Rudolph's Pediatrics, 22nd Ed.

CHAPTER 233. Sexually Transmitted Infections

Loris Y. Hwang, Anna-Barbara Moscicki, and Mary-Ann Shafer

Currently, substantial numbers of adolescents engage in sexual intercourse: 34% have experienced their sexual debut by ninth grade and 63% by 12th grade.1 Although these rates have slowly decreased from 15 years ago the adolescent age group continues to be at the highest risk for STIs.

This chapter provides an overview of common STIs including the pathogenesis, common clinical syndromes, diagnostic approach and treatment for bacterial, fungal and viral infections (see Table 233-1), and for clinical For the most contemporary guidelines on treatment regimens it is useful to refer to the Centers for Disease Control and Prevention (CDC) web site since alterations in optimal treatment approaches may change as antibiotic-resistance patterns and the availability of specific medications changes.

EPIDEMIOLOGY

Adolescents 15 to 24 years of age represent one quarter of the sexually active population, but they acquire nearly half (9.1 million) of the new STIs each year in the United States.2,3 These STIs place our youth at risk for pelvic inflammatory disease and associated sequelae of ectopic pregnancy and infertility, genital cancers, and even death through complications of STIs, especially HIV infection.

Commonly reported prevalences of STIs among sexually active adolescent girls both with and without lower genital tract symptoms include Chlamydia trachomatis (10–25%), Neisseria gonorrhoeae (3–18%), syphilis (0–3%), Trichomonas vaginalis (8–16%), and herpes simplex virus (HSV) (2–19%).4 Among adolescent boys with no symptoms of urethritis, isolation rates include C trachomatis (9–11%) and N gonorrhoeae (2–3%). Human papillomavirus (HPV) DNA has been detected in 20% to 60% of female adolescents.

Gender is an important factor in the epidemiology of STIs, because both the rates of infection and sequelae are disproportionately higher among females compared to males. In 2006, among 15- to 19-year-olds, the female-to-male ratio of rates for chlamydia was 6.4, and for gonorrhea was 2.3.2 During the same year, the ratios of C trachomatis for African American, Native American, Hispanic, and white youth were 8:4:2:1, and those for N gonorrhoeae were 18:3:2:1. The ratios for primary and secondary syphilis among these same groups were 29:< 1:2:1. Trends in rates of N gonorrhoeae among youth show an increase for the second consecutive year. From 2005 to 2006, the rate for 15- to 19-year-olds increased by 6.3%. It is important to note that the relationships between the ethnicity and STIs including AIDS have been confounded by socioeconomic factors. In addition to age, gender, and ethnicity, a number of important biological and behavioral factors may help to explain these epidemic rates of STIs among adolescents.

Although adolescents currently represent fewer than 1% of the estimated number of people living with infection with human immunodeficiency virus (HIV) infection in the United States, the number of estimated cases among ages 20 to 24 is 7-fold greater than that among ages 15 to 19.2 Because of the long latency period of the disease (2 to 7 years or more), it is probable that many young adults with acquired immunodeficiency syndrome (AIDS) were infected with HIV during adolescence. The HIV seropositivity data available from screening programs show a rate of < 1/1000 for military recruits, 3.6/1000 for Job Corps applicants, and 50/1000 for runaway youth. Among new cases of HIV/AIDS in 2000–2004, male-to-male sexual contact was cited as the most common transmission route, but the greatest increasing trend in new cases was observed among cases of heterosexual transmission, including among adolescents.

CONTRACEPTIVES AND SEXUALLY TRANSMITTED DISEASES

Condoms have been shown consistently to prevent STIs, especially gonococcal and chlamydial infections, and assist in preventing HIV infection, as well. However, only one half of 15- to 19-year-old females reported using condoms during last intercourse.5 Inadequate contraceptive use by adolescents is reflected in high pregnancy and STI rates.

Oral contraceptives have been linked to some sexually transmitted infections (STIs). For example, candidal infections have long been associated with oral contraceptive use. Controversy surrounds the role of oral contraceptives and the establishment of endocervical infection and development of PID with N gonorrhoeae and C trachomatis. It appears that oral contraceptive users have fewer gonococcal endocervical infections, and when gonococcal PID occurs, it is less severe. The impact of oral contraceptives on the establishment of chlamydial endocervical infections is less clear, but most studies show an increased risk for chlamydial infection among oral contraceptive users. Oral contraceptive users, however, appear to have less chlamydial PID.

Table 233–1. Common Sexually Transmitted Diseases in Adolescents

Of note, spermicides containing nonoxynol-9 (N-9) are no longer recommended for STI prevention, as they have not been effective in the prevention of several STIs.6 Furthermore, disturbance of epithelial surfaces has been associated with frequent use of N-9 products and places youth at even higher risk for HIV acquisition. Thus, N-9 products are actively discouraged.


BACTERIAL INFECTIONS


NEISSERIA GONORRHOEAE

N gonorrhoeae is the second most commonly reported bacterial STI in the United States. N gonorrhoeae is a gram-negative bacterium that has the unique genetic ability to change the antigenic expression of its surface-exposed proteins, making development of a vaccine challenging. For further details of pathogenesis and diseases due to Neisseria gonorrhoeae see Chapter 274.

CLINICAL FEATURES

The most common manifestation of gonococcal disease among men is urethritis, which may be asymptomatic.6 After urethral inoculation with the organism during sexual activity, it is estimated that 2 to 4 days elapse before symptoms of dysuria or discharge appear. The discharge may be scant, and mucoid may be present as a profuse purulent discharge. Untreated gonococcal urethritis in men typically resolves over 1 to 2 months but may progress in up to 10% of cases to acute epididymitis and urethral strictures. An outline of the evaluation of urethritis is presented in Figure 233-1. Although women have urethral infections, they are usually associated with endocervical infection. Most gonococcal infections in women affect the lower genital tract with a particular predilection for the columnar cells of the endocervix. Syndromes in both men and women are outlined in Table 233-1. In particular, disseminated gonococcal infection (DGI), a blood-borne infection manifested by skin lesions, tenosynovitis, and septic arthritis (culture-positive joint fluid in approximately 50% of cases only), occurs in 2% to 5% of infected individuals. It is more common in African Americans than in other race/ethnicity groups. Pelvic inflammatory disease is another important complication of gonococcal infection and is discussed later in this chapter, and in Chapter 274.

