How Syphilis Is Diagnosed

Syphilis is caused by the bacterium Treponema pallidum. The disease is typically diagnosed with blood tests that detect proteins, called antibodies, which are produced by the body in response to the infection.

Once you are infected, the antibodies for T. pallidum will remain in your blood for years. Often, lab analysis can provide clues as to whether an infection is new or one that occurred in the past.

In addition to tests performed at a clinic, your doctor's office, or pharmacy, there are a number of self-testing kits that allow you to test from the comfort of your home.

Self-Checks/At-Home Testing

One of the major barriers to STD screening is the discomfort or embarrassment that some experience when faced with having to ask a doctor for a test. For this reason, people will often avoid testing for years and even decades until the infection suddenly turns serious.

However, you can use a home-based STD kit, which a number of public health authorities have endorsed. These options help people overcome barriers to testing. 

Among the types available (and their pros and cons):

• Rapid syphilis test kits look like pregnancy tests and require a couple of drops of blood to make the diagnosis, which can often be done in as little as 15 minutes. While convenient, they can be expensive, prone to inaccuracy and user error, and not permitted in some states.
• Mail-in testing kits take this to the next level. You register online, providing medical details in advance of testing. A needle-prick blood test is then mailed to you, which you take and then send to a designated lab for analyzing. The results, which you retrieve online within two to five business days, tend to be far more accurate than those of tests you do completely on your own.

Ensure the one you choose meets the standards of the Clinical Laboratories Improvement Amendment (CLIA) and that the tests have been submitted to and approved by the U.S. Food and Drug Administration (FDA).

Labs and Tests

Because T. pallidum is too fragile to be cultured, the disease needs to be diagnosed in one of two ways: indirect detection of the infection or direct detection of the organism.

Standard Blood Tests

The indirect method, using a combination of clinician-performed blood tests, is the preferred method of testing. It involves two different classes of tests performed one after the next:

• Non-Treponemal Tests: The diagnosis typically starts with two non-treponemal blood tests called the venereal disease research laboratory (VDRL) test and the rapid plasma reagin (RPR). Both detect antibodies to the cardiolipin-cholesterol-lecithin antigen, which is produced in response to damage caused by syphilis bacteria. However, these antibodies are also produced in the context of other diseases, such as lupus and Lyme disease. While the tests are sensitive, inexpensive, and easy to use, their non-specificity makes them prone to false-positive results. As such, the results need to be confirmed with more specific, albeit costlier, treponemal tests.
• Treponemal Tests: If the non-treponemal tests are positive, the results would then be confirmed by one of several treponemal tests. Treponemal tests detect T. pallidum antibodies produced in response to the bacteria itself. While specific, they are unable to distinguish between past or current infection. It is for this reason that the tests must be used together to make a diagnosis. Treponemal test options include fluorescent treponemal antibody absorption (FTA-ABS), T. pallidum particle agglutination assay (TP-PA), enzyme immunoassays (EIA), and chemiluminescence immunoassays (CIA).

Results of a treponemal test are reported as reactive or nonreactive. Reactivity to a treponemal test implies infection but cannot reveal when the infection occurred. To determine this, the lab will compare blood test results—including the level (titer) of antibodies found in the blood—to establish the stage of infection and appropriate course of treatment.

Reverse Screening

This sequence of blood tests—non-treponemal first, treponemal second—is considered the classic way of making a diagnosis. In some cases, however, the process may be flipped so that the treponemal test is performed first and the non-treponemal tests are performed second.

Known a reverse sequence screening, this has both advantages and disadvantages. On the positive front, it is more likely to detect very early- and late-stage infections.

On the negative side, reverse screening may trigger a reactive result even if the person has been previously treated. False-reactive results can lead to unnecessary duplication of treatment.

While reverse screening has its place, the standard sequence of testing is still recommended in most cases.

Dark-Field Microscopy

Dark-field microscopy is a direct method of testing less commonly used today as it requires highly skilled technicians. It is performed by taking a sample of body fluid (either from a chancre sore or spinal tap) and looking at it under a microscope for visual evidence of the bacteria.

The test can also be performed on tissue samples or nasal mucus.

Newborns

Congenital syphilis occurs when the infection is passed from mother to child during pregnancy. Newborns with syphilis will often have no symptoms of the disease and may only develop them in the second year of life.

Diagnosis in newborns can be difficult since the mother's antibodies are circulating in the baby's blood for the first 12 to 18 months of life. During this time, doctors are unable to discern antibodies that originated from the mother or belong to the baby (meaning the baby is infected).

Dark-field microscopy may provide direct evidence of the infection.

Differential Diagnoses

Because syphilis mimics so many other diseases and often requires extensive interpretation of blood test results, extra effort needs to be made to ensure the diagnosis is correct.

This requires an extensive differential diagnosis, particularly during tertiary syphilis when symptoms can be so varied and severe.

Clinicians will test for syphilis, as well as chlamydia, gonorrhea, trichomoniasis, bacterial vaginosis, and HIV using an extensive panel of STD tests. 

Other lab and imaging tests may also be ordered to exclude other possible causes. Among the many possible investigations:

• Primary syphilis: candidiasis, cystitis, herpes simplex virus, granuloma inguinale, urethritis, other STDs
• Secondary syphilis: HIV, Kawasaki disease, mononucleosis, pityriasis rosea, Rocky Mountain spotted fever, scarlet fever
• Tertiary syphilis: a brain tumor, carcinoma, congestive heart failure, meningococcemia, mental illness, multiple sclerosis, stroke

Screening Recommendations

You should never use the absence of symptoms as the reason not to get tested. Because syphilis symptoms are often generalized and non-specific, they can be easily missed or mistaken for other diseases.

This includes men who have sex with men (MSM), persons with multiple sex partners, injecting drugs users, and people who engage in unprotected sex.