Clinical Guide > Comorbidities and Complications > Syphilis


January 2011

Chapter Contents


Syphilis is a sexually transmitted infection (STI) caused by the spirochete Treponema pallidum. It is a complex disease with protean variations that can mimic many common infections or illnesses. HIV infection may alter the natural history and management of syphilis, causing a more rapid course of illness, higher risk of neurologic complications, and potentially greater risk of treatment failure with standard regimens. Because many individuals with syphilis have no symptoms, or have symptoms that subside without treatment, sexually active individuals at risk of syphilis should receive regular screening for syphilis, as well as for other STIs. Many clinicians strongly recommend routine syphilis testing every 3-6 months for patients at risk of syphilis.

There has been a resurgence of syphilis in metropolitan areas of the United States and western Europe. This trend is concerning, because syphilis can have major health consequences if it is undetected and untreated, and because it is associated with increased risk of new HIV infections. Risk assessment should be conducted at each patient visit for unprotected sex (including oral sex), multiple sex partners, and use of recreational drugs (methamphetamine and cocaine, in particular, are associated with high-risk sexual practices among men who have sex with men [MSM]). Asymptomatic persons at risk of acquiring syphilis should be screened at regular intervals (with rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL] testing, as discussed below), depending on their risk factors. MSM with multiple partners should be tested every 3-6 months.

The natural history of untreated syphilis infection is divided into stages based on length of infection.

Primary Syphilis

Primary syphilis usually manifests after an incubation period of 1-3 weeks from exposure and is characterized by a painless self-limiting ulcer (chancre) at the site of sexual contact. HIV-infected individuals may have multiple or atypical chancres that could be misidentified. Some patients have no primary lesion, or have a primary lesion that is not visible. Associated regional lymphadenopathy can occur. HIV-infected individuals sometimes have a chancre concurrently with rash typical of secondary syphilis.

Secondary Syphilis

Secondary syphilis usually develops 2-8 weeks after initial infection and is caused by ongoing replication of the spirochete, with disseminated infection that may involve multiple systems. Rash is the most common presenting symptom; skin lesions may be macular, maculopapular, papular, or pustular, or they may appear as condyloma lata (which may look like the condyloma of papillomavirus). The rash often appears on the trunk and extremities and may involve the palms and soles of feet. Constitutional symptoms, lymphadenopathy, arthralgias, and myalgias are common, and neurologic or other symptoms may occur. In the absence of treatment, the manifestations of secondary syphilis last days to weeks, then usually resolve to the latent stages.

Latent Syphilis

Latent syphilis follows resolution of secondary syphilis. As in HIV-uninfected individuals, latent syphilis is asymptomatic and the diagnosis is determined by positive serologic tests. Latent syphilis is further classified as "early latent" if the infection is known to be <1 year in duration, "late latent" if the infection is known to be >1 year in duration, or "latent syphilis of unknown duration" if the duration of infection is not known.

Late or Tertiary Syphilis

Late or tertiary syphilis is caused by chronic infection with progressive disease in any system causing serious illness and death in untreated patients. The most common manifestations include neurosyphilis, cardiovascular syphilis, and gummatous syphilis.


Neurosyphilis can occur at any time after initial infection, owing to spread of the spirochete to the central nervous system (CNS). In HIV-infected individuals, neurosyphilis may occur more commonly early in the course of infection, during secondary or latent syphilis. It is associated with neurologic symptoms, including cranial nerve abnormalities (particularly extraocular or facial muscle palsies, tinnitus, and hearing loss) or symptoms of meningitis. Uveitis and other eye disease may occur in conjunction with neurosyphilis.

S: Subjective

Symptoms depend on the site of initial infection, the stage of disease, and whether neurosyphilis is present. Symptoms are not present in all patients.

If symptoms are present, the patient may experience the following:

Conduct a targeted history, asking the patient about symptoms listed above, including duration; inquire about other or associated symptoms. Ascertain the following:

O: Objective

Check for fever, document other vital signs.

Perform a complete examination including the following:

A: Assessment

Because syphilis has a wide range of manifestations, the differential diagnosis is broad. It is important to consider syphilis as a possible cause of many presenting illnesses. A partial differential diagnosis includes the following:

P: Plan

Diagnostic Evaluation

Darkfield examination and direct fluorescent antibody

Darkfield examination and direct fluorescent antibody (DFA) testing of a sample from suspicious genital or anal chancres or moist dermatologic lesions (not oral lesions) are definitive tests for syphilis, although these are not available in most clinic settings.

Serologic tests

Nontreponemal tests (RPR or VDRL) are most sensitive in primary and secondary syphilis when titers are high, though the response may be delayed in HIV-infected patients (nontreponemal test results typically are positive within 3 months after infection). Because false-positive results may occur, particularly in the setting of HIV infection, positive nontreponemal test results must be confirmed with a treponemal test. Titers may be used to follow response to treatment; a fourfold change in titer is considered a significant change. Note that the same nontreponemal test should be used consistently for a single patient; RPR titers cannot be compared with VDRL titers.