DIAGNOSIS AND TREATMENT

Diagnostic tests are outlined in Table 233-1, evaluation of both urethritis and vaginitis is found in Figure 233-1 and Figure 233-2, and treatment regimens are summarized in Table 233-2.6 Several tests are available for the specific diagnosis of gonoccocal infection: the traditional culture, nucleic acid hybridization tests, and nucleic acid amplification tests (NAATs).7 NAATs are rather versatile in that they are Food and Drug Administration (FDA) approved for samples obtained from the female endocervix, vagina, and urine, and the male urethra and urine. Samples taken from the female endocervix or male urethra are necessary for culture or nucleic acid hybridization tests. In men who have symptoms of urethritis, another diagnostic tool is the Gram stain of the urethral specimen. Evidence of polymorphonuclear leukocytes with intracellular gram-negative diplococci is considered diagnostic. For samples from asymptomatic men or other anatomic sites, Gram stain is considered insufficient and is not recommended. For samples taken from the rectum or pharynx, culture is the usual test of choice.

FIGURE 233-1. Assessment of urethritis in sexually active male adolescents. *First 15 mL of micturition of urine sample tested. (Left) Unspun urinary leukocyte esterase test (LET) for positive activity, or (right) spun-resuspended shows ≥10 polymorphonuclear leukocytes per high-power field. **GNID, gram-negative intracellular diplococci; #, All partners from the previous 60 days (or the most recent partner if there was no history of sexual activity in the last 60 days) should be tested, treated, and counseled on safer sex practices. hpf, high power field; oil, oil immersion field; PMNS, polymorphonuclear leukocytes.

FIGURE 233-2. Assessment of lower genital tract infection in sexually active female adolescents. Complete assessment should be performed whether or not symptoms are present. #Vaginal discharge, pruritus, dysuria/frequency; *R/O pregnancy before treatment. PMNS, polymorphonuclear leukocytes; NAAT, nucleic acid amplification test. +Guidelines for the management of abnormal cytology are found in Wright TC, Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007;197:340-345. ASCUS, atypical squamous cells of undetermined significance; HSIL, high-grade intraepithelial lesion; LSIL, low-grade intraepithelial lesion; R/O, rule out; UTI, urinary tract infection.

Table 233–2. Treatment of Uncomplicated Genital, Anal, and Pharyngeal Chlamydial and Gonococcal Infections

For uncomplicated chlamydial infection:

azithromycin 1 g orally × 1 dosea

or

doxycycline 100 mg orally twice daily × 7 days

For uncomplicated gonococcal infection:

cefixime 400 mg orally × 1 dosea

or

ceftriaxone 125 mg IM × 1 doseb

plus

(always treat for possible chlamydial coinfection)

azithromycin 1 g orally × 1 dosea

or

doxycycline 100 mg orally twice daily × 7 days

For chlamydial infection in pregnancy:

azithromycin 1g orally × 1 dose

or

amoxicillin 500 mg PO t.i.d. × 7 days

For sexual partners:

Contact, evaluate, and treat partners in the past 60 days or most recent partner if > 60 days for asymptomatic for both chlamydial and gonococcal disease. Condoms should be used. Abstain from sexual activity at least 7 days after treatment.

For follow-up:

Retest at 3 to 4 months to R/O recurrent infection. Counsel about safer sex practices.

aIt is possible to treat both uncomplicated chlamydial and gonococcal infections with 1-dose oral regimens. Cost factors must be evaluated locally. The effect of such regimens on incubating syphilis is not known.

b90% effective against gonococcal pharyngitis. Quinolones are no longer recommended in the treatment of gonococcal infection due to resistance

From CDC. Sexually transmitted diseases treatment guidelines 2006. MMWR Recomm Rep. May 10 2006;55 (RR-11). (Check www.cdc.gov/STD/treatment/ for the most current updates to the treatment guidelines.)

Treatment is determined by the following considerations: (1) the anatomic site of infection; (2) the antibiotic resistance [penicillinase-producing strains (PPNG), tetracycline-resistant strains (TRNG), quinolone-resistant strains, and chromosomally mediated resistance to multiple antibiotics]; (3) high prevalence of concurrent chlamydial infections in patients with gonococcal infection; and (4) the side effects and costs of different treatment regimens. In recent years, quinolone resistance has continued to spread substantially. It is imperative that clinicians check the up-to-date CDC Web site (www.cdc.gov/std/treatment) for the most current treatment guidelines at the time of the patient’s treatment. Unless a chlamydial NAAT is known to be negative at the time of gonococcal treatment, patients should also receive empiric chlamydial treatment concurrent to their gonococcal treatment. Treatment regimens that include ceftriaxone or a 7-day course of doxycycline (or erythromycin) may be effective against incubating syphilis, but few studies are available. Therefore, all patients with an STI should be screened for syphilis serologically as well as HIV. All partners from the previous 60 days (or the most recent partner if there was no history of sexual activity in the last 60 days) should also be tested, treated, and counseled on safer sex practices.

Treatment for disseminated gonococcal infection (DGI) requires initial parenteral therapy and evaluation for possible meningitis or endocarditis. The recommended regimen for initial treatment is ceftriaxone, 1 g IM or IV q24h; an alternative regimen (allergy to β-lactams) is spectinomycin, 2 g IM q12h. Compliant patients may be discharged 24 to 48 hours after symptom resolution but need to complete at least another 7-day course of oral medications, for example, cefixime, 400 mg PO BID.

