A 27-year-old male presents to the prison infirmary with penile pain. He reports having had the pain for the past three days, ever since accidentally catching part of the skin of his penis in his pants zipper. The patient reports previous good health. He is mildly developmentally delayed and has bipolar affective disorder for which he takes Depakote. The patient arrived at this facility one week ago and is newly incarcerated. He denies any sexual activity since he arrived. He reports being in a monogamous relationship with a woman for the past year. He denies ever having sex with men. The patient is examined by the infirmary nurse and found to have a 1.0 cm x 0.5 cm single oval lesion on the shaft of the penis and pronounced bilateral inguinal adenopathy. The on-call doctor is consulted; he prescribes a topical antibiotic ointment. Three weeks later, the patient is seen in follow-up. While the penile lesion has resolved, he now has a macular/pustular rash on his chest. A rapid plasma reagin (RPR) test is ordered. It is reactive at 1:128. The diagnosis of syphilis is confirmed by microhemagglutination assay for Treponema pallidum (MHA-TP).
What is the patient's diagnosis at initial presentation? The patient more than likely has genital ulcer disease (GUD) due to genital herpes, primary syphilis, or chancroid.
What is the patient's diagnosis on second presentation? His diagnosis is secondary syphilis.
GUD is often difficult to diagnose due to the variability in clinical presentation. A correct and rapid diagnosis is important, however, as an inaccurate or delayed diagnosis leads to a delay in treatment and therefore increases the likelihood that the inmate may infect others through sexual encounters. Incarcerated persons entering correctional facilities are at high risk for having sexually transmitted diseases (STDs) because of the high prevalence of risky sexual behaviors and limited access to health care for routine STD screening.1 In one study of adults screened for STDs on entering one of 23 jails, the prevalence of syphilis reactivity was found to be as high as 7.8% for men and 23.8% for women.2
The work-up for GUD begins by considering its infectious and non-infectious causes. Infectious causes of GUD include genital herpes, primary syphilis, chancroid, granuloma inguinale, and lymphogranuloma venereum. Genital herpes, caused by herpes simplex virus (HSV) 1 and 2, is the most prevalent cause of GUD in North America, followed by primary syphilis (Treponema pallidum), and chancroid (Haemophilus ducreyi).3 Granuloma inguinale (donovanosis), caused by the bacterium Calymmatobacterium granulomatis, and lymphogranuloma venereum (LGV), caused by Chlamydia trachomatis serovars L1-3, are rare causes of GUD in the United States. Donovanosis is endemic in certain tropical and developing areas, such as India; Papua New Guinea; Central Australia; and Southern Africa.4 A discussion of non-infectious causes of GUD is beyond the scope of this article, but should be considered if the work-up for infectious causes is negative.
It is sometimes possible to make a diagnosis of GUD based on clinical criteria (medical history and physical examination) alone. However, the accuracy of a diagnosis based solely on history and a physical is highly variable, ranging from 22% to 80%.5 A thorough evaluation of all patients who have genital ulcers should include a serologic test for syphilis. It should also include a diagnostic evaluation for genital herpes by isolation in cell culture or direct fluorescent antibody (DFA) testing for type-specific and nonspecific antibodies to HSV. In settings where chancroid is prevalent, a culture for Haemophilus ducreyi on special culture medium may be performed. However, H. ducreyi culture lacks sensitivity and the special culture medium is not widely available. A presumptive diagnosis of chancroid can be made if 1) the patient has one or more painful genital ulcers, 2) the patient is not RPR-reactive based on a test performed at least seven days after onset of ulcers, 3) the clinical presentation (appearance of genital ulcers and presence of tender, suppurative regional lymphadenopathy) is typical for chancroid, and 4) evaluation for HSV is negative. A diagnosis of syphilis can be made from a positive nontreponemal test (Venereal Disease Research Laboratory [VDRL]) or reactive RPR, confirmed by a treponemal test (serum fluorescent treponemal antibody absorption (FTA-ABS) and MHA-TP. A biopsy of the ulcers may be helpful in identifying the etiologic pathogen if response to initial therapy is poor.4 Finally, the association between GUD and risk for HIV has been shown consistently.12 HIV antibody testing should be included in the evaluation of all patients presenting with GUD.
