The cause of plantar warts, HPV, is not a single virus but rather a group of nonenveloped DNA viruses that are categorized into more than 150 types according to similarities within their DNA sequences. These types are then further classified into species. Species are categorized into 1 of 5 genera, including α, β, γ, µ, and ν.^11,15,16 The species of HPV can also be broadly categorized according to whether they preferentially cause cutaneous or mucosal lesions or both.^8,16 

The types of HPV that have been isolated from plantar warts include HPV-1, -2, -3, -4, -27, -29, -57, -60, -63, -65, -66, and -69.^15,17,18 In one randomized controlled trial, 88% of plantar warts were caused by HPV-1, -2, -27, or -57.3¹⁸ Most plantar warts are attributed to HPV-1, however.¹⁹ While most plantar wart–causing HPV types belong to the categories of cutaneous or mucosal/cutaneous lesions, there are rare instances, such as in immunocompromised persons, in which a mucosal HPV type can cause cutaneous lesions, including plantar warts.^16,20 Human papillomavirus is species specific to human hosts, and humans are the primary reservoir of the virus.^1,21,22 The virus is transmitted via contact with HPV particles.^4,23,24 

Human papillomavirus can survive months to years on surfaces.^21,24,25 Infection of a host requires direct contact with viral particles, which can occur through either direct contact via a plantar wart or indirect contact via fomites, such as flooring, socks, shoes, towels, and sports equipment.^4,23 There is no systemic dissemination or viremic phase to HPV infection. As such, contact with body fluids, except those directly from the plantar wart itself, does not transmit HPV.^14,21 Preexistent microtrauma of the epidermal barrier of the plantar aspect of the foot allows entry of the virus on contact.^5,26-29 Once in contact with a host, HPV gains entry to the basal epithelial layer, where actively dividing stem cells are located.^29,30 In the basal epithelium, the virus binds with cellular receptors and is subsequently taken up by the now-infected cell.^8,31 After an incubation period of 1 to 20 months, viral DNA is then established within the host cell, usually without integration into the host cell genome.^24,29,30 

Once infection occurs, 3 outcomes are possible: clearance of the infection with resultant immunity to that particular HPV type, latent infection, or clinically manifested infection as a plantar wart.⁴ After infection, if the virus is not cleared, the host basal keratinocyte is stimulated to divide and replicate viral DNA via HPV E1 and E2 proteins.^29,30 This process produces numerous stem cells that each contain 20 to 100 copies of the viral DNA.^11,29 The basal stem cells contain very low levels of viral proteins, which enhances the virus's ability to evade the host's immune response.^11,27,30 As the basal cells undergo normal differentiation into keratinocytes, they progress toward the outer surface of the epithelium. At the same time, the viral genome promoter region is activated, leading to increased production of viral proteins that enhance HPV genome amplification within each differentiating cell. It is thought that E5, a membrane protein produced via the viral DNA template, serves to enhance signaling from growth factor, which in turn maintains the cell's capacity for DNA replication.^29,30 Once viral DNA copies are sufficient, L1 and L2 viral coat proteins are expressed by surface keratinocytes.¹¹ Protein E2 recruits viral DNA copies to the host cell nucleus, where the viral DNA is packaged into capsids composed of proteins L1 and L2.^11,30 The infectious viral particles can then be released in high numbers from desquamated keratinocytes on the surface of the plantar wart to infect other sites or hosts.⁸ 

The induction of cellular replication throughout the process of viral genome amplification leads to the hyperkeratinized papule that constitutes a plantar wart.³¹ Plantar warts tend to develop at areas of increased pressure on the sole of the foot, including the heel and metatarsal heads.^5,25,27 Such pressure points are regions of increased microtrauma to the epidermal barrier, which increases the likelihood of HPV invasion.^15,26 Owing to the pressure exerted on the forming plantar wart, the lesion tends to progress deeper into the skin (creating an “iceberg effect”) as opposed to forming a rounded papule, which can contribute to their resistance to therapy.^1,26 As a result of normal sloughing of the epithelium, viral particles are released and may be transmitted to surfaces where the virus will lie until picked up by a new host or spread to adjacent sites (autoinoculation).^7,21 Thus, once a plantar wart develops, the host is susceptible to additional warts developing.²³ 