CHLAMYDIA TRACHOMATIS

C trachomatis is the most common reported bacterial STI in the United States. The pathogenesis of C trachomatis infections has not been clearly defined. Chlamydiae are obligate intracellular bacteria, and disease appears to result from both the destruction of cells during the growth cycle and the body’s immune response to the infection producing inflammation. An overview of syndromes, diagnosis, and treatment of C trachomatis is found in Tables 233-1 and 233-2.

CLINICAL FEATURES

Among women, 50% or more of chlamydial lower genital infections are asymptomatic. Uncomplicated endocervicitis is the most common clinical manifestation of chlamydial infection in sexually active female adolescents. Clinical findings may include mucopurulent cervicitis (MPC), which presents with a yellow endocervical discharge on a swab sample or by identification of increased polymorphonuclear cells on a Gram stain from the discharge (more than 10 to 30 per high-power field). C trachomatis has been identified in 9% to 51% of MPC cases, with N gonorrhoeae being responsible for some cases as well. However, MPC is not a sensitive diagnostic indicator of infection, because most infected women do not have MPC. Chlamydial cervicitis may also be accompanied by abnormal vaginal discharge or bleeding, especially after intercourse. Diagnosis by direct testing for C trachomatis is encouraged (Table 233-1). The most serious complication of endocervical infection is pelvic inflammatory disease (PID), including a subclinical form of PID that also may lead to infertility. Asymptomatic and symptomatic urethritis can be caused by chlamydial infection in both men and women. In men, 20% to 50% of those with gonococcal urethritis are also infected with C trachomatis. C trachomatis is the most common cause of nongonococcal urethritis (NGU) in men, responsible for 23% to 55% of cases. Men with NGU may present with discharge and dysuria. The infection is identified through contact tracing from a C trachomatis-positive partner, routine screening of those at risk, or testing of symptomatic men.

DIAGNOSIS AND TREATMENT

There are a number of situations such as NGU, PID, epididymitis, and confirmed gonococcal infection which are associated frequently with chlamydia infections and necessitate immediate “presumptive” treatment to alleviate symptoms and to prevent complications and further transmission to partners. For example, 5% to 30% of men and 25% to 50% of women with N gonorrhoeae infection have concurrent C trachomatis infection. However, regardless of whether presumptive treatment is administered to the patient and partner, chlamydia testing in both the patient and partner should still be undertaken when possible, together with screening for other STIs and thorough counseling regarding safer sex practices.8 Testing for C trachomatis is performed by using either the traditional “gold standard”—the cell culture—or the newer nonculture techniques—NAATs and other nucleic-acid-based testing.7 Although cell culture is being largely surpassed by more sensitive nonculture techniques, the use of cell culture as the test of choice is still warranted for urethral and rectal specimens in men and women, vaginal specimens in prepubertal girls, and sexual assault or abuse cases involving legal issues. In these situations, nonculture methods have not been FDA approved, have been inadequately studied, or have yielded inadequate performance profiles.

The FDA-approved NAATs include the polymerase chain reaction (PCR) that amplifies chlamydial DNA found in urine and cervical specimens. Other currently available tests for chlamydia include the direct fluorescent antibody (DFA) test, the enzyme immunoassay (EIA) test, the DNA probe test, the rapid chlamydia test, and the leukocyte esterase dipstick test (LET). Of interest to the primary-care clinician is the rapid ability to utilize the nonspecific LET in cases of possible urethritis in male patients. The LET is applied to the first-void urine specimen (first 10–15 mL voided into pre-marked container) for evaluation of urethritis, which is most frequently caused by chlamydia or gonorrhea. Because the sensitivity of the LET in screening for chlamydia and gonorrhea is 46% to 100% (it is a nonspecific indicator of the presence of polymorphonuclear cells), it is necessary to follow all positive LETs with more specific tests for C trachomatis and N gonnorhoeae (eg, NAATs, culture). Data are insufficient to support the use of the LET to screen young women for C trachomatis. The treatment protocols are outlined in Table 233-2. All patients should be retested for recurrence of C trachomatis at 3 to 4 months after treatment.


PROTOZOAN AND FUNGAL INFECTIONS


TRICHOMONAS VAGINALIS

Trichomonads are flagellated protozoans. Three species are linked to disease in humans: Trichomonas vaginalis (genital organs of men and women), Trichomonas tenax (mouth), and Pentatrichomonas hominis (intestine). T vaginalisis known to attach to epithelial cells and has been shown to be sexually transmitted. The organism has also been shown to survive for up to 1.5 hours on a wet sponge and 24 hours on a wet cloth.

The pathogenesis of disease in humans is not completely understood. The response to infection varies from little or no reaction (carrier state) to an acute inflammatory response marked by the presence of numerous polymorphonuclear leukocytes. Half of all asymptomatic carriers of T vaginalis become symptomatic within 6 months. Development of disease in women appears to be related to the menstrual period, pubertal development, vaginal pH, and environmental microbiological flora. Prevalence in adolescent women has been reported to be 2% to 30%, depending on the population examined.10,11

CLINICAL FEATURES

Syndromes associated with the Trichomonas infection include vaginitis and cervicitis in women and urethritis in both men and women.12 In infected women, 25% to 50% are asymptomatic. Genitourinary symptoms include vaginal discharge, dyspareunia, postcoital bleeding, pruritus, lower abdominal pain, dysuria, and frequency. On examination, the vulva is often erythematous, and copious vaginal discharge may be present. On speculum examination, the vaginal walls appear granular in over half the cases. Although a discharge is common, the “classical” frothy yellow-green discharge occurs in only 12% and has been described in other causes of vaginitis. The “strawberry cervix” (punctate hemorrhages on the exocervix), which in the past was erroneously considered pathognomonic for T vaginalis cervicitis, occurs in only 2% of the infections. In men, the infection is usually self-limited, and most men are asymptomatic or present with features of nongonococcal urethritis (Table 233-1). Infrequently, epididymitis or proctitis may develop.

FIGURE 233-3Trichomonas vaginalis. (A) Wet preparation, (B) Giemsa stained.