The risk for acquisition of syphilis from an infected sexual partner has been estimated at about 30%.6 Transmission via blood products is theoretically possible since syphilitic organisms may survive for up to five days in refrigerated blood. However, the risk of transmission from a blood transfusion is negligible due to uniform serologic testing of all blood donors and a shift from transfusion of fresh blood to transfusion of refrigerated blood components.7 Needle sharing does not appear to play a role in syphilis transmission.8
Patients may present for evaluation and treatment of signs/symptoms related to the different stages of syphilis infection: primary, secondary, latent, or tertiary. Primary syphilis is heralded by the appearance of a chancre, usually a single, painless, indurated ulcer with a clean base, and regional lymphadenopathy, on average three weeks after exposure. The physical appearance of these lesions may vary considerably, which makes clinical diagnosis based on visual examination unreliable.9 In men, lesions most commonly appear on the penis, specifically the coronal sulcus and glans. Anorectal chancres are common in men who have sex with men. In women, the lesions usually present on the labia majora, labia minora, fourchette, and perineum.
The onset of secondary syphilis typically occurs within a few weeks of primary chancre resolution. Manifestations are protean, ranging from a rash to central nervous system (CNS) involvement. The cutaneous lesions of secondary syphilis may easily be mistaken for other dermatologic conditions. Rashes can range from macular to maculopapular, follicular, and occasionally pustular. A rash due to secondary syphilis tends to be universally distributed and nonpruritic, commonly involving the palms and soles. Some patients may experience various degrees of pruritus.10 In untreated patients, the lesions resolve over several weeks and may heal with scarring or abnormal pigmentation. Other clinical manifestations of secondary syphilis include low-grade fever, malaise, lymphadenopathy (painless and most commonly involving the suboccipital, cervical, posterior auricular, and epitrochlear nodes), mucosal lesions (mucous patch involving the tongue, buccal mucosa, and lips), condyloma lata, alopecia ("moth-eaten appearance"), meningitis, ocular involvement and headaches.
Latent syphilis is defined as the period from the disappearance of the secondary manifestations until either a therapeutic cure occurs or tertiary manifestations develop.8 Latent syphilis is arbitrarily divided into early phase (from the onset of infection to less than one year) and late phase (more than one year after infection). The length of time for latent syphilis varies from person to person.
Tertiary syphilis may involve the skin, bones, CNS, cardiovascular system, and great vessels. The five major categories of CNS syphilis include 1) asymptomatic (presence of cerebral spinal fluid [CSF] abnormalities in the absence of neurologic symptoms or signs), 2) meningeal, 3) meningovascular (diffuse encephalitic presentation with superimposed focal signs), 4) parenchymatous (rare since modern antibiotic era; may present as paresis or tabes dorsalis), and 5) gummatous (rare). In patients who are co-infected with HIV the natural history of syphilis may be altered significantly, resulting in an overlap of syphilitic stages, making delineation of stages on clinical grounds exceedingly difficult.11 This is rare in non-HIV infected persons.
For primary and secondary syphilis, parenteral benzathine penicillin G has been the treatment of choice for 50 years and is key for achieving clinical resolution, preventing sexual transmission and preventing late sequelae. The recommended dose is 2.4 million units intramuscularly, in a single dose. In non-pregnant patients who are penicillin-allergic and who have primary or secondary syphilis, either doxycycline 100 mg orally twice daily for 14 days or tetracycline 500 mg four times daily for 14 days are the accepted alternative regimens. Pregnant patients or patients with penicillin allergy whose adherence to therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin. Follow-up should consist of a clinical reexamination and serological testing at six months and 12 months following treatment. HIV co-infected patients should be evaluated at three-month intervals instead of six-month intervals. Nontreponemal test antibody titers (quantitative RPR or VDRL) are better correlates of disease activity than are treponemal tests.
