Sexually Transmitted Diseases Of Viral Origin
Infection with the human papillomavirus (HPV) is the most common sexually transmitted infection (STI) in the world. HPV is a wily pathogen that causes a spectrum of clinical diseases, all of which involve cutaneous or mucosal squamous surfaces. From the evolutionary standpoint, HPVs are very successful infectious agents because they induce chronic infections that have no systemic sequelae and rarely kill the host. Instead they periodically shed large amounts of infectious virus for transmission to naïve individuals.
The broad spectrum of genital HPV infection includes: (i) latent infection; (ii) clinically apparent lesions (condylomata accuminata, warts); and (iii) HPV-associated neoplasia. Latent infections are identified by the presence of HPV DNA in tissue samples acquired for epidemiologic study. In the absence of tissue collection, latent infections would go unrecognized because neither microscopic nor visible lesions are present. Overt genital warts, also known as condyloma acuminata, are flesh-colored, pink or pigmented papules with a frond-like surface. Sessile warts, or flat condyloma-like lesions, are less common, accounting for only 20% of visible genital warts. Most genital warts in men are on the penis. In women, they are found most often at the vaginal introitus and on the labia. Most genital warts are asymptomatic. When symptoms do occur, they are often secondary to local friction-induced irritation from clothing or intercourse. HPV- associated neoplasias include intraepithelial lesions of the cervix (CIN) and vulva (VIN) and invasive carcinomas at both sites. Cervical cancer is discussed in detail in Chapter 44.
Because most genital warts are sexually transmitted, their presence indicates risk for other STIs. Treatment of genital warts involves cryotherapy or topical application of agents that cause cytolysis.
Epidemiology of HPV
The primary risk factor for HPV infection is sexual activity. It is estimated that 75% of sexually active women will acquire latent HPV infection. Fortunately, most HPV infections are transient; up to 90% of infections in women will resolve spontaneously within 2 years of acquisition. Unfortunately, persistent infection is more common with HPV genotypes that have neoplastic potential.
Although rare, it is possible to acquire HPV through nonsexual transmission. Neonates can become infected during delivery.
Biology of human papillomaviruses
HPV is a member of the Papovaviridae family of DNA viruses. Other well-known members of this family are the polyomaviruses (polio virus and SV40). Of the 130 different HPV genotypes identified to date, about 40 are associated with genital lesions. Types 6 and 11 are most commonly identified in genital warts, and types 16 and 18 are most closely associated with neoplasia (high-risk subtypes). HPV sub- types 1–5 are associated with common skin warts and plantar warts.
The success of HPV as an infectious agent is directly linked to a virus replication cycle that effectively evades immunologic detection by the host. The virus infects primitive keratinocytes in the basal layers of squamous epithelia followed by a round of viral DNA replication that appears independent of the host cell cycle (Fig. 47.1). Once the infected keratinocyte enters the proliferative compartment of the epithelium, viral gene expression is minimal. The oncogenes E6 and E7 are highly repressed by the viral genes E1 and E2 until the infected keratinocyte exits the cell cycle and enters the uppermost differentiating compartment (Table 47.1). Thus, high levels of viral protein synthesis and assembly only occur in the upper layers of the squamous epithelium. In this infectious cycle, the virus hitches a ride in the keratinocyte at the beginning of its journey and replicates in cells that will terminally differentiate and die by natural causes. Thus, there is no viral-induced cytolysis, necrosis or inflammation. Because there is no blood-borne phase of the HPV life cycle and only minimal amounts of replicating virus are exposed to immune defense, the virus is essentially invisible to the host. It is only when host integration occurs with E1 and E2 disruption, that E6 and E7 are overexpressed. E6 and E7 are capable of interfering with important tumor suppressor proteins in the host cell. Their overexpression is associated with neoplastic transformation, explaining the oncogenic potential of HPV.
HPV vaccines are effective because they circumvent the viral epithelial evasion strategies by introducing virus antigens through an intramuscular route. An immune cascade resulting in a robust T-cell- dependent B-cell response generates high levels of L1 specific neutralizing antibodies and immune memory.
Genital herpes is an STD that does not go away. Instead, the respon- sible agent, herpes simplex virus (HSV), establishes latent genital infection in the sacral dorsal root ganglia. It can be reactivated from latency by fever, sun exposure and hormonal changes. Herpetic infection causes the greatest morbidity in the neonate, who acquires it from the genital tract of the mother at delivery, and in immunocompromised patients for whom its disseminated form can be life-threatening.
There are two distinct serological types of HSV: HSV-1 and HSV-2. HSV-1 infection is typically asymptomatic and nearly ubiquitous. It is transmitted by primary infection of the respiratory tract. HSV-1 has been found in the trigeminal ganglion of 80% of cadavers.
