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Sexual activity is common among adolescents. A large ongoing national survey of US high school students reported that 24% of adolescents have had sexual intercourse by ninth grade and 58.1% by 12th grade, based on data collected in 2014 to 2015. Although rates of sexual activity have slowly decreased during 1991 to 2015, the adolescent age group continues to be at the highest risk for common sexually transmitted infections (STIs) compared to other age groups.
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This chapter provides an overview of STIs including the common clinical presentations, screening guidelines, and treatment for bacterial, fungal, protozoal, and viral infections. For the most up-to-date clinical guidelines on treatment regimens, readers are strongly advised to refer to the Centers for Disease Control and Prevention (CDC) web site since the optimal treatment regimens are frequently updated based on antibiotic resistance patterns and logistical availability of specific medications in the United States. Table 228-1 summarizes the major points about chlamydia, gonorrhea, human papillomavirus (HPV), Trichomonas, and Candida. Detailed discussions of syphilis, human immunodeficiency virus (HIV), and herpes simplex virus (HSV) infections are found in Chapters 283, 310, and 304, respectively.
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Adolescents and young adults 15 to 24 years of age represent one-quarter of the sexually active population, but they acquire nearly half of the 20 million new STIs each year in the United States. These STIs place our youth at risk for substantial morbidity and mortality, including pelvic inflammatory disease (PID) and its associated sequelae of ectopic pregnancy, infertility, and chronic pelvic pain; HPV-associated genital dysplasia; and HIV-associated immunosuppression and life-threatening complications.
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Annual epidemiologic data are published by the CDC, based on state and local STI case reports made from private and public sources. Chlamydia, gonorrhea, and syphilis are reportable infections, whereas other STIs such as HPV, HSV, and Trichomonas are not routinely reported to the public health authorities. In 2014, among women, the highest reported rates of chlamydia infection were found in those age 15 to 24 years (3309.4 cases per 100,000 females), compared to other age groups. The gonorrhea rate is similarly highest in women age 15 to 24 years (484 cases per 100,000 females), and the syphilis rate is highest in women age 20 to 24 years (4.5 cases per 100,000 females). HPV is not a reportable infection, but data from large surveillance studies show that 34% of women age 14 to 24 years have genital HPV, which is roughly 7.5 million females with HPV. Among the men, the highest chlamydia and gonorrhea rates are in those age 20 to 24 years (1368.3 cases per 100,000 males and 485.6 cases per 100,000 males, respectively). Syphilis rates are highest in men age 25 to 29 years (34 cases per 100,000 males), although syphilis rates in men age 20 to 24 years are similarly concerning (31.1 cases per 100,000 males).
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The higher STI rates observed in adolescents and young adults are associated with several risk factors. For example, gender is an important factor, as STIs are disproportionately more common among females compared to males, as evidenced from the gender-specific rates discussed above. Among adolescents, those with higher rates of STIs report a younger age of their first sexual encounter, have multiple concurrent sex partners, multiple sequential sex partners, inconsistent use of condoms, or use of injection drugs. Higher risk is also found in certain populations, such as young men who have sex with men (MSM), adolescents evaluated in STI clinics and some adolescent clinics, and those in detention facilities. Race and ethnicity are another important factor to consider for all age groups overall, given the correlation of race and ethnicity to other critical determinants of health, including socioeconomic status, differential educational attainment, and access to quality health care. One challenge in data collection is the missing data on race and ethnicity, since many case reports to public health are submitted without the race and ethnicity information, but population-based studies and national surveys provide clearly confirmatory evidence of the substantial burden of STIs on certain racial and ethnic groups. In 2014, the CDC reported that the overall ratios of chlamydia for African American, Native American, Native Hawaiian/Pacific Islanders, Hispanic, and whites were 6:4:6:2:1. The ratios for gonorrhea were 11:4:3:2:1, and the ratios for primary and secondary syphilis were 5:2:2:2:1. In considering the substantial risk associated with race and ethnicity, it is important to recognize that individuals who reside in geographic areas of high STI prevalence face a greater challenge to reduce their own personal risk for STI exposure. Public health interventions must address not only individual-level risk factors but also community-level risk factors involving social and cultural conditions that impact STI risk.
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SCREENING RECOMMENDATIONS
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The overall screening recommendations for adolescents and young adults are listed below:
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Sexually active females age < 25 years: Routine annual screening for chlamydia and gonorrhea is recommended, and HIV screening should be offered. The frequency of HIV screening should be based on risk factors. Cervical cancer screening by cervical cytology is recommended to start at age 21 years. Routine screening for other infections (syphilis, HSV, trichomonas, bacterial vaginosis) is not generally recommended in asymptomatic females.
Sexually active males age < 25 years: Evidence is not sufficient for a broad recommendation for routine screening for all males for chlamydia and gonorrhea, but screening for chlamydia and gonorrhea in high-prevalence settings or men with risk factors should be strongly considered. HIV screening should be offered. The frequency of HIV screening should be based on risk factors.
