This article addresses the importance of screening for sexually transmitted diseases as a form of secondary prevention. The differential diagnoses of genital ulcers or inflammatory disorders of the genitourinary tract, with a higher index of suspicion for sexually transmitted disease, are discussed, as well as currently recommended treatment options for the same.
Primary prevention through universal safe-sex precautions would eliminate the costly and sometimes tragic consequences of sexually transmitted infections (STI). However, because STI transmission remains prevalent, secondary prevention through screening and early diagnosis remains our most valuable weapon against the devastating disease sequelae. Early detection and appropriate antibiotic therapy have led to decreases in bacterial venereal diseases. For example, the incidence of syphilis in the United States has decreased from 51,000 in 1990 to 8,724 in 2005 . Likewise, the incidence of gonorrhea has decreased from one million in 1980 to less than 340,000 cases documented in 2005 .
Chlamydia trachomatis remains the most common reportable bacterial STI, with an estimated 2.8 million new cases in the United States each year and 50 million worldwide . Viral infections, for which curative therapy is not available, have been stable or increasing in prevalence. With 500,000 new cases each year, herpes simplex virus (HSV) is one of the most common viral STI. One million new cases of human papilloma virus are diagnosed each year, and the prevalence of this disease is between 24 and 40 million.
People at high risk of contracting sexually transmitted diseases are young adults between the ages of 18 and 28. The highest rate of gonorrhea and chlamydia infections is among females age 15 to 19 . It is also important to bear in mind that sexually transmitted diseases rank among the top five risks of international travelers, along with diarrhea, hepatitis, and motor vehicle accidents .
A urologist should have a high index of suspicion for underlying sexually transmitted disease in women who present with recurrent urinary-tract infections (UTIs) and in those who are symptomatic with sterile urine cultures. Up to 50% of women with signs of UTI during emergency department examination had subsequent positive cultures for sexually transmitted disease . Physicians should maintain the same level of vigilance when treating women who have sex with women. Genital human papilloma virus has been identified along with squamous intraepithelial lesions among lesbians, and occurs among those who have not had sexual relations with men . A high prevalence of bacterial vaginosis has been observed between monogamous lesbians. Because of more frequent orogenital practices, they may also be at higher risk of HSV type 1 .
Proctitis may occur in women and men who have anal sex. Causative organisms include Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, and HSV. A discussion of human immunodeficiency virus (HIV) is beyond the scope of this article; however, it is important to remember that STIs—especially the ulcerative types—facilitate the transmission and infection of HIV. HSV-2, in particular, may play a role in the transmission of HIV, as it has been identified more frequently than other STI among HIV-concordant couples .
The most common sexually transmitted diseases are discussed in this article. They include HSV, Chlamydia urethritis/cervicitis, lymphogranuloma venereum, syphilis, gonorrhea (GC), chancroid, trichomoniasis, and human papilloma virus (HPV). Other sexually associated pathogens which cause urethritis and vaginitides will also be discussed briefly.
Expedited partner therapy
A common dilemma for physicians treating patients with an STI is how to expeditiously extend treatment to the partner to both prevent complications from infection, such as pelvic inflammatory disease, and prevent the spread of disease. Traditional methods of patient or physician referral have obvious benefits and limitations. Expedited partner therapy (EPT) is the practice of treating the sexual partners of patients with STI by providing the patient with a prescription or medication to take to their partner without an intervening clinical evaluation or professional prevention counseling.
In August of 2006, the Centers for Disease Control (CDC) concluded that EPT has been shown to be at least equivalent to patient referral in preventing persistent or recurrent GC or chlamydial infection in heterosexuals and released guidelines for the uses of EPT . The guidelines recommend that EPT should only be implemented when other management strategies are impractical or unsuccessful. All recipients should be encouraged to seek medical attention, in addition to accepting therapy by EPT, through counseling of the index case, written materials, and personal counseling by a pharmacist or other personnel. The CDC guidelines suggest that EPT may be used to treat GC and chlamydial infection in heterosexual women and men. It should not be used routinely in men who have sex with men (MSM) because of a lack of data to confirm efficacy in this population and the high risk of comorbidity, especially with undiagnosed HIV. Similarly, EPT should not be used for partners of women with trichomoniasis because of the high risk of comorbidity with chlamydia or GC. EPT is not recommended for routine use in the management of patients with infectious syphilis.