Treponemal antibody tests (TP-PA [T. pallidum particle agglutination] or FTA-ABS [fluorescent treponemal antibody absorption]) confirm a positive nontreponemal test. As an alternative, many laboratories have begun to use a treponemal test, e.g., an enzyme immunoassay (EIA) as an initial screen for syphilis infection, followed by a nontreponemal test for confirmation, to reduce the workload from the titration required for nontreponemal titers.

A false-negative RPR or VDRL result may occur, usually when the test is performed in early infection, before a sufficient antibody response has developed. Another possible cause of a false-negative nontreponemal result is the prozone phenomenon, seen when antibody concentrations are very high (usually in secondary syphilis) and the specimen is not diluted sufficiently. If serologic test results are negative and suspicion of syphilis is high, perform other diagnostic tests (e.g., biopsy) or request that the laboratory perform additional dilutions on nontreponemal test specimens.

Cerebrospinal fluid evaluation

HIV-infected patients with neurologic or ocular signs or symptoms of syphilis, late latent syphilis, syphilis of unknown duration, or tertiary syphilis should undergo lumbar puncture (LP) and cerebrospinal fluid (CSF) analysis. CSF evaluation also is indicated for patients in whom treatment for early syphilis fails (see below). Routine CSF evaluation is not indicated for HIV-infected patients who have early syphilis without neurologic or ophthalmic signs or symptoms. CSF analysis should include the following:

Other testing

All patients who test positive for syphilis should be tested for gonorrhea and chlamydia, with sampling sites based on sexual practices and exposures (oropharyngeal, urethral, vaginal, or anorectal testing). Patients not known to be HIV infected also should be tested for HIV.


Treatment of syphilis in HIV-infected individuals essentially is the same as in HIV-uninfected individuals, and depends on stage and the presence or absence of neurosyphilis. It is important to follow patients closely to assure the success of treatment. For further information, see the Centers for Disease Control and Prevention (CDC) Sexually Transmitted Diseases Treatment Guidelines (see "References," below).

An RPR or VDRL test should be sent on the day of treatment; the titer will be the reference point for assessing treatment efficacy (see "Follow-Up," below).

Early syphilis

(<1 year in duration [i.e., primary, secondary, and early latent]); nonneurologic)

Late latent syphilis

(>1 year in duration or of unknown duration; no evidence of neurologic disease)

Tertiary syphilis

Consult with specialists.


(syphilis at any stage with neurologic or ocular symptoms or CSF findings of neurosyphilis)

Ideally, patients should be hospitalized and given 2 weeks of penicillin IV under close observation. Penicillin-allergic patients should be referred for desensitization, if possible.

Note that a Jarisch-Herxheimer reaction may occur after initial syphilis treatment, especially in primary, secondary, or even latent syphilis. This self-limited treatment effect should not be confused with an allergic reaction to penicillin. It usually begins 2-8 hours after the first dose of penicillin and consists of fever, chills, arthralgias, malaise, tender lymphadenopathy, and intensification of rash. It resolves within 24 hours and is best treated with rest and acetaminophen. Patients should be warned about the possibility of a Jarisch-Herxheimer reaction.


Pregnant women should be treated with penicillin, if possible, using a regimen appropriate for the stage of infection (see above). Additional treatment may be indicated; consult with a specialist. Penicillin-allergic pregnant women should be referred for desensitization to penicillin. Doxycycline and tetracycline may cause fetal toxicity and should not be used during pregnancy; erythromycin is not sufficiently effective in treating syphilis in the fetus. Azithromycin and erythromycin do not have adequate efficacy in treating pregnant women or their fetuses and should not be used. The efficacy of ceftriaxone during pregnancyhas not been studied adequately.

Women treated during the second half of pregnancy are at risk of contractions, early labor, and fetal distress if they develop a Jarisch-Herxheimer reaction; thus, they should be monitored carefully.

Sex partners

Syphilis is transmitted sexually only when mucocutaneous lesions of syphilis are present; this is uncommon after the first year of infection. Nevertheless, sex partners of a patient who has syphilis in any stage should be evaluated.


All HIV-infected patients treated for syphilis should be evaluated clinically and serologically at 3, 6, 9, 12, and 24 months (at 6, 12, 18, and 24 months for latent syphilis) to rule out treatment failure. Treatment success is determined by a fourfold decrease in RPR or VDRL titer by 6-12 months (for primary and secondary syphilis) or 12-24 months (for latent syphilis) of treatment. Patients whose titers do not decrease appropriately probably either experienced treatment failure or were reinfected. Any patient with apparent treatment failure should undergo an LP for CSF analysis and be re-treated as appropriate. If at any time symptoms develop or nontreponemal test titers increase fourfold, CSF examination should be performed and appropriate treatment should be given.

Some patients retain reactive (low-titer) nontreponemal test results after successful treatment for syphilis. In these "serofast" individuals, reinfection with syphilis is indicated by a rise in test titer of at least fourfold.

Risk-reduction counseling

All patients with syphilis should receive risk evaluation and risk-reduction counseling. Evaluate each patient's sexual practices with regard to risk of acquiring STIs and of transmitting HIV. Work with the patient to reduce sexual risks.

Patient Education


HRSA HAB Core Clinical Performance Measures