Men who have sex with men (MSM): Routine annual screening for HIV and syphilis serology is recommended. For MSM who have had insertive anal intercourse in the preceding year, routine annual screening for urethral chlamydia and gonorrhea is recommended. For MSM who have had receptive anal intercourse in the preceding year, routine annual screening for rectal chlamydia and gonorrhea is recommended. For MSM who have had receptive oral intercourse in the preceding year, routine annual screening for pharyngeal gonorrhea is recommended.
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Chlamydia trachomatis is the most common reported bacterial STI in the United States. 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.
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CLINICAL MANIFESTATIONS
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Uncomplicated endocervicitis is the most common clinical manifestation of chlamydial infection in sexually active female adolescents. However, the majority of chlamydial lower genital infections in women are asymptomatic, thus underscoring the importance of routine screening. When symptomatic, clinical findings may include abnormal vaginal discharge or bleeding, especially after intercourse. Another possible finding is mucopurulent cervicitis (MPC), which presents with a yellow endocervical discharge or by identification of increased polymorphonuclear cells on a Gram stain from the discharge (> 10–30 white blood cells per high-power field). However, MPC is not a sensitive diagnostic indicator of infection because most infected women do not have MPC. The most serious complication of endocervical infection is PID, including a subclinical upper tract infection that can lead to infertility. Routine annual screening for chlamydia has been shown to decrease PID rates in female populations. Patients with multiple risk factors or concern for possible exposures may warrant more frequent screening.
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Urethritis is the most common clinical manifestation of chlamydial infection in sexually active male adolescents and occurs commonly in women as well. In men, chlamydia is the most common cause of nongonococcal urethritis (NGU), responsible for 15% to 40% of cases. Chlamydial urethritis is typically identified through testing of symptomatic men (presenting with discharge and dysuria), contact tracing from a chlamydia-positive partner, or routine screening of asymptomatic men. Additionally, 20% to 50% of those with gonococcal urethritis are co-infected with chlamydia.
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Extragenital sites represent another clinical presentation, especially in MSM, and most are asymptomatic. In a 2003 study of 6434 MSM seen at an STI clinic, chlamydia prevalence was 7.9% rectal, 5.2% urethral, and 1.4% pharyngeal.
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Diagnosis of chlamydia by direct detection is recommended using US Food and Drug Administration (FDA)–approved nucleic acid amplification tests (NAATs) for both women and men, with or without symptoms. NAATs have demonstrated superior sensitivity and specificity compared to other testing technologies; thus, the older approaches including culture, enzyme immunoassays, nucleic acid probe tests, genetic transformation tests, and serology are not recommended. The exception is the preferred use of culture in cases of suspected sexual abuse in younger children because of the high specificity of culture. Clinicians are advised to refer cases of suspected sexual abuse to centers that are equipped to address the complex medicolegal aspects of these scenarios.
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For women, NAATs are available for vaginal, cervical, and urine specimens, with the vagina being the preferred site of collection. Self-collected and clinician-collected vaginal swabs are equivalent in assay performance, and many adolescent women appreciate the convenient option of a self-collected vaginal swab when a pelvic exam is not otherwise indicated, for example in asymptomatic women. In the setting of a pelvic exam, vaginal specimens are still appropriate, but cervical samples are also acceptable. Although a first-catch urine specimen is acceptable in women, urine is less preferred due to lower sensitivity compared to vaginal and cervical specimens.
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For men, the preferred detection method is the NAATs using the first-catch urine specimen, which demonstrate equivalent performance to urethral swabs and much higher acceptability from the patient perspective. For MSM, the CDC recommends routine annual screening of extragenital sites (rectal and/or oropharyngeal as indicated by the patient’s history of sexual behaviors) using NAATs, due to superior sensitivity and specificity compared to culture. Since NAATS are not FDA-approved for extragenital sites, rectal and oropharyngeal NAAT testing must be performed by laboratories that meet Clinical Laboratory Improvement Amendments (CLIAs) regulations for assay performance specifications.
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The recommended and alternative treatment regimens are found in Table 228-1. The goals of prompt treatment are to relieve symptoms and to prevent reproductive sequelae and further transmission to partners and neonates. Single-dose azithromycin offers the opportunity for direct administration and observation by clinical staff to ensure adherence. Patient counseling should include advice to abstain from sexual activity for at least 7 days after the single-dose azithromycin or until the other options of 7-day antibiotic courses are completed. Patients should further abstain until all sexual partners are treated. All partners in the past 60 days should ideally receive presumptive treatment and a full STI evaluation. If the patient reports no partners in the past 60 days, then the most recent partner beyond the 60 days should be offered treatment and services. If partners might not be able to access care, expedited partner treatment (EPT) should be offered as an alternative where allowed by state laws. EPT consists of prescription of antibiotic treatment and written counseling, which are delivered by the infected patient to the partner(s). EPT has been shown to decrease rates of recurrent or persistent chlamydia and is endorsed by several national medical societies and public health organizations. Of note, EPT is not ideal for MSM infected with chlamydia because of concern for co-existing STIs in the partners and thus the need for full evaluation in person. All patients diagnosed with chlamydia should also be offered testing for other STIs if not already performed and counseled about consistent condom use for STI prevention. Test-of-cure within a few weeks after treatment is not routinely recommended except in cases of questionable adherence to treatment, persistent symptoms, or repeat exposure to chlamydia. However, it is important to note that a positive result from an NAAT can persist up to 3 weeks after successful treatment due to nonviable chlamydia organisms that cause false-positive results. Rather than conducting routine tests-of-cure, retesting at 3 months after treatment is advised in order to detect reinfection from repeated exposure to an infected partner.
