Syphilis Diagnostics: Then and Now

In the early days, syphilis was often diagnosed through physical examination and the observation of characteristic symptoms such as chancres (sores) and rashes. However, due to the disease's ability to mimic other conditions, these symptoms could be confused with other diseases, leading to misdiagnosis. The introduction of the Wassermann test in 1906, a blood test that detects antibodies produced in response to Treponema pallidum, marked a significant advancement in syphilis diagnostics.¹

Diagnosing syphilis has evolved significantly over the centuries. While microbiology has played an important role in diagnosing many infectious diseases, T. pallidum is notoriously fastidious and difficult to culture. As such, after identification of the spirochete, syphilis was diagnosed using microscopy.²

Today, syphilis diagnosis involves a combination of serologic tests and direct detection methods. The most common tests include:

1. Nontreponemal Tests: These tests, such as the Rapid Plasma Reagin (RPR) and Venereal Disease Research Laboratory (VDRL) tests, are screening tests that detect antibodies against nonspecific antigens produced during syphilis infection. The antibodies are not specifically directed against T. pallidum but are produced in response to cellular damage caused by the infection.²

1. RPR: Looks for the reagin antibodies—an antibodies produced by the body in response to syphilis infection. Performed on blood samples.
2. VDRL: Measures antibodies produced within a few weeks after chancre formation. Usually performed on blood but can be performed cerebral spinal fluid when there is suspicion of neurosyphilis.

2. Treponemal Tests: Nontreponemal tests require confirmation with a treponemal test. These tests detect antibodies that specifically target T. pallidum. Historically, these tests were run after the nontreponemal test but given turnaround time and high sensitivity of currently available syphilis tests, treponemal tests can detect the bacteria before nontreponemal tests are reactive. As a result, treponemal tests are now run prior to running nontreponemal tests or microscopy testing.²

3. Direct Detection Methods: In cases where chancres or lesions are present, direct detection methods such as dark-field microscopy can be used to identify T. pallidum directly from the lesion. Unfortunately, these tests take time and require a trained microscopist and a specialized microscope (dark field), limiting its accuracy and availability.³

Who should be tested?

Of course, anyone who has symptoms of syphilis or has had sex with someone who tested positive for syphilis should be tested, and those with multiple partners should be tested every three to six months.⁴ Among others who should be tested:

HIV positive individuals
HIV-positive individuals should be tested for syphilis annually due to the increased risk of co-infection and the potential for more severe health complications.⁵ Syphilis can progress more rapidly and be harder to treat in individuals with HIV, especially if their HIV is not well-managed. Additionally, having syphilis can make it easier for HIV to be transmitted to others, as chancres provide an entry point for the virus. Regular testing ensures early detection and treatment, which can prevent the progression of syphilis and reduce the risk of transmitting both infections.^4,5

Drugs-of-abuse users
The intersection of drug use and syphilis transmission has become a growing public health concern. Studies have shown that the rates of syphilis and other STIs have risen sharply among people who use drugs.⁶ People who use illegal drugs should be tested for syphilis as a matter of course due to the high-risk behaviors often associated with drug use. Individuals who use drugs, particularly methamphetamine and heroin, are more likely to engage in unsafe sexual practices, such as having multiple partners or exchanging sex for drugs or money.⁶

Men who have sex with women
Any man who is at increased risk (e.g., men with a history of incarceration), even if asymptomatic, should be tested—especially those under the age of 29.⁴ If positive, the partner should also be tested.

Men who have sex with men
All men engaging in sexual activity with other men should be tested annually, regardless of condom use⁴—similar to men who have sex with women, especially those under age 29. If positive, the partner should also be tested.

Pregnant women
Testing pregnant women for syphilis is essential to prevent congenital syphilis, a severe and potentially life-threatening condition for newborns. Syphilis can be transmitted from an infected mother to her baby during pregnancy, leading to complications such as stillbirth, premature birth, or severe health issues in the infant, including deformities, neurological problems, and organ damage.^7,8 The rates of congenital syphilis have been rising—increasing 755% between 2012 and 2021—making it a significant public health concern.⁹

All pregnant individuals should be screened at the first prenatal care visit, during the third trimester, and at birth to ensure that no cases are missed.^4,9 This comprehensive approach will help to protect the health of both the mother and the baby, ensuring better pregnancy outcomes and reducing the burden of congenital syphilis on the healthcare system.⁹

Neurosyphilis
One of the most fascinating and tragic aspects of syphilis is its potential to affect the central nervous system, leading to neurosyphilis. Neurosyphilis can occur at any stage of the infection and can manifest as a wide range of neurological and psychiatric symptoms, including altered mental states.

Historically, when individuals presented with altered mental status that couldn’t be explained, syphilis testing was considered due to the possibility of neurosyphilis, a serious complication of syphilis that can affect the brain and nervous system.¹⁰ “In the 19^th century, neurosyphilis was the most frequent cause of dementia in Western Europe.”¹⁰ And while the introduction of penicillin has significantly decreased the presence of syphilis-induced dementia,^10,11 neurosyphilis is “still present causing many types of neuropsychiatric syndromes, from schizophreniform psychotic syndrome to dementia mimicking Alzheimer’s disease.”¹¹

As syphilis affects almost every body part, optimal syphilis diagnosis and disease management requires a team of professionals.¹² Addressing syphilis testing and monitoring requires a collaborative approach between substance use disorder programs and sexually transmitted disease control programs. By integrating syphilis testing into routine care for at-risk individuals, healthcare providers can better manage and mitigate the spread of the infection, ultimately improving public health outcomes.