To address legal and medicolegal status of EPT, the CDC collaborated with the Center for Law and the Public’s Health at Georgetown and Johns Hopkins Universities to assess the legal framework concerning EPT in all 50 states, the District of Columbia, and Puerto Rico. The objective of the research was to conceptualize and identify legal provisions that implicate a clinician’s ability to execute EPT. Currently, EPT is allowable in 11 states, potentially allowable in 28 states, and legally prohibited in 13 states. The results of the research, explanation, and legal status for each state can be found at the CDC Web site http://www.cdc.gov/std/ept/legal/default.htm .
Genital ulcers
Several sexually transmitted infections are clinically characterized by the genital ulcers typically associated with them, most commonly HSV, syphilis, and chancroid. In 2002, it was estimated that over 45 million persons had HSV, while only 6,862 cases of syphilis, and 67 cases of chancroid were reported.
Although specificity for clinical diagnosis of genital ulcer disease is good (94%–98%), sensitivity is quite low (31%–35%) . Inguinal lymph node findings did not contribute to diagnostic accuracy. Confirmatory cultures and serologic testing for syphilis, chancroid, and HSV should be performed whenever possible. Specifically, the CDC recommends: (1) serology and either darkfield examination or direct immunofluorescence for T. pallidum ; (2) culture or antigen test for herpes simplex virus; and (3) culture for H. ducreyi . It should be kept in mind that patients may be coinfected with more than one sexually transmitted disease. Approximately 10% of patients with chancroid are coinfected with HSV or syphilis. HIV testing should be strongly considered in the management of patients with confirmed STI. Clinical characteristics of sexually transmitted genital ulcers are summarized in Table 1 . Other causes that are not sexually transmitted, such as Behcet’s syndrome, drug reaction, erythema multiforme, Crohn’s disease, lichen planus, amebiasis, trauma, and carcinoma should also be considered in the differential diagnosis. Empiric treatment for the most likely cause based on history and physical should be initiated as laboratory test results are pending. If ulcers do not respond to therapy or appear unusual, a biopsy should be performed.
| Disease | Lesions | Lymphadenopathy | Systemic symptoms |
|---|---|---|---|
| Primary syphillis | Painless, indurated, clean-based, usually singular | Nontender, rubbery, nonsuppurative bilateral lymphadenopathy | None |
| Genital herpes | Painful vesicles, shallow, usually multiple | Tender, bilateral inguinal adenopathy | Present during primary infection |
| Charncroid | Tender papule, then painful, undermined purulent ulcer, single or multiple | Tender, regional, painful, suppurative nodes | None |
| Lympho-granuloma | Small, painless vesical or papule progresses to an ulcer | Painful, matted, large nodes, develop with fistula tracts | Present after genital lesion heals |
Genital ulcers
Several sexually transmitted infections are clinically characterized by the genital ulcers typically associated with them, most commonly HSV, syphilis, and chancroid. In 2002, it was estimated that over 45 million persons had HSV, while only 6,862 cases of syphilis, and 67 cases of chancroid were reported.
Although specificity for clinical diagnosis of genital ulcer disease is good (94%–98%), sensitivity is quite low (31%–35%) . Inguinal lymph node findings did not contribute to diagnostic accuracy. Confirmatory cultures and serologic testing for syphilis, chancroid, and HSV should be performed whenever possible. Specifically, the CDC recommends: (1) serology and either darkfield examination or direct immunofluorescence for T. pallidum ; (2) culture or antigen test for herpes simplex virus; and (3) culture for H. ducreyi . It should be kept in mind that patients may be coinfected with more than one sexually transmitted disease. Approximately 10% of patients with chancroid are coinfected with HSV or syphilis. HIV testing should be strongly considered in the management of patients with confirmed STI. Clinical characteristics of sexually transmitted genital ulcers are summarized in Table 1 . Other causes that are not sexually transmitted, such as Behcet’s syndrome, drug reaction, erythema multiforme, Crohn’s disease, lichen planus, amebiasis, trauma, and carcinoma should also be considered in the differential diagnosis. Empiric treatment for the most likely cause based on history and physical should be initiated as laboratory test results are pending. If ulcers do not respond to therapy or appear unusual, a biopsy should be performed.