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Neisseria 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. Gonorrhea prevalence varies by geographic communities, and clinicians are encouraged to be familiar with public health recommendations for screening in their areas. Additional discussion of N gonorrhoeae can be found in Chapter 269.
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CLINICAL MANIFESTATIONS
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The majority of gonorrhea infections in men and women are asymptomatic and found on routine screening. Endocervicitis is the most common clinical manifestation of gonorrhea in women, as most gonococcal infections in women affect the lower genital tract with a particular predilection for the columnar cells of the endocervix. When symptomatic, gonorrhea in women leads to vaginal discharge, bleeding, pelvic discomfort, and/or PID. Urethritis is another clinical presentation in women but is often associated with endocervicitis. In men, urethritis is the most common clinical manifestation of gonorrhea. Symptomatic men report dysuria and/or discharge, appearing as soon as 2 to 4 days after urethral exposure. The discharge may be scant, or mucus may be present as a profuse purulent discharge. Approximately 10% of cases progress to acute epididymitis and urethral strictures. Additionally, 5% to 30% of men and 25% to 50% of women with N gonorrhoeae infection have concurrent C trachomatis infection.
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Of particular note is the serious condition of disseminated gonococcal infection (DGI), a bloodborne infection that has been classically described as a triad of petechial or pustular skin lesions, polyarthralgia, and tenosynovitis but may also manifest as septic arthritis alone (culture-positive joint fluid in approximately 50% of cases only), which occurs in 2% to 5% of gonorrhea-infected individuals, or involvement of joint and skin alone, known as the arthritis-dermatitis syndrome. Complications of DGI include meningitis and endocarditis, which are very rare. DGI is more common in African Americans than in other race/ethnicity groups. When considering the typical STI risk factors during an evaluation for gonorrhea, clinicians should also inquire about travel history and patients’ sexual exposures outside the United States, given the antimicrobial resistance patterns observed across international geographic regions for gonorrhea in particular.
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Direct diagnosis of gonorrhea by NAATs is the preferred method because NAAT sensitivity is superior to culture but varies by the type of NAAT. FDA-approved NAATs are available for vaginal, endocervical, and urine testing for women, and urine and urethral testing for men. Similar to chlamydia, the vaginal site is recommended for gonorrhea screening for women and the urine for men. As noted, NAATs are not FDA-approved for rectal and oropharyngeal sites but can be used by laboratories that meet CLIA regulations for assay performance specifications. However, culture retains an important role in gonorrhea management due to antimicrobial resistance issues. The US Gonococcal Isolate Surveillance Project (GISP) is a national sentinel surveillance system in place since 1986. Fluoroquinolone-resistant gonorrhea became apparent in 2007, and ongoing concerns for cephalosporin resistance are being monitored in several countries. When treatment failure is suspected, it becomes essential to perform culture and antimicrobial susceptibility testing. Furthermore, similar to chlamydia, culture is preferred in cases of suspected sexual abuse in younger children. Any gonorrhea isolates should be retained for additional testing.
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Another diagnostic tool for use only in symptomatic men is the Gram stain of urethral secretions, which is considered diagnostic when polymorphonuclear leukocytes with intracellular gram-negative diplococci are observed. Gram stain is not recommended in asymptomatic men or for endocervical, pharyngeal, or rectal specimens because of low sensitivity in these scenarios.
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The recommended and alternative treatment regimens for uncomplicated gonorrhea of the cervix, urethra, rectum, and pharynx are found in Table 228-1. After fluoroquinolone-resistant gonorrhea emerged in 2007, cephalosporins became the only antibiotics sufficiently effective for gonorrhea treatment. Current guidelines recommend dual therapy using a cephalosporin plus either azithromycin or doxycycline for gonorrhea treatment, regardless of chlamydia test results. Furthermore, rising resistance to cefixime and other oral cephalosporins in several countries as well as concerns about tetracycline resistance have led to the preferred recommended regimen of ceftriaxone and azithromycin as dual treatment administered simultaneously and with direct observation by clinical staff. Of note, the older regimen of azithromycin 2 g orally as monotherapy is no longer recommended in light of concerns for macrolide resistance. In situations of azithromycin allergy, doxycycline may serve as an alternative second antibiotic agent in place of azithromycin. For patients with persistent symptoms 3 to 5 days after treatment, treatment failure should be suspected, and the clinician should perform culture and antimicrobial susceptibility testing, report the case to public health, and work with the CDC to provide isolates for further testing.
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The treatment of DGI is not as well-established as is the treatment of uncomplicated cases. The CDC has made recommendations for treatment of DGI cases involving arthritis, arthritis-dermatitis syndrome, meningitis, and endocarditis, as listed in Table 228-1. However, the CDC concurrently advises consultation with an infectious disease specialist and/or the CDC to discuss individual cases, as the optimal treatment regimen for an individual patient may vary. The antibiotic selection and duration of treatment in a particular case are influenced by the specific clinical presentation, antimicrobial susceptibility results, and clinical response to treatment.
