Association of Plantar Warts Genotype and Treatment Method

By: Daniel Lowe, B.A., Theresa Schneider, B.A., Ashley Dikis, DPM FACFAS

Des Moines University Medicine and Health Sciences

            Verrucae, or warts, are the result of an infection from the human papillomavirus (HPV). The virus infects the epidermis, thus causing thickening and results in a benign epidermal neoplasm. Warts typically infect children and young adults with the mode of transmission being direct contact. Lesions may form anywhere along the plantar aspect of the foot, though often are located at areas of maximum pressure, such as the metatarsal heads or the heel. A thick overlying hyperkeratotic tissue layer is often present, with disruption of surrounding dermatoglyphics. Dark spots are visualized within the lesion, representing areas of punctate hemorrhaging, seen in Figure 1. 1-3 Diagnosis is traditionally achieved via physical examination with the noted presence of these distinguishing characteristics, though dermoscopy can be useful in improving diagnostic accuracy. 4

Figure 1. Patient present with a plantar wart showing the common characteristics: hyperkeratotic tissue, disruption of surrounding dermatoglyphics, and punctate hemorrhaging.

            HPV has more than 100 subtypes.1 According to Planell-Mas et al., the most common types of HPV within plantar warts are HPV-57 (37.1%), HPV-27 (23.8%), HPV-1a (20.9%), HPV-2 (15.2%), and HPV-65 (2.8%).5 Al-Awadhi et al. analyzed plantar warts using real-time PCR and found HPV-27b to be the most common at 46.4%, HPV-57c at 25.8%, HPV-1a at 13.4%, HPV-2 at 9.3%, HPV-65 at 2%, followed by HPV 1a and HPV 27b at 3.1%. 6

            Current available evidence suggests some HPV genotypes of a plantar wart may have clinical distinction. Planell-Mas et al. found statistical significance in the correlation of HPV-57 favoring females and HPV-1a favoring men. After analyzing samples obtained through their study, they also noted that HPV genotypes within the alpha genus were only found in those patients over the age of 21, while genotypes from the mu genus were detected in all ages.  While warts in the alpha genus developed over a prolonged time (6 months to more than a year), those in the mu genus often developed in less than a year.5 Excluding the work reported by Planell-Mas and colleagues, there are no other publications that delineate the HPV-genotype of the plantar wart and the clinical presentation. This presents a challenge to make this determination without a PCR modality.  

            A systematic review by Garcia-Oreja et al. reported the average cure rate for treatment methods consisted of: cryotherapy (45.61%), salicylic acid (13.6%), cantharidin-podophyllum-salicylic acid formulation (97.82%), laser (79.36%), topical antivirals (72.45%), intralesional bleomycin (83.37%), and intralesional immunotherapy (68.14%).  Within the studies, the cryotherapy and salicylic acid were typically first-line treatment with low cure rates.7 They did note the issue of heterogeneity in study design, efficacy results, study size, treatment period and follow-up as a significant limitation in comparison of the available data, indicating a need for future robust randomized control trials.7 This study demonstrates the baseline treatment method for all genotypes being grouped together as one.

            At present, the question remains unanswered as to whether a correlation between treatment method and the HPV-genotype of a plantar wart exists. Hogendoorn et al. found a significant association of plantar warts with the genotype HPV 2  and HPV 27 having a decreased treatment response compared to HPV 1 with use of monochloroacetic acid or the combination of cryotherapy and salicylic acid (Figure 2).8

            A study by Bruggink et al. reported HPV 1 has better outcomes in the wait-and-see method with a cure rate at 58%, compared to HPV 2, 27, and 57 at 7%. For HPV 2, 27, and 57 the cure rate using cryotherapy was 11% and 25% with salicylic acid. For HPV 1, the cryotherapy cure rate occurred at 65% and 92% for salicylic acid (Figure 3).9

           Fichman et al. compared genotypes found in verruca vulgaris, also known as the common wart, and the treatment outcomes seen with pulsed dye laser therapy. They compared the clearance rate of HPV types 2, 10, and 57. HPV-2 clearance occurred at 75.6%, HPV–10 was 80%, and finally HPV-57 was 95.6% (Figure 4). No statistically significant difference was noted between outcomes of viral types with pulsed dye laser therapy.10 Although there was no statistical significance present between clearance rate for pulsed dye laser, when compared to Bruggink’s study within HPV 2 and 57, the clearance rates are higher than either the wait-and-see method, cryotherapy, or salicylic acid.

