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Genital ulcers are caused by syphilis, herpes virus infection, chancroid, lymphogranuloma venereum, and granuloma inguinale (donovanosis). These infections have high rates of co-infection with HIV. Not all infections associated with genital ulcers are sexually transmitted. Characteristics of the lesions and their accompanying signs and symptoms are provided in Table 149-3.
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Treponema pallidum, a spirochete, is the causative agent of syphilis as well as yaws and pinta. The organism enters the body through mucous membranes or nonintact skin. T. pallidum remains very sensitive to penicillin. The incidence of syphilis in the United States was on the rise from 2001 to 2009, possibly because of behavior associated with drug use and male-to-male transmission.1
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Syphilis consists of three phases: primary, secondary, and tertiary or latent syphilis. The disease may be diagnosed in any of these three stages.
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Primary syphilis, or the initial stage of infection, is characterized by a painless chancre with indurated borders on the penis (Figure 149-4), vulva (Figure 149-5), or other areas of sexual contact.
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The incubation period is approximately 21 days, with lesions disappearing after 3 to 6 weeks. There are no constitutional symptoms, and a lesion may even be absent with primary disease. The lesion resolves spontaneously.
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Secondary syphilis develops 3 to 6 weeks after the end of the primary stage and is characterized by rash and lymphadenopathy. Nonspecific symptoms of sore throat, malaise, fever, and headaches are common. The rash often starts on the trunk (Figure 149-6) and flexor surfaces of the extremities, spreading to the palms (Figure 149-7) and soles. The rash takes on many forms but is often dull red-pink and papular. Secondary syphilis resolves spontaneously.
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Tertiary or latent syphilis develops in about one third of patients after secondary syphilis, occurring 3 to 20 years after the initial infection. Involvement of the nervous and cardiovascular systems is characteristic, with widespread granulomatous lesions (gummata). Specific manifestations include meningitis, dementia, neuropathy (tabes dorsalis), and thoracic aneurysm.
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T. pallidum cannot be cultured in the laboratory, and there is no single optimal test. The sensitivity and specificity of tests for syphilis depend on the stage of the disease and the type of test. Direct visualization of the organism using darkfield microscopy is diagnostic of primary, secondary, or early congenital syphilis, no matter what the results on serology. However, failure to visualize the organism does not exclude syphilis. Nontreponemal tests (Venereal Disease Research Laboratory [VDRL] test, rapid plasma reagin test) detect nonspecific antibodies to cardiolipins, which are released as a result of infection. The VDRL and rapid plasma reagin tests are used as screening tests and also, once diagnosis is made, to assess disease activity and response to treatment. If used for screening, the VDRL and rapid plasma reagin tests are associated with both false-negative and false-positive results. Tests do not become positive until about 1 to 4 weeks after a chancre appears. Positive results must be confirmed with an immunoassay specific for T. pallidum antibodies. Some laboratories now begin the testing sequence with sensitive and specific Treponema-specific assays (reverse screening) and follow response to treatment with nontreponemal tests.15
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For secondary syphilis, nontreponemal antibody tests are nearly 100% sensitive with high specificity.16 The blood of treated patients usually becomes nonreactive on nontreponemal antibody tests. Patients who develop disease and have a reactive result on a specific treponemal antibody test will have a reactive test result for life regardless of disease activity or treatment.
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A presumptive diagnosis of syphilis is made if a positive result on a nontreponemal antibody test (i.e., rapid plasma reagin or VDRL) is supported by a positive confirmatory result on a treponemal antibody test (i.e., fluorescent treponemal antibody absorption test).16,17 Treat based on strong clinical grounds while results of confirmatory tests are pending, if follow-up is uncertain. When uncertain about testing interpretation, review the Centers for Disease Control and Prevention Web site (http://www.cdc.gov/STD/syphilis/default.htm) for detailed clarification of laboratory diagnosis or contact the local health department.
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For primary and secondary syphilis treat with penicillin G benzathine, 2.4 million units IM in a single dose. Doxycycline twice daily for 2 weeks may be used in penicillin-allergic patients (Table 149-2). Pregnant women should be treated with parenteral penicillin G; if allergic, they must be desensitized and then given this medication. The Jarisch-Herxheimer reaction occurs most frequently in treatment of early syphilis and is characterized by an acute febrile reaction associated with headache and myalgias within the first 24 hours after treatment. Inform patients about this possible reaction. Recommend treatment of sexual partner(s) exposed in the previous 90 days. For a more detailed explanation of partner treatment, please refer to the Centers for Disease Control and Prevention Web site: http://www.cdc.gov/std/ept/default.htm.