Sixty-five percent to 78% of cutaneous warts have been shown to regress within 2 years.³² In persons older than 12 years, the rate of spontaneous regression significantly decreases.^2,33 Wart regression relies on the development of an effective cellular immune response.^8,34 However, plantar warts may develop in an otherwise healthy person when HPV gains entry to the epithelium and evades the host's immune response.³⁵ In the most healthy persons, HPV infections are controlled by an immune response that begins on contact with the HPV particle.^1,8,27 The viral antigen is first taken up by Langerhans cells of the epidermis, which then enter the regional lymphatic drainage and thereby enter a lymph node. There they present the antigen to T cells, which are activated and induce an antigen-specific immune response in the area of viral penetration. The antigen-presenting cells activate keratinocytes to release inflammatory cytokines that promote migration of neutrophils and monocytes, activation and migration of helper T cells, maturation of B cells, and activity of natural killer cells. Tumor necrosis factor α, which is released from keratinocytes, improves the recognition of virally infected keratinocytes by T cells, which are then responsible for destroying the infected keratinocytes.⁸ This response should lead to eradication of the infection and prevent a plantar wart from occurring or lead to regression of established plantar warts. If this process fails, a persistent plantar wart is established.³⁶ Humoral immunity, if established by antibody-producing B cells, prevents future reinfection by that HPV type.²⁷ 

It is estimated that 40% of the population is infected with HPV, and in 7% to 12%, a wart develops.^5,14,24 Plantar warts exhibit an annual incidence of 14% in the general population.⁴ Risk factors center about increased exposure to HPV, increased risk of epidermal barrier penetration, and inappropriate immune responses (Table 1). Plantar wart incidence varies with age, sex, race, and health status. Further, geographic, seasonal, behavioral, and socioeconomic factors are associated with variable rates of plantar wart incidence. It is estimated that only 0.84% of the United States population have plantar warts, whereas 12.9% of the Russian population has been shown to have plantar warts.³² Furthermore, populations living in northern England have been noted to exhibit an increased incidence of plantar warts compared with populations in southern England.⁴⁴ Throughout all regions, rates of plantar warts are noted to increase during winter months.³⁹ 

Two percent of the adult population and 6% of the pediatric population seek care for a plantar wart annually.³ Plantar warts occur most frequently in children and adolescents, although they are rare in patients younger than 5 years.^6,37 Young children experience a steady increase in warts as they age until a peak incidence between 12 and 16 years of age.²⁶ Silverberg and Silverberg³⁸ found that among children, 62.6% to 85.3% of whites and 14.7% to 37.4% of blacks had warts, and they reported that nonwhite skin type was associated with a lower incidence of warts. Children who are white, part of households with higher incomes, higher maximum levels of parental education, 2 parents, and family members with plantar warts have an increased risk of plantar warts.^4,38 Having classmates with warts also poses a risk of transmission.⁴ In adulthood, there is a decline in rates of plantar warts in the general population.³ Although adults experience fewer plantar warts, their lesions tend to have a longer duration and be more resistant to treatment.^2,26 

In terms of the sex distribution of plantar warts, incidence rates have been noted to change depending on patient age. The peak incidence of plantar warts occurs at age 13 years among females and at 14.5 years among males.^9,23 In childhood, girls have been noted to be at higher risk than boys.¹ However, among adults, men have higher rates of warts than women.^1,41 Throughout the lifetime, females tend to experience higher rates of plantar warts than males.²⁷ 

Two of the most significant risk factors for developing plantar warts are (1) having a preexistent wart and (2) having close contact with someone who has a preexistent wart.^4,39 Plantar warts have a very high viral load, which increases the rate of viral shedding and the likelihood of contaminating adjacent body surfaces, inanimate communal surfaces, or close contacts.^23,24,39 Walking barefoot also increases the likelihood of contacting HPV, especially if one walks barefoot in an area where others have walked barefoot, such as pool decks or communal showers.^6,24,39 It is believed that the rough surfaces of a swimming pool promote microtrauma to the sole of the foot, and the warm, moist environment of a communal shower promotes viral survival and infectivity.^5,24 One study demonstrated a plantar wart incidence rate of 27% for communal shower users, compared with a 1.25% incidence rate for communal shower nonusers.²³ Communal locker room use alone has not been shown to increase plantar wart risk.²³ 