| Disease | Lesions | Lymphadenopathy | Systemic symptoms |
|---|---|---|---|
| Primary syphillis | Painless, indurated, clean-based, usually singular | Nontender, rubbery, nonsuppurative bilateral lymphadenopathy | None |
| Genital herpes | Painful vesicles, shallow, usually multiple | Tender, bilateral inguinal adenopathy | Present during primary infection |
| Charncroid | Tender papule, then painful, undermined purulent ulcer, single or multiple | Tender, regional, painful, suppurative nodes | None |
| Lympho-granuloma | Small, painless vesical or papule progresses to an ulcer | Painful, matted, large nodes, develop with fistula tracts | Present after genital lesion heals |
Herpes simplex virus
Diagnosis
Genital herpes infection is common, afflicting more than 50 million people in the United States. It is caused by herpes simplex virus type 2 (HSV-2) in 85% to 90% of cases and herpes simplex virus type 1 (HSV-1) in 10% to 15% of cases. HSV-1 is responsible for common cold sores but can be transmitted via oral secretions during oral-genital sex. Silent infection is common and may account for more than 75% of viral transmission . Up to 80% of women with HSV-2 antibodies have no history of clinical infection . The incubation period ranges from 1 to 26 days but is usually short, approximately 4 days. Nongenital infection of HSV-1 during childhood may be protective to some extent against subsequent genital HSV-2 infection in adults. When exposed to HSV-2, women with negative HSV-1 antibodies had a 32% risk of infection per year, whereas women with positive antibodies had a 10% risk of infection per year.
Primary infection manifests with painful ulcers of the genitalia or anus, and bilateral painful inguinal adenopathy. The initial presentation for HSV-1 and HSV-2 are the same, though HSV-1 is expected to become the more common cause of first episode . A group of vesicles on an erythematous base that does not follow a neural distribution is pathognomonic for herpes simplex .
The initial infection is often associated with constitutional flu-like symptoms. Sacral radiculomyelopathy is a rare manifestation of primary infection that has a greater association with primary anal HSV. Genital lesions, especially urethral lesions, may cause transient urinary retention in women. Recurrent episodes are usually less severe, involving only ulceration of the genital or anal area. Severe disease and complications of herpes include pneumonitis, disseminated infection, hepatitis, meningitis, and encephalitis. Asymptomatic shedding occurs more frequently with HSV-2 than HSV-1, even in patients with long standing or clinically silent infection. Asymptomatic viral shedding is more likely during the 3- to 12-month period following clinical presentation, thereby perpetuating the risk of transmission .
The diagnosis of genital herpes should not be made on clinical suspicion alone, as the classic presentation of the ulcer occurs in only a small percentage of patients. Women especially, may present with atypical lesions such as abrasions, fissures, or itching . Viral culture with subtyping has been the gold standard of diagnosis of herpes infection. The viral subtype should be determined in every patient, as it is important for prognosis and counseling. Women with HSV-2 have an average of four recurrences within the first year and women with HSV-1 have one recurrence in the first year. After the first year, HSV-1 rarely recurs while the rate of HSV-2 decreases, but slowly . Viral culture can generally isolate the virus in 5 days, is relatively inexpensive, and highly specific. However, the sensitivity of viral culture ranges from 30% to 95%, depending on the stage of the lesion and whether it is the primary infection or a recurrence. Viral load is highest when the lesion is vesicular and during primary infection. Therefore viral culture has the highest sensitivity at these times and declines sharply as the lesion heals.
There are currently four Food and Drug Administration (FDA) approved glycoprotein G-based type-specific antibody assays that identify antibodies to HSV glycoproteins G-1 and G-2, which evoke a type-specific antibody response . These tests may also be able to identify recently acquired versus established HSV infection based on antibody avidity . Point-of-care tests can provide results for HSV-2 antibodies from capillary blood or serum during a clinic visit .