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Treat tertiary syphilis with 2.4 million units of penicillin G benzathine IM weekly for 3 weeks. Either a primary care physician or the department of public health should closely follow all patients for repeat serologic testing at 6 and 12 months.
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HERPES SIMPLEX INFECTIONS
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Herpes simplex virus (HSV) type 1 or type 2 infections are lifelong. Genital herpes is caused by exposure of mucosal surfaces or nonintact skin to the HSV virus. Approximately 25% of the U.S. population has serologic evidence of herpes infection. Most genital infections are caused by the HSV-2 virus; but anogenital infections are also caused by HSV-1.18 Only 10% to 25% of individuals who are HSV-2 seropositive report a history of genital herpes, which suggests that most infected people have unrecognized symptomatic or completely asymptomatic infections. Viral shedding in persons who are unaware that they are infected is likely responsible for the majority of HSV transmission.3
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"Classic" outbreaks of primary genital HSV infection begin with a prodrome lasting 2 to 24 hours that is characterized by localized or regional pain, tingling, and burning. Next, constitutional symptoms of headache, fever, painful inguinal lymphadenopathy, anorexia, or malaise are common. Women are more likely to have constitutional symptoms than men. As the disease progresses, papules and vesicles on an erythematous base become evident. The vesicles erode in hours to days. Patterns of HSV-1 and HSV-2 infection appear identical: vesicles usually are uniform in size, and the tense center umbilicates to form a depressed center. Lesions usually crust and then re-epithelialize and heal without scarring.
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In men, HSV ulcers often appear on the shaft or glans of the penis (Figure 149-8). In women, ulcers can occur on the introitus (Figure 149-9), urethral meatus, labia, and perineum. Lesions are exquisitely painful and sometimes are associated with serous discharge. In both sexes, lesions may be found on the perianal area, thighs, or buttocks. Dysuria is common in women and may progress to urinary retention secondary to severe pain.
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Complete healing usually occurs within 3 weeks, and viral shedding persists for 10 to 12 days after the onset of the rash. Recurrent outbreaks generally are milder than the initial episode. There are typically fewer grouped lesions, and viral shedding occurs at a lower concentration and for a shorter duration (i.e., about 3 days).19 The disease can be transmitted despite the absence of ulcers.
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Diagnosis is usually made on clinical features. If uncertain, a Tzanck test may demonstrate large intranuclear inclusions. Laboratory diagnosis is either by cell culture or polymerase chain reaction. When obtaining a specimen for analysis, puncture the vesicle and swab the fluid. Swab the base of the lesion vigorously, because the virus is cell associated.3 Lack of HSV detection does not indicate a lack of HSV infection, because viral shedding is intermittent.
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Treatment hastens recovery but does not cure. Antiviral medications decrease the time until all lesions are crusted and healed, decrease pain and constitutional symptoms, and decrease the period of viral shedding by several days.3
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Treat the first clinical episode with acyclovir, famciclovir, or valacyclovir (Table 149-2). Extend treatment duration if lesions persist. To treat proctitis or oral infections, use higher dosages (acyclovir, 400 milligrams five times a day for 7 to 10 days). For hospitalized patients, give acyclovir, 5 to 10 milligrams/kg IV every 8 hours for 5 to 7 days. Famciclovir and valacyclovir have high oral bioavailability and are alternative oral agents with easier dosing regimens for patients.
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Treat episodic recurrent infection for 5 days with acyclovir, famciclovir, or valacyclovir at dosages reduced from primary therapy (Table 149-2). Begin treatment within 1 day. Suppressive therapy is available for individuals who experience more than six episodes per year, which reduces recurrence and shedding but does not eliminate either event. Treat severe recurrent infections (seen primarily in immunocompromised patients) with acyclovir, 5 to 10 milligrams/kg every 8 hours IV, for at least 2 days before switching to oral therapy. A primary diagnosis of HSV should prompt the search for other STIs including HIV.