DIAGNOSIS AND TREATMENT

Diagnosis of vaginitis caused by T vaginalis is made in the presence of vulvovaginal symptoms, a vaginal pH over 5.0, and identification of organisms on wet mount, Pap cytology, or direct culture (Figure 233-3). Detection of the organism depends on their number in the inoculum for both wet mount and culture and on the ability to maintain the specimen at body temperature and examine the wet mount immediately to preserve motility of the organism. The wet mount and Pap smear detect only about 60% of infections, with the Pap smear having the disadvantage of a 31% false-positive rate. Culture techniques (Diamond media) and direct monoclonal antibody techniques detect 82% to 95% of infections. There is a commercially available culture technique (Trich In-Pouch). An overview of the diagnostic assessment is outlined in Figure 233-1 and Figure 233-2, and treatment is described in Table 233-1.6

CANDIDA ALBICANS

Vaginal colonization with Candida mainly from perianal areas. Approximately 90% of candidal species detected in vaginal secretions are C albi-cans.9 Of the remaining 10% non-albicans species, C glabrata(Torulopsis) is the next most common. Although the number of organisms is not related to production of disease, other factors are related to establishment of infection, including host factors (genetics), disease states (eg, immunosuppressive states, diabetes mellitus, AIDS), medications, estrogen-containing oral contraception, and behavioral factors (eg, douching).

Vulvovaginal candidiasis (VVC) caused by the albicans and non-albicans species are clinicially indistinguishable with the non-albicans species more resistant to therapy. Although it is nonspecific, the most common symptom related to infection is vulvovaginal itching, with or without vaginal discharge. One challenge is distinguishing pathogenic infection from nonpathogenic colonization. It is estimated that 75% of women will have one episode of VVC, with 40% to 45% having a recurrence, and less than 5% will have repeated recurrences (defined as more than 4 episodes per year). Although sexual transmission of C albicans may occur, the role of such transmission in promoting infection among sexually active women is unclear. Specific aspects of diagnosis and treatment are detailed in Table 233-1.


VIRAL INFECTIONS


HUMAN PAPILLOMAVIRUS

Human papillomavirus (HPV) is a member of the Papovavirus family and is a closed, circular, double-stranded DNA virus. The viral genome is enclosed in an icosahedral capsule composed of several protein capsomeres and lacks the lipid-containing envelope common to many other viruses such as herpes simplex virus. Unlike other human sexually transmitted infections (STI), such as herpes simplex, HPV growth in cell culture has been difficult because its replication is dependent on epithelial cell differentiation and maturation.16

PATHOPHYSIOLOGY

Genital HPV infection occurs through sexual behavior and may include genital-to-genital contact or intercourse. The role of hands or sex toys in transmission has not been established. Sites most vulnerable to infection are those where basal cells are actively dividing including the active squamous metaplasia of the transformation zone of the female cervix and areas of wound healing in the genital area. Although perinatal transmission has been shown to occur, the infections are usually only found in the oropharynx of the infant. Rarely, genital wars occur in infants from perinatal transmission. Common clinical presentations of HPV include genital warts or condyloma acuminatum. In addition, HPV is the cause of precancerous and cancerous lesions of the genitals, including cervical, anal, vulvar, vaginal, and penile cancers.13 Genital HPV types are also associated with oropharyngeal cancers.14Subclassification of HPV into over 100 types has been based on differences in degree of DNA homology. Of the 100 types, approximately 40 are considered genital types because they are found predominantly in the genital area only. Genital condyloma are usually associated with HPV type 6 or 11. These types are considered to be low-risk HPV types because they are rarely seen in cancers. Fourteen types have been ranked as cancerous (referred to as high risk) and include types 16, 18, 31, 33, 35, 39, 45, 51, 52, 58, 59, 68, 73, and 82.15HPV types 26, 53, and 66 are considered probably carcinogenic. The most common type in all anogenital cancers is HPV 16.

EPIDEMIOLOGY

In adolescents and young women, infections are extremely common with over 50% of young women acquiring the infection within 2 to 4 years after initiating sex.17 The infections, however, are mostly transient with 70% to 90% of HPV infections clearing within 1 to 2 years.18 Persistence of the infection is the key factor in the development of anogenital precancers and cancers. The length or time of persistence required for cancer development is not known. Because HPV is acquired commonly through sexual intercourse during adolescence and cancer is not seen until 2 or 3 decades later, it is thought that years of persistence are required for most individuals before cancer develops. Viral–host protein interactions result in the loss of cell cycle control and are considered crucial steps in the development of the cancers. Viral proteins are capable of interfering with cell cycle control, including enhanced p53 degradation; disruption of the E2F/pRb complex resulting in activation of E2F, an important cellular transcription factor; and blockade of apoptosis and activation of telomerase (an enzyme responsible for telomere lengthening, resulting in prolonged life of epithelial cells). The roles of other cofactors are less compelling. Those thought to play important roles include cigarette use and immune suppression. Other more questionable factors include prolonged use of hormonal oral contraceptives, increased parity, and infection with C trachomatis.18

CLINICAL FEATURES

The HPV can cause multicentric disease, including much of the anogenital area: the vaginal introitus, vulvar labia minora and majora, clitoris, perineum, urethra, vagina, anus, and cervix in women; and the penis, including the prepuce, frenulum, corona, glans, urethra and shaft, with the anus and scrotum in men. The common genital warts, condyloma acuminatum, seen on the skin surfaces, present as polypoid masses with fissured and irregular surfaces. They are often multiple and polymorphic and commonly coalesce into large masses. When on mucosal surfaces, condyloma acuminatum appears as finger-like projections with central dilated capillary loops.

