pa ents having extensive warts • Pa ents who have taken no treatment for the past 3 months

Exclusion Criteria
The following pa ents were excluded from our study: • Pregnant and lacta ng females • Pa ents on immunosuppressive drugs • Pa ents having ac ve tuberculosis and on an tubercular drugs • Pa ents having any severe allergic reac on to tuberculin PPD The response to treatment was graded as follows: Complete clearance -75 -100% response Par al Clearance -50 -74% response No Clearance -< 25% response Follow up of the pa ents was done for a period of 6 months.
Wri en informed consent was taken from all the pa ents before the study.Prior permission of hospital ethical commi ee was taken for the study.

Results
The data was collected, tabulated and the results were analyzed sta s cally using chi square test.

Results
There were 15 males and 10 females and male: female ra o was 1.5:1.Maximum number (56%) of pa ents were between 21 -40 years of age followed by 8 (32%) pa ents between 0 -20 years of age and 3 (12%) pa ents were between 41 -60 years of age.
Commonest type of wart seen in our study was verruca vulgari in 15 (60%) pa ents, verruca plana in 5 (20%) pa ents, palmoplantar warts in 3 (12%) pa ents and genital warts in 2 (8%) pa ents.Regarding the number of warts, 15 (60%) pa ents had more than 20 warts, 5 (20%) pa ents had number of lesions between 11 -20 and another 5 (20%) pa ents had lesions between 1 -10.Complete clearance of lesions a er 3 sessions was seen in 18 (72%) pa ents, par al clearance of lesions was seen in 4 (16%) pa ents and no response was seen in 3 (12%) pa ents.The side eff ects of injec on PPD seen were erythema in 5 (20%) pa ents, edema and recurrence a er treatment in 2 (8%) pa ents each, pain and fever in 1 (4%) pa ents each.Oedema and redness responded to cold compresses.Recurrence was seen in 2 pa ents during the follow up period.In most of the pa ents in whom immunotherapy was given, no scarring was observed in any of the pa ents and also recurrence was very less as compared to the other modali es.

Discussion
Tuberculin purifi ed protein deriva ve is presently used for detec on of infec on by mycobacterium tubercules. 6The fi rst prepara on of tuberculin was prepared by Robert Koch in 1890, by heat killing the culture of tubercle bacilli at 100 0 C.In 1941, PPD was a purifi ed product.In India, tuberculin PPD is available as diluted and ready to use solu ons in 1 ml, 2 ml, 5ml and 10 ml vials.Intradermal injec on of PPD results in s mula on of sensi zed T cells and results in delayed hypersensi vity reac on, which begins at 5 -6 hours and becomes maximum at 48-72 hours a er the administra on of tuberculin PPD.Since PPD is a biological product, adrenaline should be available to treat anaphylac c or acute hypersensi vity reac on, though such reac ons are extremely rare a er administering tuberculin PPD. 7All the rou ne modali es have a tendency to cause depigmenta on and scarring and frequent recurrences can occur.Regression of warts can occur spontaneously due to the development of cell mediated immunity.It is important that the PPD injec on should be used with cau on in pa ents on beta blockers as they may become unresponsive to adrenaline if anaphylac c reac on occurs.
In our study, complete clearance of lesions a er 3 sessions was seen in 18 (72%) pa ents, par al clearance of lesions was seen in 4 (16%) pa ents and no response was seen in 3 (12%) pa ents.The result of the our study was comparable to a study by S. Wananukul et al, in which 67% cure rate was seen as compared to 72% in our study. 10In another study by Ibraheem, there was complete cure in 32 cases (94.1%), which is much more as compared to our study. 9 a study by Easaa et al, a total of 40 pregnant women, aged 20-35 years with anogenital warts were enrolled.The pa ents were treated with weekly injec ons of PPD given intradermally in the forearms, and evaluated for the response regularly. 8Nineteen (47.5%) pa ents demonstrated complete clearance, 15 (37.5%) had par al response, and three (7.5%) had minimal response.Three (7.5%) cases did not respond to treatment.Side eff ects were minimal and insignifi cant.Treatment of anogenital warts in pregnant women with intradermal injec on of PPD was found to be a unique, safe, and eff ec ve modality of immunotherapy.
Ibraheem evaluated the eff ect of intradermal and intralesional Purifi ed Protein Deriva ves (PPD) in treatment of warts. 9One hundred and ten pa ents with warts were included and classifi ed into 3 groups: fi rst group included 40 pa ents treated with intralesional PPD, second group included 50 pa ents treated with intradermal PPD & the third group included 20 pa ents as a control group treated with intralesional saline with a dose of 0.1 ml.The response to PPD was complete cure in 32 cases ( 94.1%) in the fi rst group,48 cases 96% in the second group.
In another study by S.Wananukul et al, tuberculin PPD injected intralesionally to the largest wart resulted in 67% cure rate with three treatments. 10tralesional immunotherapy with PPD is used to induce a delayed hypersensi vity response to various an gens and the wart ssue. 11,12It is associated with produc on of Th1 cytokines which ac vate cytotoxic and natural killer cells to eradicate HPV infec on.This helps to clear both local and distant warts.PPD injec on s mulates the local immunity and also causes circula on of ac vated T cells in the body and ul mately causes clearance of both injected as well as other non-injected warts.
The main advantage of PPD is that it is very cheap and freely available in India and is easy to administer. 13ommon side eff ects a er administra on of PPD include pain, pruri s and discomfort at injec on site.Development of ulcer or necrosis may rarely occur at the site of injec on.There are various therapeu c modali es for the treatment of warts including electrocautery, cryocautery and chemical cautery.Since all these are destruc ve therapies, there are increased chances of scarring and pigmentary changes with these methods.Also, since the warts are known to clear spontaneously a er the development of cell mediated immunity, so immunotherapy is benefi cial and it is modality of choice as there are less chances of recurrence of warts and it is less destruc ve. 14

Conclusion
The main limita on in our study was the absence of control group.Also, the sample size was small.More trials with larger number of pa ents need to be undertaken to prove the effi cacy of PPD for the treatment of warts.

Fig 1 :
Fig 1: Pre and Post Treatment Photograph of 45 years old female pa ent of Genital Warts

Fig 2 :
Fig 2: Pre and Post Treatment Photograph of 25 years old male pa ent of Verruca Plana

Table 1 :
Age wise distribu on of pa ents

Table 2 :
Type of Warts

Table 3 :
Number of Lesions

Table 4 :
Response to Treatment

Table 5 :
Side Eff ects Of Treatment