Athletes have been observed to have higher rates of warts, including plantar warts, compared with the general population.²³ Hyperhidrosis of the feet is associated with increased risk of plantar warts.⁴⁵ Some athletes, such as gymnasts or dancers, have the predilection for practicing and performing barefoot on surfaces where others have also walked barefoot.²⁷ Such behavior could increase exposure to HPV.^13,27 Sharing equipment increases the risk of HPV infection and warts.^27,43 Plantar warts present a significant problem to athletes, as the pain can affect the athlete's ability to ambulate.¹⁹ 

Immunocompromised patients have higher rates of plantar warts, along with increased severity and duration of the lesions.^15,16 In particular, cell-mediated immunodeficiency, including primary, secondary, and iatrogenic, has been noted to lead to increased rates of plantar warts.^16,42 Such patients may also be at increased risk of atypical HPV types as the etiologic agent of plantar warts.^15,20 For example, HPV-69, which is not typically isolated from plantar warts in the general population, has caused plantar warts in a patient infected with HIV.²⁰ Such lesions, especially plantar warts, have also been noted to undergo dysplastic changes and lead to verrucous carcinoma.^46-48 Malignant lesions tend to be more painful, friable, and erythematous than benign lesions.¹⁹ Therefore, it is imperative that physicians consider that patients who present with large numbers of plantar warts or treatment-resistant plantar warts may have an underlying immunodeficiency and that patients with an established immunodeficiency and plantar warts may harbor a malignant neoplasm within the lesion.^20,39,42 

Patients with plantar warts most commonly present with pain or the sensation of a stone or swelling under their foot.^4,37 Pain most commonly occurs with activities that exert pressure on the soles of the feet.¹⁹ Patients may also seek care because of their concern for transmitting the infection.^19,26 Patients may complain of a gradually enlarging wart on the plantar aspect of their foot or of increasing numbers of such lesions.^7,19 

Plantar areas of increased pressure, such as the heels or metatarsal heads, should be carefully examined. On gross inspection, plantar warts may appear as a singular rough, flesh-colored to yellow or grey-brown, hyperkeratotic papule, or a thickened “cobblestoned” plaque, termed a mosaic wart, which consists of multiple plantar warts that have coalesced (Figure 1).^7,36,37 A key feature of plantar warts is disruption of the normal skin lines, dermatoglyphics, which are reestablished on resolution of the plantar wart.^7,26,45 Another distinguishing characteristic of plantar warts is the presence of small black dots, formed by thrombosed capillaries within the lesion, that exhibit pinpoint bleeding when the wart is pared (Figure 2). Visualization of thrombosed capillaries and pinpoint bleeding along with the loss of normal dermatoglyphics differentiate a plantar wart from other cutaneous lesions, such as calluses or corns.^7,13 On palpation, plantar warts feel rough and are tender when squeezed along the sides.²⁷ 

The overwhelming majority of plantar warts are histologically benign, with only rare instances of malignant transformation, such as verrucous carcinoma.^11,36,46-48 Thus, plantar warts are usually diagnosed clinically.⁴³ In cases of diagnostic uncertainty or treatment resistance, biopsy with histopathologic evaluation may be indicated.³⁹ On histopathologic analysis, increased numbers of mitotic figures can be noted among the basal and suprabasal keratinocytes, evidencing the rapid cell replication that is occurring at this level of the epidermis in the region of HPV infection.⁴⁹ The basal layer of cells also exhibits papillomatosis, in which the basal layer becomes increasingly convoluted. Cells of the stratum spinosum and stratum granulosum exhibit increased numbers of proteinaceous, basophilic, granular inclusion bodies, formed by keratohyaline.^11,26,36 Furthermore, there is hypertrophy of the keratinocytes, which leads to acanthosis (thickening of the epidermis).^11,26,36 Hypertrophy and increased numbers of keratinocytes also lead to hyperkeratosis, seen on histopathologic analysis as thickening of the stratum corneum.^11,26,27 The keratinocytes also exhibit cytoplasmic vacuoles and retain nuclei within the stratum corneum (parakeratosis).^16,26,27 