Infections with HPV can result in the development of neoplasias referred to as low-grade intraepithelial lesions (LSIL) and high-grade intraepithelial lesions (HSIL). The term low grade refers to benign changes caused by the virus described in cell morphology. These lesions will usually clear spontaneously and require no intervention.19High grade refers to changes that are considered truly precancerous. The chance of progression is high and regression less. The cellular changes associated with these lesions are identified on cytology screening. The lesions can usually be visualized with the aid of colposcopy. Typical appearances on colposcopy associated with LSIL, HSIL, and invasive cancers assist in directing biopsy. Final diagnosis is dependent on histologic interpretation of the biopsy, not colposcopic appearance or cytologic diagnosis. Histology diagnosis is made using the categories of cervical intra-epithelial neoplasia (CIN) I, II and III of the World Health Organization (WHO). CIN I is equivalent to LSIL, and CIN II and III are equivalent to HSIL. HPV DNA detection can be commonly found in women with normal cytology, specifically in young women. Whether these women truly have no lesion remains controversial because cytology alone is an insensitive test to detect SIL. However, most of these infections in women with normal cytology appear transient, as in LSIL, and therefore detection of HPV DNA in young women is not cost-effective as a clinical tool.

DIAGNOSIS AND TREATMENT

Screening for HPV infections in adolescents is currently limited to visual inspection for external genital warts and cytology screening for intraepithelial lesions, high-grade intraepithelial lesions, and invasive cancers during the pelvic examination.

Genital Warts Diagnosis of genital warts by visual inspection is considered adequate, and HPV testing plays little to no role in confirming the diagnosis unless the diagnosis is questioned. In this case, biopsy is the best confirmation. The differential diagnosis includes bowenoid papulosis, vulvar intraepithelial neoplasia, Bowen disease, condylomata lata, skin tags, nevocellular nevus, benign tumors, sebaceous glands, seborrheic keratosis, pearly penile papules, molluscum contagiosum, squamous cell carcinoma, vulva papillomatosis, and vestibular papillae. Treatment for genital warts includes primary ablative therapy, including application of trichloroacetic or bichloroacetic acid (85–90%) to the wart.6 Cryotherapy with liquid nitrogen is also quite effective. Treatments are usually applied weekly for 4 to 6 weeks. If there is no improvement, therapy should be switched, or the diagnosis should be questioned. The current role of podophyllin resin in therapy is questioned because its potency is unpredictable, and it is contraindicated on mucosal surfaces and in pregnancy. Other methods include excisional and laser therapy. Self-applied therapies are also available and may be more cost-effective. Podofilox is applied directly to the warts twice daily for 3 consecutive days and repeated weekly up to 4 to 6 weeks. Imiquimod (5%), which is a cytokine-inducing agent, is also applied directly once daily at bedtime 3 times a week (alternating days) for up to 16 weeks. Disadvantages to all therapies include irritation, inflammation, and ulceration from local applications. Veregen (sinecatechins) is a new FDA-approved therapy based on the antioxidative effect of green tea extract. It can be used 3 times daily topically for up to 16 weeks. Other therapies include intralesion interferon or 5-fluorouracil/epinephrinegel implant, and Cidofovir topical gel (1%). Cidofovir gel is a topical preparation that has been evaluated in a limited number of adults. Topical Cidofovir may result in systemic absorption and be associated with renal toxicity. Surgical removal by experienced clinicians is also an alternative utilizing tangential scissor excision, tangential shave excision, curettage, or electrosurgery. Despite known limitations in sensitivity cytology remains the primary screening tool for SIL and invasive cancers in adolescents. Although HPV testing has recently been shown to help in triage of abnormal cytology (ASCUS) and SIL screening in older women, its role appears less specific in adolescents because of the high rates of HPV infections and intraepithelial lesions (LSIL) and low rates of high-grade intraepithelial lesions (HSIL) and invasive cancer in this age group. HPV DNA testing in adolescents is not currently recommended under any circumstance.20Because HPV is often acquired early after the onset of sexual activity and is likely to be transient, cytology screening is not recommended within the first 3 years after the onset of sexual activity. After 3 years, annual Pap smears are recommended in sexually active women. If using liquid-based cytology, screening can go to every 2 years after 3 consecutive normal annual cytology results. Pap smears in virgin adolescents are not necessary.

ASCUS or LSIL on cytology in adolescents is considered benign and can be followed with cytology at 1-year intervals.20 If repeat cytology at 1 year is HSIL, referral to colposcopy is recommended. If the 1-year cytology remains ASCUS/LSIL, then cytology should be repeated at 12 months. If ASCUS/LSIL persist at 2 years or HSIL is detected, referral to colposcopy is recommended. Confirmed LSIL by histology (CIN I) should be followed with cytology at 12-month intervals as described above for cytologic LSIL.20 After 2 negative cytology results at 12-month intervals, routine screening can be reimplemented. If the patient is compliant and the colposcopy examination is satisfactory, HSIL (CIN 2) on biopsy can also be followed with colposcopy and cytology at 6-month intervals.20 Persistence of HSIL disease by cytology, histology, or colposcopy at 2 years is an indication for treatment. Progression to carcinoma in situ by histology at any time is an indication for treatment. Treatment should be conservative to preserve fertility because excisional therapy is associated with preterm labor and infant low birth weight.21 Treatment includes either excisional therapy (LEEP) or cryotherapy. Conizations should be reserved for adults. Referral of partners to women with condyloma or SIL is controversial, because most partners of women appear to have latent HPV infection. There is general agreement, however, that partners of women with SIL should be encouraged to use condoms because lesions regress more quickly in couples who use condoms.22 As with all sexually transmitted infections, examination should include tests for other cosexually transmitted infections.

There are no treatments available or indicated for herpes papillomavirus (HPV) DNA detection without abnormal cytology or histology. Prevention of HPV types 6, 11, 16, and 18 can now be achieved with vaccination prior to exposure. In the United States, the vaccine is currently recommended for females aged 9 to 26 years, particularly targeting those not yet sexually active. The vaccine is not therapeutic and has no effect on women already infected with HPV types included in the vaccine.23 A bivalent vaccine for HPV 16 and 18 is under FDA review.

HUMAN IMMUNODEFICIENCY VIRUS

Human immunodeficiency virus (HIV) is the newest viral sexually transmitted infections to infect youth. An in-depth description of its clinical syndrome, AIDS, is beyond the scope of this section. For primary-care clinicians, the focus regarding HIV infection is prevention. See Chapter 315 for a detailed description of HIV infection.