Treatment
Antiviral therapies approved for treatment include oral acyclovir, valacyclovir, and famciclovir. Recommended antiviral regimens are listed in Table 2 . Topical antiviral medications are not effective. Recurrences can be treated with an episodic or suppressive approach. When used for episodic treatment, medication must be initiated during the prodrome or within 1 day of the onset of lesions. Daily suppressive therapy has been shown to prevent 80% of recurrences and is an option for patients who suffer from frequent recurrences. It has been shown to decrease the frequency and duration of recurrences as well as viral shedding, and therefore reduction in the rate of transmission. The safety and efficacy of daily suppressive therapy has been well documented.
| Agent | First clinical episode | Episodic therapy | Suppressive therapy |
|---|---|---|---|
| Acyclovir |
|
| 400 mg bid |
| Famiciclovir | 250 mg tid for 7–10 days | 125 mg bid for 5 days | 250 mg bid |
| Valacyclovir | 1 g bid for 7–10 days |
|
|
Chancroid
Diagnosis
Chancroid, caused by Haemophilus ducreyi, is the most common STI worldwide. It affects men three times more often than women. The incubation period ranges from 1 to 21 days. It causes a painful, nonindurated ulcer on the penis or vulvovaginal area. The ulcer has a friable base covered with a gray or yellow purulent exudate and a shaggy border. It can spread laterally by apposition to inner thighs and buttocks, especially in women. It is associated with inguinal adenopathy that is typically unilateral and tender, with tendency to be become suppurative and fistulize.
Haemophilus ducreyi is fastidious and difficult to culture. The special culture media is not widely available and sensitivity of culture remains under 80%. Gram-stain of a specimen obtained from the undermined edge of the ulcer may be more helpful in identifying the short, fine, Gram-negative streptobacilli, which are usually arranged in short, parallel chains. Recently, polymerase chain reaction (PCR) assays have been shown to be a sensitive and specific means of detecting Haemophilus ducreyi. Although no PCR test is currently FDA approved, testing can be performed by commercial agencies. Approximately 10% of persons who have chancroid are coinfected with T. pallidum or HSV . HIV and syphilis screening should be performed at the time of diagnosis and 3 months after treatment, if initially negative.
Four criteria should be considered in formulating the diagnosis of chancroid: presence of one or more painful ulcers, presence of regional lymphadenopathy, a negative T pallidum evaluation or negative serologies at least 7 days after the onset of symptoms, and negative HSV culture from the ulcer exudates .
Treatment
Single dose treatments consist of azithromycin, 1 g orally or ceftriaxone, 250 mg intramuscularly. Alternative regimens include ciprofloxacin, 500 mg twice daily for 3 days, or erythromycin base, 500 mg by mouth three times daily for 7 days; however, antibiotic susceptibility varies geographically. Resistance has been reported to ciprofloxacin and erythromycin in some regions. Ciprofloxacin is contraindicated during pregnancy and lactation. Subjective improvement should be noted within 3 days and ulcers generally heal completely in 7 to 14 days. Healing may be slower in uncircumcised men with ulcers below the foreskin and in patients with HIV . Patients should be re-examined in 5 to 7 days. Sexual partners should be examined and treated if sexual relations were held within 2 weeks before or during the eruption of the ulcer. Symptomatic relief of inguinal tenderness can be provided by needle aspiration or incision and drainage of the buboes.
Syphilis
Diagnosis
Syphilis is caused by a spirochete, Treponema pallidum . Incubation periods range between 10 and 90 days. It is spread through contact with infectious lesions or body fluids. It can also be acquired in utero and through blood transfusion. Primary syphilis is characterized by a single painless, indurated ulcer occurring at the site of inoculation, that appears about 3 weeks after inoculation and persists for 4 to 6 weeks. The ulcer is typically found on the glans, corona, or perianal area on men and on the labial or anal area on women. It is often associated with bilateral, nontender inguinal or regional lymphadenopathy. Since the ulcer and adenopathy are painless and heal without treatment, primary syphilis often goes unnoticed.
Latent syphilis is defined as seroreactivity with no clinical evidence of disease. Early latent syphilis is latent syphilis acquired within the past year. All other latent syphilis is either referred to as late latent syphilis or latent syphilis of unknown duration.
Secondary syphilis usually begins 4 to 10 weeks after the appearance of the ulcer, but may present as long as 24 months following the initial infection. Secondary syphilis manifests with mucocutaneous, constitutional, and parenchymal signs and symptoms. Frequent early manifestations consist of maculopapular rash, which is commonly seen on the trunk and arms, and generalized nontender lymphadenopathy. After several days or weeks, a papular rash may accompany the primary rash. These papular lesions are associated with endarteritis and may therefore become necrotic and pustular. The distribution widens and commonly affects the palms and soles. In the intertriginous areas, these papules may enlarge and erode to produce condyloma lata, which are particularly infectious. Less common manifestations of secondary syphilis include hepatitis and immune complex-induced glomerulonephritis.