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Similar to the management of chlamydia, gonorrhea-infected patients should receive counseling about partner treatment, EPT if indicated (cefixime 400 mg and azithromycin 1 g), abstaining from sex until all partners are treated, consistent condom use for future STI prevention, testing for other STIs, and retesting in 3 months to monitor for reinfection.
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Treatment for DGI requires hospitalization for parenteral therapy and further evaluation for possible meningitis or endocarditis.
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PROTOZOAN AND FUNGAL INFECTIONS
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Trichomonas is the most common nonviral STI in the United States (Fig. 228-1). These organisms are sexually transmitted flagellated protozoans that attach to epithelial cells and can survive for up to 1.5 hours on a wet sponge and 24 hours on a wet cloth. Trichomonas is not reportable to public health authorities, but a US national survey reported an overall prevalence of 3.1%, with the highest prevalence of 13.3% found in non-Hispanic African American women. Similar to other STIs, higher prevalence is observed in populations such as patients with multiple partners, inconsistent condom use, racial/ethnic minorities, those seen in STI clinics, and those in detention facilities, but it is notable that the epidemiology of Trichomonas differs from chlamydia and gonorrhea in that older women also bear the burden of higher prevalence, and lower prevalence is found in MSM.
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CLINICAL MANIFESTATIONS
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The majority of infected patients are asymptomatic or have minimal symptoms. Untreated infections can persist for months to years. In women, Trichomonas can cause vaginitis, cervicitis, and urethritis. Symptoms include pruritus, vaginal discharge, dyspareunia, postcoital bleeding, lower abdominal pain, dysuria, and frequency. The vulva may appear erythematous, and the vaginal walls may appear granular. The “classical” frothy yellow-green vaginal discharge occurs in only 12% and can be found with other infections. The “strawberry cervix” consisting of punctate hemorrhages on the ectocervix occurs in only 2% and is not pathognomonic for Trichomonas cervicitis. Important implications of Trichomonas infection include the 2- to 3-fold increased risk for HIV acquisition and adverse pregnancy outcomes (eg, preterm birth). In HIV-infected women, Trichomonas carries a higher risk for PID, and thus annual screening is advised in this population. In men, the infection is usually self-limited, and most men are asymptomatic or present with features of nongonococcal urethritis. Infrequently, epididymitis or proctitis may develop.
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In the last several years, new diagnostic assays for Trichomonas have become available. Currently, the most sensitive tests are the FDA-approved NAATs. The APTIMA NAAT (Hologic Gen-Probe, San Diego, CA) can be used for vaginal, endocervical, or urine specimens from women, with both sensitivity and specificity of 95% to 100%. Laboratories fulfilling CLIA regulations can use APTIMA for urine or urethral specimens from men. The BD Probe Tec Qx Amplified DNA Assay (Becton Dickinson, Franklin Lakes, NJ) is another NAAT available for vaginal, endocervical, or urine specimens from women. Point-of-care assays are also available and FDA-approved for women only. The OSOM Rapid Test (Sekisui Diagnostic, Framingham, MA) is an immunochromatographic capillary flow enzyme immunoassay dipstick that can be used for vaginal specimens, with sensitivity of 82% to 95%, specificity of 97% to 100%, and results in 10 minutes. The Affirm VP III (Becton Dickinson) is a DNA hybridization probe used for vaginal specimens with a sensitivity of 63%, a specificity of 99.9%, and results in 45 minutes.
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These newer assays are becoming more widely available, but the traditional wet mount microscopy continues to be commonly used because of convenience, low cost, and immediate results, although sensitivity is only 51% to 65% for vaginal specimens and even lower for specimens from men. Wet mount also requires prompt evaluation for the motile organisms as Trichomonas motility decreases quickly with time. Some clinicians may adopt the option of wet mount first and then NAAT if the wet mount is negative. Culture was traditionally considered the gold standard because of the specificity close to 100%, but it offers sensitivity of only 75% to 96% and is not commonly used currently. Pap cytology sometimes identifies an incidental Trichomonas infection but should not be used for routine testing because of false negatives and false positives.
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The recommended and alternative treatment regimens are found in Table 228-1. For metronidazole and tinidazole, the consumption of alcohol can cause a disulfiram-like reaction. Thus, patients should avoid alcohol-containing drinks until at least 24 hours after metronidazole use or 72 hours after tinidazole use. Metronidazole gel is not recommended because of subtherapeutic levels and insufficient efficacy for the urethra and perivaginal glands.
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VULVOVAGINAL CANDIDIASIS
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Vulvovaginal candidiasis (VVC) is estimated to occur at least once in 75% of women, and 2 or more episodes are estimated to occur in 40% to 45%. The majority are caused by Candida albicans, but other Candida species are possible. Risk factors include immunocompromise, genetic host factors, medication use, and behavioral factors such as douching. Although sexual transmission of C albicans may occur, the role of such transmission in promoting infection among sexually active women is unclear.
