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Pathogen:
Treponema pallidum, a spirochetal bacterium.
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Sites of Infection:
Soon after initial infection, the organism enters the lymphatic system and/or blood stream and disseminates throughout the body. Nearly all organs can be invaded, including the central nervous system.
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Symptoms:
Primary syphilis is characterized by a painless chancre sore or lesion) at the site of inoculation in the genital tract. This chancre does not always develop, however, and multiple chancres are also possible which heal within 3-6 weeks. Lymphadenopathy accompanies the chancre. The principal manifestation of secondary syphilis which typically begins to occur as the primary canchre is starting to heal, is a diffused rash, condyloma lata, lymphadenopathy, and various constitutional symptoms such as fever. It should be noted that neurosyphilis can occur at any stage of syphilis; syphilitic meningitis and meningovascular syphilis occur early (months to a few years after infection) and general paresis and tabes dorsalis occur later (5-30 years after infection). In addition to neurosyphilis, late syphilis can affect almost any organ through gummatous lesions and cardiovascular involvement. Johns et al. hypothesize that co-incident HIV infection accelerates the course of syphilis, and Flood et al. report that symptomatic early neurosyphilis may be more common in HIV-infected people.
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Diagnosis:
In early syphilis, dark field examination of exudate from lesions and direct florescent antibody tests on lesions or tissue are definitive. Non-specific serologic tests are useful for syphilis screening and for monitoring response to treatment. Specific serologic tests are used for establishing the diagnosis. They usually remain positive for life and therefore cannot be used to monitor response to treatment. CSF examination is necessary for diagnosis of neurosyphilis.
In HIV-infected individuals, false-positive serological tests despite adequate therapy are possible due to polyclonal B-cell activation or auto-immune processes. Conversely, but extremely rarely, false-negative serological tests have been reported. Extraordinary means (such as direct examination of lesion material) may be necessary to establish the diagnosis in these unusual cases.
Gordon et al. have concluded that cerebrospinal fluid (CSF) PCR is not a sensitive test for neurosyphilis in HIV-infected patients. Despite clinical improvements reported in a trial of intravenous penicillin G, CSF VDRL levels measured by PCR remained high in all patients examined.
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Treatment Results:
Standard treatment for early syphilis is parenteral penicillin (benzathine penicillin G). However, prospective studies to establish the most effective drugs and dosages have not been conducted. CDC recommends a single dose of 2.4 million units of benzathine penicillin G administered intramuscularly for both HIV-negative and HIV-infected patients. Musher et al. propose higher doses (three 2.4 million unit doses at weekly intervals) in order to prevent possible relapse to neurosyphilis. While ceftriaxone (500 mg or 1g IM qd for10 days) may be an effective alternative regimen, it has not been adequately evaluated. In the penicillin-allergic HIV-positive patients with early syphilis, some clinicians use doxycycline as an alternative to desensitization or ceftriaxone.
CDC guidelines recommend 7.2 million units of benzathine penicillin given in three weekly doses IM for late latent syphilis of more than one year's duration with no CSF evidence of neurosyphilis.
CDC guidelines for neurosyphilis recommend aqueous crystalline penicillin G potassium 2 to 4 million units IV every four hours for 10 to 14 days (total dose 12-24 million units). Alternative regimens include procaine penicillin 2 to 4 million units IM daily plus probenecid 500 mg IM four times daily for10 to14 days.
A study of 11 HIV-positive patients with symptomatic neurosyphilis receiving aqueous crystalline penicillin G potassium (18-24 million units daily for 10 days) concluded that HIV infection may affect both the natural course of syphilis and the response to treatment (Gordon et al.). At 24 weeks after treatment, serum titers on rapid plasma reagin (RPR) of four patients decreased by at least two doubling dilutions, and four patients had reductions in the cerebrospinal fluid filters. In two patients, there was no normalization or improvement in serum titers, and one patient relapsed with meningovascular syphilis six months after therapy.
Gourevitch et al. conducted a cohort study of 50 intravenous drug users with syphilis. 31 were HIV-positive and 19 were HIV-negative. HIV infection did not alter the response to treatment. Most patients had late latent syphilis at presentation (15/31 and 13/19 patients in the HIV-positive and HIV-negative groups, respectively). Follow-up was adequate to assess treatment outcomes in 43 patients (26 HIV-positive and 17 HIV-negative). A variety of treatment regimens were used. Among the evaluable HIV-positive patients, 12 received the standard CDC-recommended regimen of penicillin and14 received other therapy (either high doses of penicillin or non-penicillin regimens). All responded adequately to therapy. Among the HIV-negative subjects, 9 received standard therapy and 8 received other therapy. One patient (who received two weeks of tetracycline) did not respond adequately.
Dowell et al. retrospectively compared ceftriaxone (1-2 g/day for 10-14 days) and benzathine penicillin (2.4 million units weekly for three weeks) for late latent syphilis or asymptomatic neurosyphilis in HIV-infected patients. 28/44 ceftriaxone recipients and 8/13 benzathine-penicillin recipients responded to treatment. The investigators concluded that ceftriaxone and benzathine penicillin appear equivalent for patients with normal CSF.
Trials are underway comparing IV ceftriaxone and IV penicillin G for neurosyphilis, and alternate penicillin regimens for syphilis.
REFERENCES:
Dowell ME et al. Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus. Amer J Med 93:481-8,1992.
Flood JM et al. Neurosyphilis in San Francisco during the AIDS epidemic, 1985-1989. 3lst ICAAC, abstract 334, 1991.
Gordon SM et al. The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection. NEJM 331:1469-1473, 1994.
Gourevitch MN et al. Effects of HIV infection on the serologic manifestations and response to treatment of syphilis in intravenous drug users. Ann Int Med118:350-5. 1993.
Johns DR et al. Alteration in the natural history of neurosyphilis by concurrent infection with the human Immunodeficiency virus. NEJM 316: 1569-72,1987.
Musher DM et al. Effect of HIV infection on the course of syphilis and on the response to treatment. Ann Int Med 113: 872-881, 1990.
Johnson PDR et al. Specific syphilis serological tests may become negative in HIV infection. AIDS 5:419-23, 1991.
Matlow AG et al. Syphilis serology in HIV-infected patients with symptomatic neurosyphilis case report and review. Rev Infect Dis12: 703-7, 1990.
Musher DM et al. Neurosyphilis in HIV-infected persons. NEJM 331:1516-1517,1994.
Pope V et al. Effect of syphilis and HIV coinfection on expression of peripheral blood lymphocyte immunophenotypes. Abstract #L8, 34th ICAAC, Orlando, 1994.
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Centers for Disease Control and Prevention. Primary and secondary syphilis among HIV-infected patients. MMWR, 42:RR-14, 27-44,1993.
OTHER REPORTS:
Hook EW and Marr CM. Acquired syphilis in adults (review). NEJM 326: 1060-9, 1992.