HSV-2 has a predilection for genital disease, although HSV-1 infections of the genitalia and HSV-2 infections of the oral cavity do occur. HSV-2 is much more likely than HSV-1 to become a latent infection of the sacral ganglion and to cause neonatal disease.
Patients with herpetic infections present with three clinical scenarios: primary first episode, nonprimary first episode and recurrent episodes. These presentations inform our understanding of the biology and epidemiology of genital HSV infections. First episodes describe the initial recognition by the patient or health-care provider that a genital herpes infection is occurring. In primary first episodes, no HSV antibodies can be detected in acute phase serum samples, demonstrating that there has been no prior HSV infection. HSV antibodies will be present at the time of the first recognized genital herpes outbreak in nonprimary first episodes. Recurrent episodes require recognition that the patient has had a prior episode(s) of symptomatic HSV. The severity of clinical manifestations and the incidence of complications at presentation vary according to whether the infection is primary, nonprimary or recurrent.
Primary genital HSV disease is typically the most severe although it can be totally asymptomatic. Over 80% of patients with primary genital HSV will have local painful penile or vulvar lesions, dysuria, urethral or vaginal discharge and painful inguinal adenopathy. The mean duration of viral shedding from mucocutaneous lesions in primary genital HSV-2 infections is 2–3 weeks. Nonprimary first infections tend to be milder than primary first infections, presumably because acquired humoral and cellular immunity partially contain infectious spread.
Recurrent genital HSV-2 disease typically involves painful recrudescence of the mucocutaneous lesions on the penis or vulva and cervix. Local viral shedding occurs at the site of lesions, although cervical shedding has also been documented in the absence of visible cervical lesions. Systemic symptoms are absent. The mean duration of symptoms and viral shedding is much shorter with recurrences.
Medications that inhibit viral DNA synthesis have been developed to treat the symptoms of HSV infection. Treatment will stop viral DNA replication and spread but will neither prevent latent infections nor eradicate the virus.
Abstinence from sexual contact with an infected partner when lesions are visible is the only way to prevent genital HSV infection. Unfortunately, even this is not completely protective because trans- mission can occur during asymptomatic viral shedding. Condoms are also not completely protective. The penile shaft may be partially exposed to the vulva during intercourse using a condom. In addition, HSV is capable of penetrating latex.
Epidemiology of genital HSV infection
Symptomatic genital HSV infection accounts for 2–4% of visits to STD clinics in the UK and the USA. Genital HSV infections are reported more commonly among Caucasians than non-Caucasians. A higher prevalence of anti-HSV antibodies is noted with decreasing age at first coitus and with increasing number of sexual partners. The incidence of neonatal herpes is about 1 in 7500 live births.
Biology of HSV
HSV is a member of the herpesvirus class of DNA viruses. Herpes- viridae include the two serotypes of HSV, cytomegalovirus (CMV), varicella zoster (chickenpox, shingles) and Epstein–Barr virus (mono- nucleosis, chronic fatigue syndrome). Herpesviruses would be better called “complex” rather than “simplex” because they have the most complicated structure and replication cycles of all the viruses.
Genital HSV is acquired by sexual contact with contaminated secretions or lesions. Herpesviruses are very susceptible to desiccation and extremes of temperature, making transmission by fomites very rare. Once the virus has gained access to mucosal cells, it destroys the host DNA during productive replication of its own and kills the cell. HSV spreads by contiguity to adjacent cells and tracks toward autonomic nerve endings. Mucosal and skin cells infected with HSV produce serous transudates that result in the classic vesicles seen in the disorder.
Following primary genital mucocutaneous infection, HSV virions travel to the dorsal root ganglia of the sacral plexus (S2–S4) via the intra-axonal route. Here, they persist in a nonreplicative state until reactivation. Reactivation is heralded by a dramatic increase in viral DNA synthesis. This is followed by spread of virus back down the sensory neurons to the skin.
HSV in pregnancy and the neonate
Ninety per cent of women with primary genital HSV-2 infection shed virus from their cervix during the acute infection. This level drops to 70% both in women with primary genital HSV-1 infection and in women with nonprimary first episodes of genital HSV-2 infection. These numbers stand in stark contrast to the 12–20% rate of cervical shedding among women with recurrent external genital lesions. There- fore, it is not surprising that 50% of pregnant women with primary genital HSV will transmit infection to the neonate while only 5% of women with recurrent genital HSV will do so. Neonatal herpetic infec- tions are life-threatening. They may be prevented with appropriate use of cesarean delivery.