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CLINICAL MANIFESTATIONS
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Uncomplicated VVC typically presents with nonspecific symptoms of vaginal pruritus, discomfort, or discharge; vulvar edema, fissures, or excoriations; dyspareunia; or dysuria. Approximately 10% to 20% of cases are classified as complicated VVC, including recurrent VVC, severe VVC, or non-albicans species VVC. Recurrent VVC is defined as 4 or more episodes of symptomatic VVC in 1 year. Many of these patients do not have any clear risk factors, and non-albicans species VVC is found in 10% to 20% of recurrent VVC cases. Severe VVC involves extensive vulvar erythema, edema, excoriations, and fissures.
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DIAGNOSIS AND TREATMENT
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One diagnostic challenge is distinguishing pathogenic infection from nonpathogenic colonization. Accordingly, diagnosis is typically made when a woman has signs and symptoms of vaginitis and either wet mount microscopy that shows budding yeast forms or hyphae (pH is usually < 4.5) or culture that shows yeast species. For patients with signs or symptoms but negative wet mount microscopy, empiric treatment is an option. However, positive culture without signs or symptoms may simply indicate normal colonization because 10% to 20% of women have yeast in the vagina and would not warrant treatment. Treatment regimens are found in Table 228-1.
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HPV is a member of the papillomavirus family capable of infecting humans. It is a closed, circular, double-stranded DNA virus of approximately 8000 base pairs. The viral genome is enclosed in an icosahedral capsule composed of 2 protein capsomeres (referred to as late [L] 1 and 2 proteins) and lacks the lipid-containing envelope common to many other viruses such as HSV. Unlike other human STIs such as HSV, HPV growth in traditional cell culture has been difficult because its replication is dependent on epithelial cell differentiation and maturation requiring the use of cell raft systems.
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PATHOGENESIS AND EPIDEMIOLOGY
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For infection, HPV requires access to basal epithelial cells through a wound or inflammation. 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 respiratory tract of the infant. Rarely, genital warts 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 vulvar, vaginal, cervical, anal, and penile cancers. Genital HPV types are also associated with oropharyngeal cancers. Subclassification 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. Twelve types are considered high risk (HR; 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59), 1 probable HR (68b), and 7 possible HR (66, 26, 53, 67, 70, 73, and 82), The most common type in all anogenital cancers is HPV-16.
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Genital HPV infection occurs primarily 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, but HPV DNA can be detected on hands and under fingernails. 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. The infections, however, are mostly transient, with 70% to 90% of HPV infections clearing within 1 to 2 years. Persistence of the infection is the key factor in the development of anogenital precancers and cancers. The length of 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. The roles of other cofactors are less compelling. Those thought to play important roles include cigarette use and immune suppression. More specifically, HIV-infected persons and organ transplant patients are at higher risk for cervical and anal cancers. Other factors with conflicting data include prolonged use of hormonal oral contraceptives, increased parity, and infection with C trachomatis.
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CLINICAL MANIFESTATIONS
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HPV can cause multicentric disease, including much of the anogenital area, including the vulvar labia minora and majora, clitoris, vaginal introitus, vagina, cervix, urethra, anus, and perineum in women, and the penis (including the prepuce, frenulum, corona, glans, urethra, and shaft), scrotum, and anus 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. Genital HPV types also often appear as flat, smooth, or pedunculated papules, specifically on mucosal surfaces. These lesions can also occur on conjunctival, nasal, oral, respiratory, gastrointestinal, and bladder mucosa.
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Infections with HPV can result in the development of lesions in the anogenital area referred to as low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous 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. High grade refers to changes that are considered truly precancerous (ie, the chance of progression is high and regression less).
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Screening for HPV infections in adolescents and young adult women is currently limited to visual inspection for external genital warts, and for women 21 years and older, cervical cancer screening using cytology is recommended for intraepithelial lesions and invasive cancers. No routine screening recommendations are made for vulvar, anal, and penile precancerous lesions in adolescents and young adults (defined as < 25 years of age) including MSM. This includes immunocompromised individuals.
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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, skin tags, nevocellular nevus, benign tumors, sebaceous glands, seborrheic keratosis, pearly penile papules, molluscum contagiosum, squamous cell carcinoma, vulva papillomatosis, and vestibular papillae.
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Treatment (see Table 228-1) for genital warts includes self-administered and provider-administered options. Provider-administered therapies are primarily ablative including application of trichloroacetic acid (TCA) or bichloroacetic acid (BCA) (85–90%) to the wart. 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 therapies include cidofovir, intralesion interferon, or 5-fluorouracil/epinephrine gel implant or laser therapy. Surgical removal by experienced clinicians is also an alternative using tangential scissor excision, tangential shave excision, curettage, or electrosurgery. Urethral meatus and vaginal wart treatments include liquid nitrogen or surgical removal. Cervical and intra-anal warts should be treated with cryotherapy with liquid nitrogen, surgical removal, or TCA/BCA. Referral to a trained specialist is recommended for both cervical and anal warts. Cervical warts require biopsy prior to treatment to rule out HSIL.