         Planell-Mas and colleagues also looked at the heal rates for plantar warts using 1064 laser and cooling. Within this study laser treatment demonstrated the following results: HPV-1 100% cured, HPV-2 50% cured, HPV-27 85.7% cured, HPV-57 94.1% cured, and HPV-65 100% cured (Figure 5).11

          A physician can easily determine a plantar wart genotype. Koning demonstrated that genotyping a wart via swabbing had a 100% specificity, compared to biopsy, and a 96% sensitivity. Utilizing this technique, a physician can simply use a sterile swab and send the sample to pathology, allowing for the ability to determine genotype in the outpatient clinic setting.12 

            At this time, HPV-1 demonstrates the best outcomes with the wait-and-see method when compared to first line treatment methods, suggesting monitoring may be advised before proceeding with intervention.9 Further research is needed to investigate the best treatment method for other common HPV genotypes (HPV 2, 27, 57, and 65). Based on these studies, 1064 nm laser and cooling demonstrates the highest clearance rate compared to monochloroacetic acid or a combination therapy of cryotherapy and salicylic acid within the HPV genotyping of 2, 27, 57, and 65. New research needs to compare a greater diversity of treatment methods within the different genotypes to limit the vast number of treatment methods currently available. Future patient encounters may begin with a swab of a plantar wart to determine the best treatment modality. The goal would be to offer more detail in diagnosis, guide therapy in an evidence-based fashion, and overall improve outcomes.  Ultimately this should reduce treatment time, potentially decrease cost, and improve patient satisfaction. 

References
  1. Habif T. Clinical Dermatology. Elsevier Health Sciences, 2015
  2. Ferri FF. Ferri’s Fast Facts in Dermatology: A Practical Guide to Skin Diseases and Disorders. Elsevier Health Sciences, 2017
  3. Marks JG, Miller JJ. Lookingbill and Marks’ Principles of Dermatology. Elsevier Health Sciences, 2017
  4. Bhatti A, Chowdhary S, Ferrise T, Govardhanam N, Parish A, Tropper Y, Vlahovic TC. Plantar Verruca and Dermoscopy: An Update. Clin in Podiatr Med Surg 2021; 38:513-520
  5. de Planell‐Mas E, Martínez-Garriga B, Zalacain AJ, Vinuesa T, Viñas M. Human papillomaviruses genotyping in plantar warts. J Med Virol 2017; 89:902-907
  6. Al-Awadhi R, Nawaf A, Wassim C. Prevalence of HPV Genotypes in adult male patients with cutaneous warts: a cross-sectional study. Med Princ and Pract 2020; 29:458-464
  7. García‐Oreja S, Álvaro-Afonso FJ, García-Alvarez Y, García-Morales E, Sanz-Corbalán I, Martínez JLL. Topical treatment for plantar warts: A systematic review. Dermatol Ther 2021; 34
  8. Hogendoorn GK, Bruggink SC, de Koning MNC, Eekhof JAH, Hermans KE, Rissman R, Burggraaf J, Wolterbeek R, Quint KD, Kouwenhoven STP, Bouwes Bavinck JN. Morphological characteristics and human papillomavirus genotype predict the treatment response in cutaneous warts. Br J Dermatol 2018; 178:253-260
  9. Bruggink SC, Gussekloo J, de Koning MNC, Feltkamp MCW, Bouwes Bavinck JN, Quint WGV, Assendelft WJJ, Eekhof JAH. HPV type in plantar warts influences natural course and treatment response: secondary analysis of a randomised controlled trial. J Clin Virol 2013; 57:227-232
  10. Fichman Y, Levi A, Hodak E, Halachmi S, Mazor S, Wolf D, Caplan O, Lapidoth M. Efficacy of pulsed dye laser treatment for common warts is not influenced by the causative HPV type: a prospective study. Lasers Med Sci 2018; 33:773-777
  11. de Planell-Mas E, Martínez-Garriga B, Viñas M, Zalacain-Vicuña AJ. Efficacy of the Treatment of Plantar Warts Using 1064 nm Laser and Cooling. Int J Environ Res Public Health. 2022 Jan 12;19(2):801.
  12. de Koning MN, Khoe LV, Eekhof JA, Kamp M, Gussekloo J, Ter Schegget J, Bouwes Bavinck JN, Quint WG. Lesional HPV types of cutaneous warts can be reliably identified by surface swabs. J Clin Virol. 2011 Oct;52(2):84-7.