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Haemophilus ducreyi is a pleomorphic gram-negative bacillus that causes chancroid, seen as painful genital ulcers and lymphadenitis. This disease is on the decline in most of the world with sporadic male outbreaks.20 Chancroid increases HIV transmission and often is accompanied by other infections when chancroid is present; 10% of infected patients in the United States also have HSV or T. pallidum.20
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A painful erythematous papule appears at the site of infection (usually confined to the genital region) after an incubation period of 4 to 10 days. One to 2 days later, the lesion becomes eroded, ulcerated, and often pustular (not vesicular). The ulcers are usually 1 to 2 cm in diameter with sharp, undermined margins and are very painful (Figure 149-10). The friable base of the ulcer is covered with yellow-gray necrotic exudates. Multiple lesions are present in up to 50% of patients (more so in women), and "kissing lesions" (infection of adjacent skin areas due to autoinoculation) are frequent. Painful inguinal lymphadenopathy develops 1 to 2 weeks after primary infection (Figure 149-11). A bubo will develop if chancroid is untreated, and the lymph nodes become necrotic or pus filled. Constitutional symptoms are rare, and ulcerations are rarely recurrent.
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Diagnosis can generally be made on clinical grounds with a painful ulcer and regional lymphadenopathy, but other infections (such as HSV infection and syphilis) are possible. A swab of a lesion or pus from a suppurative lymph node can be cultured, but a special medium is required that is not widely available, and culturing has a sensitivity of <80%. There is no current Food and Drug Administration–approved polymerase chain reaction test.
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Azithromycin PO in a single dose, ceftriaxone IM in a single dose, ciprofloxacin for 3 days, or erythromycin base for 7 days are all effective for the treatment of H. ducreyi infection (Table 149-2), with the choice based on local antibiotic resistance patterns and patient factors. Generally, azithromycin and ceftriaxone are used in patients without HIV infection, with ciprofloxacin as an alternative. Erythromycin is inexpensive, but the need for multiple doses and GI toxicity make it less desirable. Incision and drainage or aspiration of buboes can be considered for symptomatic relief, prevention of fistulas, and secondary ulcers.
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Symptoms improve in about 3 days, and lesions are visibly improved within a week. Larger ulcers may require 2 to 3 weeks to heal. Partners should be treated if they have had sexual contact in the last 10 days, regardless of symptoms.3 Pregnant women are usually treated with ceftriaxone or erythromycin as an alternative. All patients should be tested for HSV, syphilis, and HIV at or near the time of diagnosis of chancroid and again 3 months later if tests are initially negative.
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LYMPHOGRANULOMA VENEREUM
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Three specific serotypes (L1, L2, and L3) cause lymphogranuloma venereum, also referred to as struma, tropical bubo, or Durand-Nicolas-Favre disease. Lymphogranuloma venereum is endemic worldwide but is seen only sporadically in the United States. The Netherlands has seen an increased incidence of this STI in homosexuals.21 The primary lesion can take many forms and be confused with the lesions of other STIs (Table 149-3).
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The painless primary chancre is almost never noticed and lasts only 2 to 3 days (Figure 149-12). Generally, 1 to 3 weeks after the appearance of the initial lesion, unilateral inguinal lymphadenopathy is noted (60% of cases) (Figure 149-13). Often the overlying skin has a purplish hue. The initial lesion progresses to suppurative lymphadenopathy, resulting in either spontaneous abscess rupture or firm inguinal masses. Lymphogranuloma venereum proctitis (rectal ulcers, bleeding, and discharge) is also seen, primarily in homosexual men, and can be confused with new onset of ulcerative colitis. Scarring of these masses may cause linear depressions parallel to the inguinal ligament, forming the so-called groove sign (Figure 149-14). Lymphogranuloma venereum infections can cause fever, chills, arthralgias, erythema nodosum, or rarely meningoencephalitis. Lymphogranuloma venereum is easily confused with syphilis, chancroid, and HSV, and it also facilitates the transmission and acquisition of HIV.
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Chlamydia serologic testing for lymphogranuloma venereum is not standardized and not helpful except to support the diagnosis in the appropriate setting. Culture, direct immunofluorescence testing, and nucleic acid detection of a lesion swab or bubo aspirate are not widely available, nor is genotyping. Given these diagnostic constraints, patients with a clinical picture suggestive of lymphogranuloma venereum and epidemiologic information should simply be treated. The Centers for Disease Control and Prevention may be able to assist with testing.