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There are now several options for self-applied therapies. 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 applied directly once daily at bedtime 3 times a week (alternating days) for up to 16 weeks. Sinecatechins is used 3 times daily topically for up to 16 weeks. Disadvantages to all therapies include irritation, inflammation, and ulceration from local applications.
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Despite known limitations in sensitivity, cytology remains the primary screening tool for squamous intraepithelial lesions (SIL) and invasive cancers in women age 21 years and older. Although HPV testing assists in triage of borderline abnormal cytology (atypical squamous cells of undetermined significance [ASCUS]) and SIL screening in older women, its role appears less specific in adolescents because of the high rates of HPV infections and LSIL and low rates of HSIL and invasive cancer in this age group. HPV DNA testing in adolescents is not currently recommended under any circumstance. Because HPV is often acquired early after the onset of sexual activity and is likely to be transient, cytology screening is not recommended under 21 years of age unless the patient is immunocompromised. Screening with cytology is then recommended every 3 years. At 25 years of age, primary screening with HPV DNA using the FDA-approved assays is allowed. Immunocompromised adolescent females should be screened within 1 year after the onset of sexual activity.
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The cellular changes associated with these lesions can be identified on cytology (cervical cancer screening) and histology. 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, specifically in adolescents. HPV DNA detection can be common 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 adolescents and young women is not cost-effective as a clinical tool and, as noted, should not be used. There are no treatments available or indicated for HPV DNA detection without abnormal cytology or histology.
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Prevention of HPV types 6, 11, 16, 18 31, 33, 45, 52, and 58 can now be achieved with vaccination prior to exposure. In the United States, the nonavalent (HPV9) vaccine is currently recommended for all females and males age 11 to 12 years. It is also recommended for males and females up to age 26 years, particularly targeting those who are not yet sexually active. In the United States, the HPV vaccine is a 2-dose regimen for those starting the vaccine before their 15th birthday, and a 3-dose regimen for those starting the vaccine after their 15th birthday. The vaccine is not therapeutic and has no effect on women already infected with the HPV types included in the vaccine. A bivalent vaccine for HPV-16 and -18 is also approved for females only. The vaccine can be given starting at 9 years of age. If there is a history of sexual abuse, it is recommended to vaccinate starting at the age of 9 years. Readers should refer to vaccine guidelines frequently updated from the CDC Advisory Committee on Immunization Practices (ACIP).
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A constellation of symptoms and signs is characteristic of specific STI syndromes. Common lower genital tract syndromes in women include those characterized by vaginal discharge, which include bacterial vaginosis, Trichomonas vaginalis, and candidiasis, as well as endocervicitis and urethritis. In men, urethritis is the most common STI syndrome, but epididymitis also occurs. Proctitis occurs in both females and males.
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The dominant organism (> 95% of organisms) in the normal flora of healthy women is hydrogen peroxide–producing Lactobacillus species. Bacterial vaginosis (BV) results from the replacement of vaginal hydrogen peroxide–producing Lactobacillus species with high concentrations of anaerobic bacteria, including Bacteroides species, Mobiluncus and Prevotella species, and other bacteria such as Gardnerella vaginalis and Mycoplasma hominis. Reported prevalence varies widely from 10% to 50%, depending on the population sampled.
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CLINICAL MANIFESTATIONS
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BV 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 non–sexually active women and is associated with multiple sexual partners and lack of condom use as well as douching. However, the cause of the microbial alterations remains unknown. BV has been associated with premature labor, as well as increased risk of acquiring HIV, gonorrhea, chlamydia, HSV, and HPV. Symptoms include pruritus, irritation, and a thin white vaginal discharge with a “fishy” odor.
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Various criteria have been used to diagnose BV. Amsel’s clinical criteria are based on presence of 3 of the following 4 factors: (1) homogenous, thin white discharge that coats the vaginal walls; (2) > 20% of squamous cells with a clue cell appearance (vaginal epithelial cells studded with adherent coccobacilli); (3) pH of vaginal fluid > 4.5; and (4) fishy odor before or after addition of 10% KOH (whiff test). Nugent’s gram stain criteria are used to quantify the absence of lactobacilli, and abundance of gram negative and variable rods and cocci and curved gram negative rods, which are seen in BV. The Nugent score is calculated and categorized as follows: 0 to 3 (normal), 4 to 6 (intermediate abnormal), and 7 to 10 (BV). Newer tests include the Affirm VP III (Becton Dickinson), which detects high concentrations of G vaginalis, and the OSOM BV Blue Test (Sekisui Diagnostics), which detects sialidase activity. Cervical Pap tests should not be used because they have low sensitivity and specificity.
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Treatment of nonpregnant women is linked only to relief of symptoms; male partners of infected women are almost always asymptomatic, and treating men does not affect the woman’s disease course. Treatment may lower risk of other STIs including HIV. Treatment regimens are found in Table 228-1. Additionally, treatment of symptomatic pregnant women is recommended using oral or vaginal treatments as recommended for nonpregnant women. Evidence is insufficient to recommend routine screening and treatment in asymptomatic pregnant women for the prevention of preterm birth.
