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EPIDEMIOLOGY
Cutaneous warts are caused by a small group of specific HPV types, with a prevalence of up to 30% in primary schoolchildren and a decline thereafter with increasing age. Patients living in larger households often report an infected cohabitant, supporting the concept of personto-person transmission. The majority of warts will regress spontaneously within 1โ2 years. After clearance occurs, reinfection with the same HPV type appears to be uncommon, suggesting that protective type-restricted immunity may develop.
Genital infection with HPV occurs most commonly by intimate contact, while infection of non-genital skin may occur via direct skin-to-skin contact or indirectly through contaminated surfaces and objects (e.g. swimming pool, gymnasium). Basal keratinocytes, which serve as the primary targets for HPV infection, are exposed to the virus through minor abrasions, and infection is promoted by maceration. Autoinoculation of virus from the lesion to adjacent skin is observed frequently, especially for digital or flat warts. Using sensitive polymerase chain reaction (PCR)-based detection, normal-appearing skin surrounding HPV-associated lesions and even skin of healthy volunteers may contain HPV DNA. These observations help to explain the high recurrence rate of warts (e.g. 20%โ50% for genital condylomata) and the observation that treatment may not prevent further transmission of the virus. Papillomaviruses are resistant to heat and desiccation due to the absence of a viral envelope, and even laser fumes may contain infectious virions.
Genital warts in prepubertal children are uncommon and their diagnosis raises special concerns. Although viral transmission may occur during delivery, from close family contacts, or by autoinoculation from skin warts, the possibility that these lesions may have been caused by sexual abuse should always be carefully considered (see below).
In the US, HPV infection of the lower anogenital tract was the most common sexually transmitted infection (STI), with a historical overall prevalence of ~40% in those ages 19โ59 years. However, following the introduction of the quadrivalent HPV vaccine, the prevalence of HPV types 6, 11, 16, and 18 in cervicovaginal specimens decreased in women ages 14โ19 years, declining from 11.5% in the prevaccine era (2003โ
2006) to 5% in the years 2007โ2010. Behavioral risk factors include sexual intercourse at an early age and the number of lifetime sexual partners. Circumcised men are less likely to carry and transmit HPV infection. In men who have sex with men (MSM), anal HPV infection is very prevalent (up to 75%). The public health impact of genital HPV infection is evidenced by the high number of initial visits to physiciansโ offices for treatment of genital warts and the frequency of consequences such as abnormal Pap smears and cervical neoplasia. In the US, the estimated prevalence of sexually acquired HPV infection is 42 million people and the estimated annual cost burden of genital HPV infection is $6โbillion, making it the second most costly STI after HIV infection.
Most genital papillomavirus infections resolve spontaneously, whereupon HPV DNA becomes undetectable by PCR. The median duration of high-risk HPV infections in women is 8 months and persistence is found in 30% after 1 year and in 9% after 2 years. Persistent cervical infection with a high-risk HPV type is required for the development of cervical intraepithelial neoplasia (CIN) and carcinoma. HPV-16 is detected in ~50% of cervical cancers and high-grade CIN. Together, HPV-16, -18, -31, -33, -45, -52, and -58 have been identified in ~90% of cervical cancers, and all are targeted in the nine-valent HPV vaccine.
Worldwide, an estimated 570โ000 cases of cervical cancer were diagnosed in 2018, resulting in about 310โ000 deaths. The disease occurs predominantly in low-income countries that lack effective cervical screening programs. In the US, prevention and early detection programs have reduced the incidence rate of cervical cancer by ~75%, to 8 per 100โ000 women per year. According to the American Cancer Society, an estimated 14โ500 new cases of cervical cancer occurred in 2021, resulting in ~4300 deaths. Although high-risk oncogenic HPV types account for most of the observed risk for developing cervical cancer, smoking, cervical inflammation, parity, and oral contraceptive use have been proposed as cofactors. While there is little evidence for hematogenous spread of HPV, ~60% of patients with anogenital infections develop low-titer, type-restricted antibodies during the course of infection. Titers tend to decrease slowly and may persist for years after viral clearance.
Immune suppression in HIV-infected patients and organ transplant recipients results in HPV infections that are more frequent, persistent, and likely to progress to intraepithelial neoplasia, with CD4+ T cell depletion and HIV viral load being important risk factors. In studies analyzing anal swabs, up to 93% of HIV-seropositive MSM were positive for HPV DNA, compared to 60% of HIV-negative MSM. HPV-associated anal intraepithelial neoplasia (AIN), a likely anal cancer precursor, is found in up to a third of HIV-infected MSM, compared to 20% of HIV-negative MSM. Antiretroviral therapy has shown no or only a modest beneficial effect on the incidence and progression of AIN or CIN. Similarly, organ transplant recipients are at an increased risk for developing warts and genital neoplasias. They also have a higher incidence of premalignant and malignant skin neoplasias, e.g. actinic keratoses, Bowen disease, and SCCs, especially in sun-exposed areas.
Cutaneous tumors from organ transplant recipients as well as โhealthy skinโ and plucked hairs from immunocompetent patients often contain DNA from ฮฒ HPV types (see below). Only in patients with EV and immunocompromised hosts do ฮฒ HPV infections result in highly active viral replication with cytopathic effects and clinical lesions. In skin swab samples, children from 1 month to 4 years of age have a high prevalence (from 50% to 70%) of HPV DNA, indicating that normalappearing human skin is colonized with a multiplicity of ฮฒ HPV types very early in life, most likely through close skin-to-skin contact. Beta HPV DNA has also been detected in psoriatic lesions and skin cancers from PUVA-treated patients; however, highly sensitive PCR-based methods were required for detection and viral gene transcription has not been reported.
Recurrent respiratory papillomatosis (RRP) is characterized by exophytic lesions of the airways. It occurs in juvenile- and adultonset forms and is usually caused by HPV-6 and -11. Despite its low incidence of 0.4โ1.2 per 100โ000, RRP is the most common benign tumor of the larynx. It is believed that in childhood-onset RRP, vertical HPV transmission from mother to child occurs by aspiration during delivery through an infected birth canal. Although treatment should be considered in pregnant women with condylomata in order to reduce viral load, there is insufficient evidence to support cesarean section to prevent development of RRP in the offspring. Adult-onset RRP more likely results from genital-to-oral transmission.