About the Authors

This online journal article was written by Daniel Lowe of De Moines University’s Podiatric Medicine program and by Theresa Schneider of De Moines University’s Osteopathic Medicine program. Daniel Lowe will receive his D.P.M. degree in 2023, and Theresa Schneider will receive her D.O. degree in 2023. Both students collaborated with Ashley Dikis D.P.M., FACFAS.

NFAR AND AGK Collaboration: Literature vs. Systematic Review

Interested in research but don’t know where to start? This Saturday, November 13th from 9:00AM to 10:00AM PST, NFAR’s co-editor-in-chief Tiffany Tran will be collaborating with AGK Gamma Chapter at CSPM to present “Literature Review vs. Systematic Review” to go over the methods and components of a good review essential to getting published in an academic journal. Hope to see you there! Here is the meeting link.

2021-2022 NFAR: Call for Papers Open!

To the podiatry classes of 2022, 2023, 2024, and 2025:

The National Foot & Ankle Review is an annual student-produced journal, created 20 years ago by Dr. Burns to help students gain experience in podiatric medical research and showcase your research interests during the clerkship/residency application process. NFAR is being led by Dr. Stamps for the eighth year in a row at the California School of Podiatric Medicine (CSPM) at Samuel Merritt University. NFAR accepts original manuscripts from all schools of podiatric medicine. The finished product is distributed to schools, clerkship programs, and residencies around the country.

Submission guidelines:

Please submit a proposed topic and await approval as we do not want repeats from previous years or duplicates for the current year’s publication. Articles published in the past have been predominantly limited to reviews, meta-analyses, and case reports. A list of NFAR articles from 2005-2021 can be found in the attached documents. Topic submissions are due October 10th, 2021 at 11:59pm PST. To make things clear, all you need to submit is just a phrase i.e. Flexible Fixation of Lisfranc Injuries. There is no written proposal. The NFAR editors will help you improve your paper over the next few months and the manuscript will be finalized mid-late spring. You do NOT need a team to submit a topic but is highly recommended so you don’t get overwhelmed with the workload. Please email your topic to nationalfootandanklereview@pilot.samuelmerritt.edu. Note: the earlier you submit your topic for approval, the more time you have to write your articles.

When writing your paper, pay special attention to the NFAR guidelines, which details the types of sections that are typically included in each type of article, as well as, instructions for proper text and file formatting. Submissions that do not meet these requirements will not be accepted for publication. The abstract must be submitted by October 24th, 2021 at 11:59pm PST. All completed articles must be received by November 7th, 2021 at 11:59pm PST in order for the journal to be sent out to all the residency programs in the country, as well as to CSPM alumni and associates. A guideline for proper formatting of submissions can be found in the attached documents.

If you would like to submit an article, but are having trouble picking a topic, utilize your faculty members and faculty clinicians. Also, it is a great idea to use your clinical experience as a starting point for finding topics of interest.

Please let us know if you have any questions.

Regards,

Tiffany Tran, Editor-in-Chief of National Foot & Ankle Review

Necrotizing Fasciitis in the Lower Extremity: A Literature Review

Farheen Iqbal, B.S., Mohammad Junayed Khan, B.A.

ABSTRACT
Necrotizing fasciitis in the lower extremity is a lifethreatening soft tissue infection and is one of the few podiatric surgical emergencies. With a nonspecific clinical presentation, this infection can often be misdiagnosed. Diabetes mellitus is the most common predisposing factor. Behavioral risk factors include smoking and intravenous drug use. Necrotizing fasciitis is subdivided into three types based on bacterial etiology: type
I is a polymicrobial form, type II is a Streptococcus form, and type III is a gram negative form. In addition to clinical findings, diagnostic imaging such as ultrasound, computed tomography, and magnetic resonance imaging can assist diagnosis. Antibiotic therapy and surgical debridement are the keys to treatment, with amputation occurring frequently, especially among patients with diabetes mellitus.

Aurotherapy: A Literature Review and its Implications for the Treatment of Hypergranulation Tissue in Wounds

Lisa Yoon, B.A., Jose Lingao, B.A.

ABSTRACT
Chronic ulcerations account for a large proportion of the total cost of wound care in the United States, yet only a small fraction of the population suffers from these wounds. Therefore, it is imperative to research and develop alternative treatment options that are both efficacious and economical. Aurotherapy, the use of gold compounds in wound care, has been gaining traction in nonhuman trials. Gold is proposed to increase healing rates by inhibiting matrix metalloproteinases and TGF-B and by enhancing angiogenesis and collagen synthesis. Trials involving human applications, however, are limited in the medical literature. This paper reviews the research to date investing gold and its
potential application in wound care.