Approximately one third of untreated patients will develop tertiary syphilis. It is very rare in industrialized countries, except for occasional cases reported in HIV patients. Syphilis is a systemic disease that can affect almost any organ or system, especially the cardiovascular, skeletal, and central nervous systems, and skin. Aortitis, meningitis, uveitis, optic neuritis, general paresis, tabe dorsalis, and gummas of the skin and skeleton are just some of the sequalae associated with tertiary syphilis.
Dark-field microscopy and direct fluorescent antibody (DFA) are tests of specimens obtained from primary or secondary lesions. Dark field microscopy is not widely available but DFA testing of a fixed smear from a lesion can be performed at many commercial laboratories. Nontreponemal serologic testing, with rapid plasma regain (RPR) or venereal disease research laboratory (VRDL) are the most common methods of screening suspected individuals. Sensitivity is 78% and 86% for RPR and VDRL, respectively, in primary syphilis, 100% for both in secondary syphilis, and over 95% in tertiary syphilis . The false positive rate is approximately 1% to 2% and may be secondary to a large variety of causes . Therefore, all positive tests should be confirmed with treponemal testing using T. pallidum particle agglutination or florescent treponemal antibody absorbed. HIV can cause false negative results by both treponemal and nontreponemal methods . Positive treponemal antibody tests usually remain positive for life and do not correlate with disease activity. Nontreponemal antibody titers, RPR and VDRL, correlate with disease activity. These tests usually become negative 1 year after treatment. For following disease activity, the same test, either RPR or VRDL, should be performed at the same lab, as the results are not interchangeable and may vary from laboratory to laboratory.
The United States Preventive Services Task Force recommends that pregnant women and people who are at higher risk for syphilis infection receive screening tests for the disease . People at higher risk for syphilis include men who have sex with men and engage in high-risk sexual behavior, commercial sex workers, persons who exchange sex for drugs, and those in adult correctional facilities. The CDC recommends that HIV testing should be considered in the initial evaluation of all patients with syphilitic infection, and that screening for hepatitis B and C, gonorrhea, and chlamydial infection also should be considered. The presence of chancres increases the risk of HIV acquisition two to five fold .
Treatment
Benzthiazide penicillin G (2.4 million units intramuscularly as a single dose) remains the treatment of choice. Other parental preparations or oral penicillin are not acceptable substitutes. The Jarisch-Herxheimer reaction is a reaction consisting of headache, myalgia, fever, tachycardia, and increased respiratory rate that occur within the first 24 hours after treatment with penicillin. Patients should be warned about the reaction and it is usually managed with bed rest and nonsteroidal anti-inflammatory agents. It may cause fetal distress and preterm labor in pregnant women.
If the patient has penicillin allergy, doxycycline 100 mg by mouth twice daily or tetracycline 500 mg four times daily for 14 days, are accepted alternatives. Ceftriaxone 1 gram IM or IV daily for 8–10 days has also been recommended by some specialists. For late latent syphilis, latent syphilis of unknown duration, or tertiary syphilis, benzthiazide penicillin injection of 2.4 million units should be repeated weekly for a total of three doses, or doxycycline or tetracycline therapy extended for a total of 4 weeks. Doxycycline and tetracycline are contraindicated in pregnancy. Therefore desensitization to penicillin is recommended if a pregnant patient has a penicillin allergy.
Neurosyphilis is treated with aqueous crystalline penicillin G, 3 to 4 million units intravenously every 4 hours for 10 to 14 days; or penicillin G procaine, 2.4 million units intramuscularly (IM) once daily, plus probenecid, 500 mg orally four times daily, with both drugs given for 10 to 14 days. Probenecid cannot be used in patients with an allergy to sulfa. Patients should be followed with nontreponemal antibody titers at 6 and 12 months. Patients with neurosyphilis require repeat examination of cerebrospinal fluid 3 to 6 months following therapy and every 6 months afterwards until normal results are achieved.
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