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PELVIC INFLAMMATORY DISEASE
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PID is used to describe a variety of inflammatory disorders of the upper female genital tract including endometritis, salpingitis, tubo-ovarian abscess, and peritonitis. PID is thought to reflect ascending infections initiated in the vagina or endocervix. STIs, in particular, C trachomatis and N gonorrhoeae, are often identified, but other vaginal organisms have also been implicated (eg, anaerobes, G vaginalis, Haemophilus influenzae, enteric gram-negative rods, Streptococcus agalactiae, M hominis, Ureaplasma urealyticum, and possibly Mycoplasma genitalium). The notable sequelae of PID include ectopic pregnancy and infertility. Risk factors that may predispose young women to develop acute PID include young age, history of an STI, previous PID diagnosis, greater number of sexual partners, and recent gynecologic interventions (eg, therapeutic abortion or endometrial biopsy). 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.
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PID is challenging to diagnose because there is no single historical, physical, or laboratory finding that is definitively diagnostic. The clinical diagnosis for PID is imprecise and requires the consideration of multiple possible findings. Although laparoscopy is thought to offer a definitive diagnosis, endometritis and subtle fallopian tube inflammation will be missed. In addition, laparoscopy is frequently unavailable. Since most episodes go undiagnosed because of mild symptoms such as dyspareunia or abnormal vaginal bleeding, it is recommended to have a low threshold for diagnosis. Symptoms and signs of acute PID include lower abdominal pain, vaginal discharge, cervical motion tenderness, and uterine and adnexal tenderness (Table 228-2). The differential diagnosis to be considered in a young woman presenting with acute lower abdominal pain, in addition to PID, includes acute appendicitis, acute cholecystitis, mesenteric lymphadenitis, acute cystitis, acute pyelonephritis, ectopic pregnancy, intrauterine pregnancy, septic abortion, endometriosis, ovarian cyst with or without torsion, hemorrhagic ovarian cyst, ovarian tumor, severe constipation, and trauma.
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Principles to remember in the clinical approach to PID include the following: rule out other causes including pregnancy; when in doubt, err on the side of “overdiagnosis” of PID to prevent sequelae, especially in view of the possibility of subclinical infections, while pursuing further workup for other causes; treat with broad-spectrum antibiotics to cover C trachomatis, N gonorrhoeae, and other pathogens discussed earlier and begin the course promptly; and, finally, follow up with clinical evaluations (within 24–48 hours) to confirm the original clinical diagnosis and reevaluate the treatment regimen.
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Treatment regimens are outlined in Table 228-3. 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; and inability to arrange follow-up within 72 hours of starting antibiotics. Some recommend inpatient treatment for HIV-infected women because of greater sequelae. A serious complication of 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(s) are important parts of PID management, as with any STI. Intrauterine devices (IUDs) do not need to be routinely removed. If no improvement is noted after 48 to 72 hours of treatment, IUD removal should be considered.
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FITZ-HUGH-CURTIS SYNDROME
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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 PID. Bacteria that are typically associated with PID spread from the pelvis along the paracolic gutters to the liver capsule. N gonorrhoeae was the most common cause, but now C trachomatis is causative in about 80% of cases.
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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 on the symptoms and a finding of a positive cervical culture for gonorrhea or chlamydia. Liver function tests are usually normal. Imaging studies may be normal, although ultrasonography or abdominal computed tomography scan may identify perihepatic adhesions. Diagnostic laparoscopy demonstrates the pathognomonic finding of “violin-string” adhesions from the anterior abdominal wall to the liver capsule. Treatment is the same as for PID.
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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 6 weeks. The patient’s age and sexual history are important in determining the causative agent. C trachomatis and N gonorrhoeae are the most common organisms in sexually active adolescents, being responsible for approximately two-thirds of infections. Enteric organisms such as Escherichia coli must be considered in youth who have engaged in insertive anal intercourse.
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CLINICAL MANIFESTATIONS
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The patient typically presents with acute onset of unilateral testicular and/or scrotal pain and swelling (hydrocele), often accompanied by asymptomatic urethritis. Urinary frequency, dysuria, and urethral discharge may also occur. 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 epididymo-orchitis, thereby making it difficult on examination to differentiate the epididymis from a swollen and tender testicle. The cremasteric reflex may be absent. Fever is a sign of systemic infection.
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Proper STI evaluation is similar to that for urethritis. Epididymitis is often difficult to differentiate from torsion of the spermatic cord. If the diagnosis is unclear, evidence for urethritis is not found, or the pain is very sudden and severe, urgent referral to a urologist should be made since testicular viability is at risk. Diagnosis should include evaluation by 1 of the following point-of-care tests: > 2 white blood cells (WBCs) per oil immersion field on Gram, methylene blue, or gentian violet stain of urethral secretions (this test also allows for the diagnosis of gonococcal infection showing intracellular gram-negative or purple diplococci); positive leukocyte esterase test on first-void urine; or > 10 WBCs per high-power field from a spun first void urine sediment.
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Radionucleotide scanning is currently the most accurate method to diagnosis epididymitis. Ultrasound is often unable to distinguish between spermatic cord torsion and epididymitis. 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, when there is fever or concern for systemic disease, or when there is inability to adhere to treatment.