SEXUALLY TRANSMITTED INFECTIONS: SYNDROMES


A constellation of symptoms and signs is characteristic of specific sexually transmitted disease syndromes. Common lower genital tract syndromes in women include urethritis, vaginitis, endocervicitis, and bacterial vaginosis (Table 233-1 and Fig. 233-2). In men, urethritis is the most common sexually transmitted infections syndrome (Table 233-1 and Fig. 233-1), but epididymitis also occurs. Proctitis occurs in both genders.

BACTERIAL VAGINOSIS

PATHOGENESIS

The dominant organism (> 95% of organisms) in the normal flora of healthy women is Lactobacillus species. Bacterial vaginosis (BV) results from the replacement of vaginal Lactobacillus species with a number of anaerobic bacteria in high concentrations, including Bacteroides species, Mobiluncus species, and other bacteria such as G vaginalis and Mycoplasma hominis.24 Reported prevalence varies widely from 10% to 50%, depending on the population sampled.

CLINICAL MANIFESTATIONS

Bacterial vaginosis is the most common cause of abnormal vaginal discharge, although half the women who meet the clinical criteria for the diagnosis have no symptoms. BV is rarely found in nonsexually active women, but transmission is not clearly from a direct sexual route. Symptoms include prurutis, irritation, and a thin white vaginal discharge with a “fishy” odor.

DIAGNOSIS AND TREATMENT

The diagnostic criteria and treatment are outlined in Table 233-1 and Figure 233-2.6 Treatment of nonpregnant women is linked only to relief of symptoms; male partners of infected women are asymptomatic, and treating men does not affect the woman’s disease course. Metronidazole, 500 mg orally BID for 7 days, yields a 95% cure rate compared to the alternative regimen of 2 g orally in a single dose (84% cure rate). Although experience is limited, use of intravaginal clindamycin cream, 2%, 1 applicator at bedtime for 7 days, and metronidazole gel, 0.75%, 1 applicator BID for 7 days appear efficacious. Because bacterial vaginosis may be related to prematurity and postpartum endometritis, treatment of pregnant women is encouraged using oral metronidazole 500 mg orally twice daily for 7 days, or metronidazole 250 mg orally 3 times daily for 7 days, or clindamycin 300 mg orally twice daily for 7 days. Vaginal clindamycin has been associated with adverse events during pregnancy and is discouraged.

PELVIC INFLAMMATORY DISEASE

Pelvic inflammatory disease (PID) is the leading cause of chronic reproductive morbidity in young women, with over 1.25 million cases diagnosed annually in the United States.2 The term PID is used to describe a variety of inflammatory disorders involving the uterus, ovaries, and peritoneal tissues, as well as the fallopian tubes. Sexually transmitted infections, in particular, C trachomatis and N gonorrheoea, are often identified, but other vaginal organisms have also been implicated (eg, anaerobes, Gardnerella vaginalis, Haemophilus influenzae, enteric gram-negative rods, Streptococcus agalactiae, Mycoplasma hominis, and Ureaplasma urealyticum). The notable sequelae of PID include ectopic pregnancy and infertility. Repeated episodes of PID are associated with exponential increases in risk for these sequelae. Risk factors that may predispose young women to develop acute PID include youth, with sexually active female adolescents diagnosed 3 times more frequently than 25 to 29 year olds; endocervical sexually transmitted infections (STIs), especially Chlamydia trachomatis, and Neisseria gonorrhoeae; previous salpingitis resulting in tubal damage, which may predispose to recurrent episodes of infection; sexual behaviors, such as a number of sexual partners, that place women at increased risk for STIs; intrauterine devices (IUDs) placed during a current STI that is not treated; and recent gynecologic interventions (eg, therapeutic abortion or endometrial biopsy).6 Although the relationship of oral contraceptives to acute PID has been controversial, most current research supports a protective role of oral contraceptives in the development of PID.

PATHOGENESIS

The proposed pathogenesis of PID involves ascending canalicular spread of the causative sexually transmitted agent(s) from the vaginocervical compartment during sexual intercourse. The organisms pass through the mechanical and immunologic barriers of the endocervix, along the endometrial surface to the tubal mucosa, and finally onto peritoneal surfaces by leakage from the tubal fimbria.

DIAGNOSIS AND TREATMENT

PID is challenging to diagnose as there is no single historical, physical, or laboratory finding that is definitively diagnostic.6 The clinical diagnosis for PID is imprecise and requires the consideration of multiple possible findings. Symptoms and signs of acute PID include lower abdominal pain, vaginal discharge, cervical motion tenderness, and uterine and adnexal tenderness (Table 233-3). Only about 60% of cases are correctly diagnosed, based on verification by laparoscopy. The differential diagnosis to be considered in a young woman presenting with acute lower abdominal pain, in addition to PID, includes acute appendicitis, acute cystitis, acute cholecystitis, acute pyelonephritis, ectopic pregnancy, endometriosis, hemorrhagic ovarian cyst, intrauterine pregnancy, mesenteric lymphadenitis, ovarian cyst with or without torsion, ovarian tumor, septic abortion, severe constipation, and trauma. Because laparoscopy is not warranted in most cases to define PID, reliance must be placed on an accurate sexual history and application of clinical criteria (Table 233-3).

Principles to remember in the clinical approach to PID include these: rule out other causes including pregnancy; use the CDC guidelines to assist but not dictate the diagnosis; when in doubt, err on the side of “overdiagnosis” of PID to prevent sequelae, especially in view of the possibility of subclinical chlamydial infections, while pursuing further workup for other causes; treat with broad-spectrum antibiotics and begin the course promptly; and, finally, follow up with clinical evaluations (within 24 to 48 hours) to confirm the original clinical diagnosis and reevaluate the treatment regimen. Empiric treatment is advised in sexually active women with pelvic or lower abdominal pain and any one of these minimum criteria on physical examination: cervical motion tenderness or uterine tenderness or adnexal tenderness. Specificity of diagnosis is improved by the following additional criteria: temperature greater than 101°F; abnormal cervical or vaginal discharge; numerous WBCs on wet prep; increased erythrocyte sedimentation rate (ESR); increased C-reactive protein; or cervicitis that is positive for N gonorrhoeae or C trachomatis.

