Treatment of Multiple Recalcitrant Warts in an Immunocompromised Patient Using Purified Protein Derivative (PPD) Injection: A Case Report

Introduction

Warts are common cutaneous viral infections caused by human papillomavirus (HPV). [1] They are most prevalent in the second decade of life, affecting over 40% of children; however, they can occur in all age groups, particularly in immunosuppressed patients. The primary manifestations of HPV infection include common warts, genital warts, flat warts, palmoplantar warts, focal epithelial hyperplasia, and epidermodysplasia verruciformis [1].

Immunosuppressed patients are at higher risk of developing warts, including individuals with conditions such as HIV/AIDS, organ transplant recipients, and those on immunosuppressive medications [2]. These patients are also more likely to develop severe and persistent warts, requiring multiple treatment modalities [3]. Conventional wart treatments include cryotherapy, electrocautery, laser therapy, and topical agents such as salicylic acid and imiquimod. While these methods can be effective, they often have recurrence rates, particularly in immunosuppressed patients, due to their compromised immune response. Immunotherapy, an alternative therapeutic approach, aims to induce a systemic immune reaction that promotes wart resolution. Several immunotherapy options, including purified protein derivative (PPD), Candida antigen, and measles-mumps-rubella (MMR) vaccine, have demonstrated efficacy in wart treatment [4]. Purified protein derivative (PPD) is an extract of Mycobacterium tuberculosis used for testing exposure to tuberculin protein, either from active infection or vaccination [5]. However, despite decades of clinical experience and supporting evidence, PPD immunotherapy remains underutilized, particularly in immunosuppressed patients, due to a lack of standardized treatment protocols, limited awareness among clinicians, and the preference for more established treatment modalities.

Herein, we report the case of a 70-year-old immunosuppressed woman with multiple recalcitrant warts on her hand, successfully treated with PPD injection without adverse effects or recurrence. To our knowledge, this is the first reported case of wart resolution with PPD injection in an immunosuppressed patient.

Case Report

A 70-year-old female post-renal transplant recipient taking immunosuppressive therapy agents, including azathioprine, tacrolimus, and prednisolone, presented to the clinic with multiple verrucous papules over her left hand, which were asymptomatic (Figure 1A, 1B). She had previously undergone 4 sessions of liquid nitrogen cryotherapy and 1 session of pulsed dye laser (PDL) therapy, without improvement.

During her routine clinic visits, immunotherapy injections, specifically PPD, were suggested and explained to her as a treatment option. She received her first PPD intralesional injection of 0.1 mL in the largest lesion. She received a total of 3 PPD intralesional injection sessions in the same lesion, administered at monthly intervals. By her fourth visit, all her warts had cleared completely (Figure 2). A follow-up at 6 weeks showed no signs of recurrence.

Discussion

Purified protein derivative (PPD) is classified as an intralesional immunotherapy, used particularly for multiple or recalcitrant warts, along with other immunotherapies such as Candida antigen, mumps antigen, the combined measles, mumps, and rubella (MMR) vaccine, and bacillus Calmette-Guerin (BCG) vaccine [6].

PPD exploits a type IV delayed hypersensitivity reaction, inducing cell-mediated immunity (CMI). CMI plays a critical role in the clearance of HPV infection by increasing the expression of Toll-like receptors 3 and 9 and producing virally-induced cytokines IFN-β and TNF-α [7].

Although topical salicylic acid and cryotherapy are first-line treatments for warts – used individually or in combination – their cure rates remain modest, at 15% and 49%, respectively. [6]. Additionally, pain and blistering are common adverse effects, limiting their use in sensitive areas and pediatric populations. Immunotherapy injection is a viable alternative. Bleomycin injection, another useful treatment for recalcitrant warts, has high cure rates (67.8% to 99.23%) but is associated with adverse effects such as pain, necrosis, and dyspigmentation [8].

Several studies have demonstrated the efficacy of intralesional PPD injection for warts. A large systematic review analyzing 834 studies on immunotherapy for wart treatment reported a 99.4% cure rate with PPD, compared to 88% with Candida antigen and 90% with MMR injection [9]. A study conducted on 110 adult patients with single or multiple warts by Kerure et al reported a 99.4% cure rate with no significant adverse effects [10].

Notably, in patients with multiple warts, both injected and distant untreated lesions resolved, offering a significant advantage over conventional lesion-by-lesion treatments. A randomized, double-blind study found that among patients receiving 6 biweekly PPD injections, 77.1% had good responses, 22.9% had intermediate responses, and 0% had poor responses, compared to 48.5% success with cryotherapy [11].

Immunosuppression can impair multiple immune functions, such as the delayed hypersensitivity reaction. Higher doses of azathioprine and mycophenolate have been associated with impaired delayed hypersensitivity responses in transplant recipients [12]. Similarly, HIV-positive patients may exhibit reduced responses compared to non-HIV-infected individuals [12].

Various therapeutic modalities have been explored for the management of recalcitrant warts in immunocompromised individuals, given their often-poor response to conventional treatments. Other than PPD, topical imiquimod 5% cream, an immune response modifier, has also demonstrated efficacy, particularly in treating anogenital and plantar warts among immunosuppressed individuals [13]. Cryotherapy remains a commonly used option, but its efficacy may be limited as monotherapy in severely immunocompromised hosts and is often used in combination with other agents [14]. Intralesional bleomycin has been effective for periungual and resistant warts, even in immunocompromised patients, although care must be taken to avoid tissue necrosis [15]. Additionally, systemic retinoids such as oral acitretin, sometimes used in combination with topical agents like diphencyprone (DPCP), have yielded positive results in patients with extensive, treatment-resistant warts [16].

Table 1 presents the details provided in a recent case report describing an immunocompromised patient with warts successfully treated with PPD, including documentation of any reported adverse effects.

Despite theoretical concerns that PPD immunotherapy might be less effective in immunocompromised patients, our case demonstrates that it is a viable and effective wart treatment option in this population.

Conclusions

PPD injection may serve as a safe and effective treatment option for viral warts in select immunocompromised patients with preserved cell-mediated immunity. In our case, no significant adverse effects were observed. A notable advantage of this approach is the potential for the resolution of both injected and distant lesions, suggesting a systemic immune response. However, further studies are needed to determine its broader applicability across different immunocompromised populations.