Failure of nontreponemal test titers to decline fourfold within six months after therapy for primary or secondary syphilis, or signs/symptoms that persist or recur are indicative of probable treatment failure. Patients who fail to respond should be reevaluated for HIV infection. Other reasons for a lack of therapeutic response that should be considered include re-infection with T. pallidum and unrecognized CNS infection; however, re-infection usually cannot be reliably distinguished from treatment failure. To rule out possible CNS infection, CSF analysis is generally recommended. Patients who fail to respond should be re-treated with benzathine penicillin G 2.4 million units intramuscularly given weekly on three doses if CSF analysis for CNS infection is negative. In rare situations where serologic titers do not decline despite a negative CSF examination and a repeated course of therapy, no additional treatment or repeat CSF examinations are warranted.
For early latent syphilis, benzathine penicillin G 2.4 million units intramuscularly in a single dose is recommended. For late latent syphilis or latent syphilis of unknown duration, benzathine penicillin G 2.4 million units intramuscularly weekly for three weeks is recommended. For non-pregnant, penicillin-allergic patients presenting with early latent syphilis, either doxycycline (100mg orally twice daily for 14 days) or tetracycline (500mg orally four times daily for 14 days) are acceptable alternative regimens. For non-pregnant, penicillin-allergic patients presenting with late latent syphilis or latent syphilis of unknown duration, doxycycline 100mg orally twice daily or tetracycline 500mg orally four times daily, either to be given for 28 days, are acceptable alternative therapies, in conjunction with close serologic and clinical follow-up. An important caveat to the use of these alternative therapies is that the efficacy of these regimens in HIV-infected patients has not been studied and should be used with caution. Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin.
Follow-up should include serial quantitative nontreponemal serologic tests repeated at six, 12, and 24 months. Persons with HIV should be monitored more frequently (six, 12, 18, and 24 months after therapy). Patients who fail to respond (i.e., titers increase four-fold, or an initially high titer of = 1:32 fails to decline at least fourfold within 12-24 months of therapy, or signs/symptoms consistent with syphilis develop) and whose CSF analysis to rule out unrecognized CNS infection is normal, should be re-treated for latent syphilis. Patients with HIV infection or patients who fail to respond should be managed in consultation with an infectious diseases specialist.
Key public health strategies that will help prevent and control the transmission of syphilis, HIV, and other STDs in correctional settings include educating inmates about STDs and routine screening for STDs. Most public health departments require reporting of some types of STDs; make sure your correctional facility complies with the reporting rules of your local and state health departments. Partner notification with evaluation, treatment, and follow-up are also essential to limiting the transmission of syphilis and other sexually transmitted infections. The time frames for partner notification for primary, secondary, and early latent syphilis are three, six, and 12 months, respectively, before the development of symptoms in the index case. All sexual contacts of patients with late latent syphilis should be evaluated.8
Incarcerated persons are at high risk for STDs. Even the most astute clinician may find it challenging to correctly diagnose genital ulcer disease based on medical history and physical examination alone. Appropriate serologic and microbiologic tests should always be performed to determine whether the cause of GUD is infectious and to improve diagnostic accuracy. A thorough work-up of genital ulcer disease should always include HIV screening. Once the diagnosis has been determined it is important to begin treatment promptly and to schedule the patient for follow-up. This will prevent sexual transmission and late sequelae, and ensure an adequate response to therapy. In the event of treatment failure, HIV status should be re-evaluated.
Case presentation by Stephen Tabet, M.D., M.P.H., Assistant Professor of Medicine, University of Washington, and Director, Northwest Correctional Medicine Education Program. Case discussion by Kinji Hawthorne, M.D., Senior Infectious Diseases Fellow, University of Washington School of Medicine. A collaboration with the Northwest AIDS Education and Training Center, with Stephen Tabet, M.D., and Kate Willner, trainer. They have nothing to disclose.
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