Treatment regimens are outlined in Table 233-4. Criteria for hospitalization include uncertain diagnosis or the need to rule out surgical emergencies; presence of a pelvic or tubo-ovarian abscess; pregnancy; severe illness, nausea, and vomiting; inability to take oral medications; failure of outpatient therapy within 48 hours; inability to arrange follow-up within 72 hours of starting antibiotics; and patient being HIV-positive. A major serious complication to acute PID is the development of a tubo-ovarian abscess. Although most abscesses can be managed medically, occasional surgical intervention is necessary when medications fail. Screening and treatment of the sexual partner is an important part of PID management, as with any STI.

Table 233–3. Diagnostic Criteria for Pelvic Inflammatory Disease (PID)

Diagnostic Criteria

Treat empirically if all are present:

Lower abdominal tenderness or pelvic tenderness

No cause can be identified other than PID

Cervical motion tenderness

OR uterine tenderness

OR adnexal tenderness

Additional Criteria

These criteria help in differential diagnosis and increase the specicity of the diagnosis:

Oral temperature > 38.3°C

Abnormal cervical or vaginal discharge

Elevated erythrocyte sedimentation rate

Laboratory-documented Neisseria gonorrhoeae or Chlamydia trachomatis cervical infection

Abundant WBC on saline wet prep

Definitive Criteria (selected cases)

These criteria are based on findings consistent with PID delineated during additional testing when appropriate and available:

Evidence of endometritis on biopsy

Tubo-ovarian mass on transvaginal ultrasound or other imaging techniques

Laparoscopic ndings of PID

From CDC. Sexually transmitted diseases treatment guidelines 2006. MMWR Recomm Rep. May 10 2006;55(RR-11). (Check www.cdc.gov/STD/treatment/ for the most current updates to the treatment guidelines.)

FITZ-HUGH-CURTIS SYNDROME

Fitz-Hugh-Curtis (FHC) syndrome results from ascending pelvic infection and inflammation of the liver capsule and/or diaphragm. It presents in females with right upper quadrant pain that can occur without other signs of pelvic inflammatory disease. Bacteria that are typically associated with pelvic inflammatory disease spread from the pelvis along the paracolic gutters to the liver capsule. Neisseria gonorrhoeaeinfection was the most common cause but now Chlamydia trachomatis is causative in about 80% of cases.

The disorder initially presents with acute pain that is similar to cholecystitis, and may be referred to the right shoulder. It can then become chronic with persistent, but not severe, right upper quadrant pain. Physical findings are otherwise not specific except for an occasional finding of a friction rub over the right upper quadrant. Diagnosis is most often inferred based upon the symptoms and a finding of a positive cervical culture for gonorrheal or chlamydial organisms. Liver function tests are usually normal. Imaging studies may be normal, although ultrasonography or abdominal CT scan may identify perihepatic adhesions. Diagnostic laparoscopy demonstrates pathognomonic finding of “violin-string” adhesions from the anterior abdominal wall to the liver capsule. Treatment is the same as for PID.

Table 233–4. Treatment Regimens for Acute Pelvic Inflammatory Disease (PID)

Recommended Inpatient Regimens

Parenteral regimen A

Cefotetan 2 g IV q12h or cefoxitin 2g IV q6h, plus doxycycline, 100 mg IV q12h. Use IV for minimum of 24 hours after patient improves. After hospital discharge, continue doxycycline 100 mg PO b.i.d. to complete 14-day course

or

Parenteral regimen B

Clindamycin, 900 mg IV q8h, plus gentamicin 2 mg/kg IV or IM in one loading dose, followed by a maintenance dose of 1.5 mg/kg IV q8h in patients with normal renal function.

Use IV for minimum of 24 hours after patient improves. After hospital discharge, continue doxycycline 100 mg PO b.i.d. to complete 14-day total; or continue clindamycin 450 mg PO q.i.d. to complete 14-day course as an alternative.

Recommended Outpatient Regimens

Ceftriaxone, 250 mg IM

or

Cefoxitin, 2 g IM and probenecid 1 g PO given concurrently in a single dose

or

Other third-generation cephalosporin (ceftizoxime or cefotaxime)

plus

Doxycycline, 100 mg PO b.i.d. for 14 days

with or without

Metronidazole 500 mg PO b.i.d. for 14 days

Patients should demonstrate substantial clinical improvement within 3 days of start of treatment. Recommended to have a test of cure as part of evaluation (7–10 days if use culture; 1 month if testing with NAATs)

Management of sex partners

As with any STD, partners should be evaluated for other STDs and treated empirically for Neisseria gonorrhoeae and Chlamydia trachomatis infection and counseled

aFrom CDC. Sexually transmitted diseases treatment guidelines 2006. MMWR Recomm Rep. May 10 2006;55(RR-11). (Check www.cdc.gov/STD/treatment/ for the most current updates to the treatment guidelines.)

NAATs, nucleic acid amplication tests.

EPIDIDYMITIS

CAUSATIVE ORGANISMS AND CLINICAL SYNDROME

Epididymitis is a clinical syndrome of inflammation of the epididymis caused by infection or trauma. Acute epididymitis is defined as pain and swelling of the epididymis for less than 6 weeks; chronic epididymitis is defined as discomfort in the scrotum, testicle, or epididymis for more than 3 months. The patient’s age and sexual activity history are important in determining the causative agent. C trachomatis and N gonorrhoeae are the most common organism in sexually active adolescents, being responsible for approximately two thirds of infections, Coliform organisms, Pseudomonas, and gram-positive cocci must be considered in youth who have engaged in anal intercourse.