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If chlamydial or gonococcal epididymitis is suspected, empiric treatment should start promptly. The recommended regimen is ceftriaxone 250 mg intramuscularly (IM), plus a 10-day course of doxycycline 100 mg twice daily. For infection likely caused by sexually transmitted chlamydia, gonorrhea, and enteric organisms (men who practice insertive anal intercourse), suggested treatment includes ceftriaxone 250 mg IM plus levofloxacin 500 mg orally once a day for 10 days or ofloxacin 300 mg orally twice a day for 10 days. For infection most likely caused by enteric organisms, suggested treatment is levofloxacin 500 mg orally once a day for 10 days or ofloxacin 300 mg orally twice a day for 10 days. All sexual partners within the prior 60 days should be contacted for evaluation and treatment. If last intercourse was > 60 days, the most recent partner should be evaluated. Additional therapy should include bed rest, 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 diagnostic possibilities include abscess, tuberculosis, fungal epididymitis, infarction, or tumor. Full resolution of discomfort may take weeks after treatment.
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Epididymitis usually resolves without sequelae if treatment is administered promptly. However, there are some indications that oligo- or azoospermia may result, particularly if C trachomatis was the etiologic agent. Other sequelae include atrophy, infarct, or abscess formation.
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PROCTITIS, PROCTOCOLITIS, AND ENTERITIS
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Proctitis is defined as inflammation of the distal 10 to 12 cm of the rectal mucosa and is associated with anorectal pain, mucus or blood in stools, tenesmus, or rectal discharge. 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 MSM, they may also occur in heterosexual men and women. Such infections in women are less well defined and, with gonorrhea, are often asymptomatic and associated with endocervical gonorrhea. The most common sexually transmitted anorectal infections among sexually active adolescents include N gonorrhoeae, C trachomatis (including lymphogranuloma venereum [LGV] strains), HSV, and Treponema pallidum (syphilis). HIV-infected persons may also have severe herpes proctitis. Proctocolitis is proctitis with inflammatory extension to the colonic mucosa (> 12 cm above the anus) and is associated with diarrhea or abdominal cramps. Sexually transmitted enteric organisms, most commonly associated with anal intercourse or oral-anal sex, include Entamoeba histolytica, Campylobacter species, Shigella species, and LGV serovars of C trachomatis. Enteritis can present with or without proctitis or proctocolitis and commonly presents with diarrhea and abdominal cramping. It is most commonly associated with oral-anal sex practices. Giardia lamblia is the most common pathogen. Among HIV-infected persons, enteritis may be associated with organisms generally not sexually transmitted, including cytomegalovirus, Mycobacterium avium-intracellulare, Cryptosporidium, Microsporidium, Isospora, and others.
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Diagnostic evaluation for acute proctitis includes a careful sexual history to determine risk (eg, oral-anal sex, anal intercourse); examination including anoscopy; Gram stain of an anal sample; rectal sample tests (NAAT or culture) for N gonorrhoeae, C trachomatis, and HSV (or polymerase chain reaction [PCR]); and T pallidum (and darkfield, if available) serologic testing. If C trachomatis is identified, a molecular PCR test for LGV should be done.
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Empiric treatment is indicated if the examination reveals anorectal exudates or if a Gram stain smear of an anorectal sample reveals polymorphonuclear leukocytes. Ceftriaxone 125 mg IM plus doxycycline 100 mg orally twice daily for 7 days are given while awaiting other test results. Presumptive treatment for HSV in addition to ceftriaxone and doxycycline is indicated for painful perianal or mucosal ulcers found on examination. If symptoms of proctocolitis and enteritis are found in association with oral-anal or anal intercourse, tests for enteric pathogens can be obtained. 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 405). Partners of patients with STI-associated (eg, gonorrhea, chlamydia, including LGV) proctitis who had sexual contact within the prior 60 days should be evaluated and treated presumptively.
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The majority of genital ulcers in sexually active youth in the United States are caused by HSV. Syphilis and chancroid are less common. Rates of chancroid have declined in the United States, and chancroid is associated with sporadic outbreaks. Patients infected with chancroid also have a high prevalence of HIV, HSV, and syphilis. Typical signs include painful genital ulcer and tender suppurative inguinal adenopathy.
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Presumptive diagnosis is made when all of the following criteria are present:
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One or more painful genital ulcers
Negative darkfield examination of the ulcer exudate or negative syphilis serology within 7 days
Regional inguinal adenopathy
Negative HSV test from ulcer exudates
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A definitive diagnosis of chancroid requires special culture media that is not widely available in many labs. Currently, there is no FDA-cleared PCR test for Haemophilus ducreyi (the causative agent), but some labs have developed in-house assays.
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Four treatment options are currently recommended: azithromycin 1 g orally once; ceftriaxone 250 mg IM once; ciprofloxacin 500 mg orally twice daily for 3 days; or erythromycin base 500 mg orally 3 times daily for 7 days. Repeat examination should occur within 3 to 7 days of starting treatment in order to confirm improvement. Suppurative inguinal adenopathy may require needle aspiration or incision and drainage if no improvement is seen. 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. Sex partners should be evaluated and treated if they had sexual contact within 10 days prior to the onset of symptoms.
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