Primary syphilis is manifested by one or more chancres (painless indurated ulcers) at the site of inoculation, typically the genitalia, anus, or mouth. It is often accompanied by regional lymphadenopathy.

Secondary syphilis occurs 3 to 6 weeks after the appearance of the chancre, often after the chancre has resolved. The secondary stage is characterized by a polymorphic rash, most commonly maculopapular, generalized, and involving the palms and soles. Sore throat, fever, headache, diffuse lymphadenopathy, myalgias, arthralgias, alopecia, condylomata lata, and mucous membrane plaques may also be present. The symptoms resolve without treatment. Some patients develop recurrences of the manifestations of secondary syphilis.

Latent syphilis is defined as those periods of time with no clinical symptoms but with positive serologic evidence of infection. A variable latent period usually follows the manifestations of secondary syphilis, sometimes interrupted by recurrences of the secondary symptoms.

Tertiary syphilis usually occurs 4 to 12 years after the secondary stage and is characterized by gummata—nonprogressive, localized lesions that may occur in the skin, bones, or viscera. These lesions are thought to be due to a pronounced immunologic reaction. The tertiary stage can also be marked by cardiovascular syphilis, especially inflammation of the great vessels.

Neurosyphilis may occur at any stage of the disease. Early manifestations include meningitis and neurovascular disease. Late manifestations include dementia, posterior column disease (tabes dorsalis), and seizures, among others.

Nontreponemal tests include the rapid plasma reagin (RPR) test, the Venereal Disease Research Laboratory (VDRL) test, and the automated reagin test (ART). These tests measure antibodies directed against a cardiolipin-lecithincholesterol antigen from T. pallidum and/or its interaction with host tissues. These antibodies give quantitative results, are helpful indicators of disease activity, and are useful for follow-up after treatment. Titers usually rise with each new infection and fall after effective treatment. A sustained fourfold decrease in titer of the nontreponemal test with treatment demonstrates adequate therapy; a similar increase after treatment suggests reinfection.

Nontreponemal tests will be positive in approximately 75% of cases of primary syphilis, nearly 100% of cases of secondary syphilis, and 75% of cases of latent and tertiary syphilis. In secondary syphilis, the RPR or VDRL test result is usually positive in a titer > 1:16. In the first attack of primary syphilis,
the RPR or VDRL test will usually become nonreactive 1 year after treatment, whereas in secondary syphilis, the test will usually become nonreactive approximately 2 years after treatment. In latent or tertiary syphilis, the RPR or VDRL test may become nonreactive 4 or 5 years after treatment or may never turn completely nonreactive. A notable cause of false-negative nontreponemal tests is the prozone phenomenon, a negative or weakly positive reaction that occurs with very high antibody concentrations. In this case, dilution of the serum will result in a positive test.

In 1% of cases, a positive RPR or VDRL result is not caused by syphilis. This has been called a biologic falsepositive (BFP) reaction and is probably related to tissue damage from various causes. Acute BFPs, which usually resolve in approximately 6 months, may be caused by certain viral infections (particularly infectious mononucleosis, hepatitis, measles, and varicella), endocarditis, intravenous drug abuse, and mycoplasma or protozoa infections. Rarely, BFPs are seen as a result of pregnancy alone. Patients with BFPs usually have low titers (1:8 or less) and nonreactive treponemal tests. Chronic BFPs may be seen in chronic hepatitis, cirrhosis, tuberculosis, extreme old age, malignancy (if associated with excess gamma globulin), connective tissue disease, or autoimmune disease. Patients with systemic lupus erythematosus may have a positive RPR or VDRL test result. The titer is usually 1:8 or less.

Treponemal tests include the fluorescent treponemal antibody absorption test (FTA-ABS) and the T. pallidum particle agglutination (TP-PA) test. Although these tests are more specific than nontreponemal tests, they are also more expensive and labor-intensive and are therefore not used for screening. Rather, they are used to confirm positive nontreponemal tests. The treponemal tests correlate poorly with disease activity and usually remain positive for life, even after successful therapy, and therefore should not be used to assess treatment response.

False-positive treponemal tests occur occasionally, particularly in other spirochetal diseases such as Lyme disease, yaws, pinta, leptospirosis, and ratbite fever; nontreponemal tests should be negative in these situations. In addition, in some cases where antibodies to DNA are present, such as in systemic lupus erythematosus, rheumatoid arthritis, polyarteritis, and other autoimmune diseases, a false-positive FTA-ABS test result may occur. Rarely, pregnancy itself will cause a false-positive treponemal test.