The patient typically presents with an acute onset of unilateral testicular and/or scrotal pain and swelling, often accompanied by asymptomatic urethritis. Urinary frequency, dysuria, and urethral discharge may also occur. Fever is a sign of systemic infection. Upon examination, the epididymis is swollen and tender. Early in the course of the infection, the epididymis is easily discernible from the testicle, but with progression, the testis becomes involved, producing epididymoorchitis, thereby making it difficult on examination to differentiate the epididymis from a swollen and tender testicle. The cremasteric reflex may be absent.

DIAGNOSIS AND TREATMENT

Proper STI evaluation is similar to that outlined for urethritis (Fig. 233-1).6 Epididymitis is often difficult to differentiate from torsion of the spermatic cord (see Chapter 476 regarding scrotal masses). If the diagnosis is unclear, evidence for urethritis is not found, or the pain is very sudden and severe, urgent radiologic techniques should be used to distinguish these two clinical entities. Urgency is indicated because of the substantial risk to testicular viability. Scrotal masses are discussed in other sections. Hospitalization for presumptive acute epididymitis is typically not necessary but should be considered in cases of severe pain when further workup is indicated, fever or concern for systemic disease, or inability to adhere to treatment.

If chlamydial or gonococcal epididymitis is suspected, empiric treatment should start promptly. The recommended regimen is ceftriaxone, 250 mg IM, followed by a 10-day course of doxycycline, 100 mg b.i.d. (Table 233-2). For infection likely caused by enteric organisms or in those with allergies to cephalosporins or tetracyclines, suggested treatment includes ofloxacin, 300 mg PO b.i.d. for 10 days, or levofloxacin 500 mg orally once daily for 10 days. All sexual partners should be contacted for evaluation and treatment. Additional therapy should include scrotal elevation and analgesics. If there is no improvement within the first 3 days of treatment, the diagnosis and treatment plan should be reconsidered. Other possibilities are abscess, tumor, tuberculosis, fungal epididymitis, or infarction.

Epididymitis usually resolves without sequelae if treatment is administered promptly. However, there are some indications that oligoor azoospermia may result, particularly if C trachomatis was the etiologic agent. Other sequelae include atrophy, infarct, or abscess formation.

PROCTITIS

CAUSATIVE ORGANISMS AND CLINICAL SYNDROMES

Proctitis is defined as an inflammation of the distal 10 to 12 cm of the rectal mucosa. Many infections involve the anus as well and are therefore considered “anorectal” infections. Although STI-related rectal infections are frequently associated with anal intercourse among homosexual men, they may also occur in women. Such infections in women are less well defined and, with gonorrhea, are often asymptomatic and associated with endocervical gonorrhea. The microbiological etiologic agents of anorectal infection among sexually active adolescents include N gonorrhoeae, C trachomatis (including lymphogranuloma venereum [LGV] strains), herpes simplex virus, T pallidum, and food-borne enteric organisms. Sexually transmitted enteric organisms, such as Giardia, Entamoeba, Campylobacter, Shigella, and hepatitis A, can be associated with anal intercourse. HIV-infected individuals may also have severe herpes proctitis or be infected with organisms generally not sexually transmitted, including CMV, Mycobacterium avium-intracellulare, and others.

Whereas the anus is highly innervated, resulting in pain with inflammation, the rectum lacks such innervation; thus, proctitis that does not involve the anus is usually painless. Symptoms of anorectal disease include mucus or blood in the stools, loose stool, cramping, anal itching, pain with defecation leading to constipation, and tenesmus. On examination, the anus may appear inflamed and tender. Mucopurulent discharge with or without blood may be present. Anoscopy may reveal the presence of mucopurulent discharge and erythema of the mucosa with friability and ulceration.

DIAGNOSIS AND TREATMENT

Diagnostic evaluation includes a careful sexual history to determine risk for anal intercourse; examination including anoscopy; testing for STIs; testing for STI-related urethritis in men (Fig. 233-1) and endocervicitis in women (Fig. 233-2); rectal cultures for N gonorrhoeae, C trachomatis, and HSV; appropriate stool and rectal specimens for enteric bacteria and parasites; and syphilis serology (Table 233-1).6 Empiric treatment is indicated if the examination reveals anorectal exudates or if a Gram stain smear of an anorectal sample reveals polymorphonuclear leukocytes with gram-negative intracellular diplococcin. Ceftriaxone 125 mg IM plus doxycycline 100 mg PO b.i.d. for 7 days is given while awaiting other test results. Presumptive treatment for HSV is indicated by painful perianal or mucosal ulcers found on examination. In the absence of this typical history and findings other causes of proctitis need to be considered such as non-STI infectious colitis or inflammatory bowel disease (see Chapter 410).

CHANCROID

The majority of genital ulcers in sexually active youth in the United States are caused by either HSV, syphilis, or chancroid. Rates of chancroid vary by geographic areas and may occur in endemic or episodic fashions. Patients infected with chancroid also have a high prevalence of HIV infection, HSV, and syphilis. Typical signs include painful genital ulcer and painful inguinal adenopathy.

Presumptive diagnosis is made when all of these criteria are present:

1. painful genital ulcer,

2. negative dark-field examination of the ulcer exudate or negative serologic syphilis test within 7 days of ulcer onset, genital ulcer,

3. inguinal adenopathy found on examination, and

4. negative HSV test applied to the ulcer exudates.6

Four treatment options are currently recommended: azithromycin 1 gram PO once; or ceftriaxone 250 mg IM once; or ciprofloxacin 500 mg PO b.i.d. for 3 days; or erythromycin base 500 mg PO t.i.d. for 7 days. Repeat examination should occur within 7 days of starting treatment in order to confirm improvement. Complete healing of larger ulcers may require more than 2 weeks. Patients who are uncircumcised or infected with HIV tend to demonstrate slower healing. All patients infected with chancroid should routinely be tested for HIV and receive repeat testing for syphilis and HIV 3 months later if initial tests were negative.