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Doxycycline for 21 days is the usual regimen (Table 149-2). Alternatives include erythromycin, azithromycin, or extended treatment with fluoroquinolones.3 Mild untreated cases resolve spontaneously in 8 to 12 weeks. Treat pregnant or lactating women with erythromycin or azithromycin. Refer partners with whom the individual has had sexual contact within the past 60 days for treatment. Sexual activity should be avoided until the full course of antibiotic treatment is completed and lymphadenopathy has resolved.3
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GRANULOMA INGUINALE (DONOVANOSIS)
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Granuloma inguinale, also called donovanosis, is caused by Klebsiella granulomatis, a gram-negative intracellular bacterium. The disease is rare in the United States but is endemic in India, southern Africa, and central Australia.
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After a variable incubation period of 2 weeks to 6 months, granuloma inguinale begins as subcutaneous nodules on the penis or labial-vulvar area. The nodules then progress to the more classic painless, ulcerative lesions (Figure 149-15). These lesions are highly vascular, which explains both their appearance (beefy red) and their tendency to bleed easily on contact. Lymphadenopathy is not usually present, but subcutaneous granulomas may occur and mimic lymphadenopathy. Superinfection may complicate these open, bleeding lesions and complicate the diagnosis. Granuloma inguinale is not highly contagious, and multiple exposures are required to contract the disease. Autoinoculation can occur, leading to oral and GI tract involvement.
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K. granulomatis is difficult to culture, and diagnosis often requires visualization of characteristic Donovan bodies on tissue biopsy.
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Doxycycline PO for at least 3 weeks stops progression of the lesions (Table 149-2), although longer treatment may be needed to allow complete healing of the ulcers. Azithromycin, ciprofloxacin, erythromycin base, and trimethoprim-sulfamethoxazole are alternatives for at least 3 weeks and until the lesions heal. Doxycycline, ciprofloxacin, and sulfonamides are contraindicated in pregnancy. Erythromycin base is the recommended treatment for pregnant or lactating women with the potential addition of a parenteral aminoglycoside. Individuals with whom the patient had sexual contact within 60 days of the appearance of the lesions should also be treated if symptomatic.22
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Over 40 different genotypes of human papillomavirus (HPV) can infect the human genital tract by direct transmission. It is estimated that just under 25% of the U.S. population is currently infected with genital HPV.23 As many as half of these infections are in adolescents and young adults, age 15 to 24 years.23 HPV infection is so common that most sexually active adults become infected at some point in their lives. The significance of genital warts goes beyond their discomforting presence, with many genotypes being oncogenic.
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Two Food and Drug Administration–approved vaccines are available against HPV. The quadrivalent vaccine (Gardasil®) works against the two most important oncogenic HPVs (genotypes 16 and 18) and those that cause genital warts (genotypes 6 and 11). The bivalent vaccine (Cervarix®) works against genotypes 16 and 18 only. The three-dose vaccine is routinely recommended for 11- and 12-year-old girls and is given over 6 months. The vaccine series can be started at 9 years of age. Catch-up vaccination is recommended for 13- through 26-year-old females who have not yet received or completed the vaccination series.24 Gardasil is used in males age 9 to 27 years old to prevent genital warts.
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Genital warts are flesh-colored papules or cauliflower-like projections that usually appear after an incubation period of 1 to 8 months and may coalesce to form condylomata acuminata (Figure 149-16). In women, they are seen on the external genitalia (Figure 149-17) and in the perianal region. Genital warts are usually painless, but depending on their anatomic location can be friable, painful, or pruritic and often enlarge during pregnancy. Infected males often complain of nonhealing penile lesions, occasionally with pruritus and urethral discharge. Perianal condylomata have been seen in up to 80% of women with vulvar condylomata and are seen frequently in homosexual males.
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Many topical treatments exist that can be used for days to weeks, but these are not usually initiated in the ED. Treatment decisions are based on the size and number of lesions, the amount of discomfort they are causing, and patient preferences. The treatment of external genital warts may help reduce viral load but is not a cure. All treatment options are considered equally effective and chosen based on the discretion of the patient and provider.
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Patients with HPV infections rarely require emergent management. However, counseling in the ED regarding this distressing condition is relatively common. Emphasize the following: it is common for sexually active people to have HPV at some point in their lives, and most people clear serologic evidence of HPV spontaneously without external evidence of the disease. Condoms are protective with HPV, but they are not preventative, and the only way to decrease exposure is to limit the number of sexual partners. It is an incorrect assumption that having HPV indicates an oncogenic certainty or a change in fertility.