The Use of Prophylactic Vitamin C for Prevention of Complex Regional Pain Syndrome in the Foot and Ankle: A Review of the Literature

Stephen Kriger, B.A., Shontal Behan B.S., Sara Shirazi, B.A.

ABSTRACT
Complex regional pain syndrome is a chronic pain disorder, which typically occurs following trauma or surgery. The condition involves the extremities and is
characterized by disabling pain out of proportion, edema, vasomotor instability, and impaired motor function. While research has not been able to agree on a specific
treatment or prevention of the syndrome, prophylactic vitamin C has been described as a promising, effective form of prevention if given directly following traumatic fracture or surgical intervention.

Literature Review: Double Osteotomy of the First Metatarsal for Hallux Abducto Valgus

Caroline Ko, B.S., Isaiah Song, B.S.

ABSTRACT
A double osteotomy of the first metatarsal is a combined procedure of a proximal and distal osteotomy of the first metatarsal. The technique provides a large angular correction for severe cases of hallux abducto valgus while minimizing the rate of recurrence and preserving the first metatarsophalangeal joint articulation. Historically, this procedure has had major complications, including shortening of the first metatarsal, stiffness of the first metatarsophalangeal joint, and avascular necrosis of the first metatarsal head. The traditional double osteotomy of the first metatarsal has evolved
with the goal of minimizing the aforementioned complications. The Peterson approach maintains the length of the metatarsal while preserving the recurrence rate.
The modified Peterson approach incorporates a medial plate and screws and reduces first metatarsophalangeal joint stiffness. Minimally invasive percutaneous approaches
of the procedure have been suggested to lower risk of avascular necrosis. This literature review provides an overview of double osteotomies of the first metatarsal and a discussion of associated outcomes and complications.

An Alternative for Minimally Invasive Osteotomies: The Gigli Saw Technique

Megan Ishibashi, B.S., Toby Ishizuka, B.A.

ABSTRACT
Osteotomies that require a large incision site and  are performed with a high-energy instrument may result in neurovascular injury and postoperative wound complications.
The Gigli saw technique is a minimally invasive alternative to open dissection osteotomies. This technique uses a flexible stainless steel cable with attached
handles in a reciprocating pattern to cut through bone. This review aims to introduce this procedure to the podiatric medical student, so that one can consider this technique as a surgical option in a patient with peripheral vascular disease, soft tissue injury, or osteoporotic bone quality. This article will review several studies and surgical textbooks to explain how to use a Gigli saw in podiatric surgeries and describe the strengths, weaknesses, and future implications of this minimally invasive technique.

Assessment and Treatment of Ankle Joint Equinus

Luke McCann, B.S., M.S.

ABSTRACT
Ankle joint equinus is frequently mentioned as a major deforming force of the lower extremity. However, it is rarely considered as a primary diagnosis of foot and ankle problems, rather, it is viewed as a secondary factor that often receives inadequate attention. Visual inspection of non-weightbearing ankle dorsiflexion, without the use of a goniometer, is frequently how clinicians diagnose equinus. Interventions including
heel lifts, stretching, injections, and splinting are some of the conservative treatment options available. Surgical treatment is a more definitive treatment option, of which there are a variety of procedures available. A thorough understanding of assessment, as well as treatment options for equinus, is critical for the podiatric physician when making decisions managing this condition.

Literature Review: Implementing Angiosome-guided Revascularization for Lower Extremity Wounds

Meghan Teague, B.S., Lewis Kane, B.A. M.S., Shontal Behan, B.S

ABSTRACT
Angiosome theory was originally described in the context of plastic surgery and is commonly used to guide revascularization interventions in patients with ischemic foot wounds. This approach asserts that the foot and ankle can be divided into territories (angiosomes) that are each supplied by a primary vessel. Restoring arterial supply to an angiosome may therefore enhance wound healing. However, dynamic vascular anatomy, diseased patient populations, and varied wound distributions have made research on angiosomedirected revascularization strategies difficult to interpret. As a result, there is no current consensus regarding the validity of angiosome theory in ischemic wound therapy. Here we provide a brief overview of angiosome theory, the data supporting and refuting it, and potential approaches for future research.