Numerous treatment options for plantar warts exist (Table 2). Each therapeutic method has been met with varying rates of success and adverse effects.^9,26 Evidence for nearly all available treatments is lacking, and no treatment has been found to have consistent efficacy for all patients.²⁶ Owing to the generally benign course of plantar warts, treatment should be pursued if the wart is symptomatic or causes psychological distress, if there are many lesions or if lesions are large, if the patient requests therapy or is concerned about transmission to others or self, or if the patient is immunocompromised.^26,51 The treatment modality that is pursued should have a relatively benign side effect profile and low cost.²⁶ 

Physicians may choose to initially pursue a wait-and-see approach for immunocompetent patients, with most plantar warts resolving within 2 years.^3,31 However, lack of treatment can allow the wart to persist longer.⁵⁰ A plantar wart is considered to be recalcitrant when it has been present for more than 6 months. Such warts are usually more resistant to treatment, suggesting that it may be beneficial to initiate therapy before wart recalcitrance.^2,26,42 The 2 most common treatments for plantar warts are topical salicylic acid and cryotherapy with liquid nitrogen.^9,14,52 

Salicylic acid is available in topical formulations both over the counter and by prescription.^9,26,51 It promotes wart regression by chemically debriding the wart of excess keratin and by inducing a local inflammatory response.⁵¹ Salicylic acid therapy generally requires weeks to months of daily applications, along with paring of the hyperkeratotic wart.^2,3,7 It is generally considered the most common initial therapy, because many patients use over-the-counter, self-applied preparations before seeking care from a physician.^7,26 However, certain patients, such as those with diabetic peripheral neuropathy or peripheral vascular disease, should be cautioned against using self-guided, at-home plantar wart therapy.⁵³ 

Cryotherapy with liquid nitrogen has been shown to be less effective than salicylic acid and is considered to be a second-line therapy for plantar warts by some.^3,9,51 Cryotherapy works by freezing the plantar wart, causing cell damage and leading to a local inflammatory response.⁵¹ Liquid nitrogen is not available over the counter. Although other forms of cryotherapy, such as dimethyl ether and propane, are available without a prescription, these forms demonstrate even less efficacy. Cryotherapy is also associated with more significant adverse effects than salicylic acid, such as mobility-limiting pain.^7,43 Double-freeze therapy, in which the lesion is frozen until a 1- to 2-mm ice halo forms and then completely thawed and immediately refrozen, has demonstrated increased efficacy but with greater risk of adverse effects.^9,26,45 Treatment is repeated as needed every 2 to 3 weeks for up to 3 months.^9,51 Because of the pain associated with this therapy, it is not recommended for young children.⁴ 

Salicylic acid and cryotherapy, while most common, are not suitable for treatment-resistant warts. Other treatment modalities have been used with variable benefit and minimal evidence for recalcitrant warts (Table 2). Although these step-up therapies have been shown to cause regression of recalcitrant plantar warts, their inadequacy lies in addressing the pathologic process of lesion development. The longer the plantar wart remains established, the greater its ability to transmit infection and cause pain and embarrassment.⁹ Management of the plantar wart and implementation of behavioral modifications can decrease viral transmission and reduce the risk of warts. Thus, prevention of the lesion altogether by diminishing risk factors for HPV infection, maintaining the integrity of the epidermal barrier, and promoting the immune system's ability to clear early infections is the ideal, yet still elusive, approach to addressing plantar warts (Figure 3). 

Plantar wart management strategies are met with high degrees of variability in success rates and often fail to adequately manage a recalcitrant wart. Because all currently available plantar wart management modalities address the lesion itself, none adequately manage the risk of transmission, which is intrinsic to the pathophysiologic mechanism by which the plantar wart develops and sheds viral particles.^9,23,26 On the basis of these considerations, further research is warranted in plantar wart prophylaxis. Preventing the lesion will reduce viral shedding and transmission and thereby reduce the risk of HPV infection and plantar warts among the population.