IDCM Issue 6: Syphilis: The Great Masquerader

Post Date: 
Natasha Chida, MD, MSPH

Why should I care about syphilis?


Syphilis (caused by the organism Treponema pallidum) is still prevalent across the globe; the WHO estimates annually there are 5.6 incident cases of syphilis worldwide and 305,000 deaths due to congenital syphilis.1,2In addition, the rates of primary and secondary syphilis in the United States (US) have been increasing; in 2014 there were 6.3 cases/100,000 of primary and secondary syphilis, the highest rate reported since 1994.3 The epidemic in the US has been driven primarily by increasing cases among men who have sex with men (MSM), but the heterosexual population has been affected as well. Among US women, the rate of primary and secondary syphilis rose 22% between 2012-2014, which coincided with an increase cases of congenital syphilis by 38% (from 8.4 to 11.6 cases per 100,000 live births).4 Incident syphilis infection has been associated with a significantly increased risk of HIV acquisition.5


Syphilis Stages and Symptoms 35-6


Average incubation period



2-4 weeks

Chancre; heals spontaneously in 4-5 weeks


6-12 weeks

  • Rash is resenting complaint in 70% and found in up to 90%.  Involves palms/soles 50-80% of the time

  • Systemic symptoms: Fever, malaise, generalized lymphadenopathy, etc

  • Infectious lesions: condyloma lata and mucous patches

  • Any organ system can be affected. Hepatitis, glomerulonephritis, periostitis, arthritis and alopecia have all been reported

  • Spontaneous improvement in 3-6 weeks, but 25% relapse with symptoms (usually within the first year)



  • Cardiovascular; occurring in large vessels or myocardium

  • Gummatous syphilis (granulomas)

  • Neurosyphilis:* Tabes dorsalis and general paresis



Asymptomatic with positive serology

  • Split into “early latent” (infection acquired within one year) and “late latent (infection acquired more than a year ago or unknown acquisition). Untreated, approximately a third will develop tertiary syphilis

*Neurosyphilis as well as ocular syphilis can occur at any stage. Generally cranial nerve disease, meningitis, and meningovascular disease including stroke occur in early infection, while tabes dorsalis and general paresis occur later—many years after infection.3


How do I diagnose syphilis?


Treponema pallidum
 cannot be cultured; therefore, the diagnosis generally relies upon serologic tests, which detect antibodies to the disease and are categorized as either “treponemal” or “non-treponemal.” Importantly, serologies will be negative in up to 30% of cases of patients with primary syphilis.7

Treponemal tests: These tests can take 3-6 weeks to turn positive, and are unable to distinguish between active and latent infection.5,8 They usually remain positive for life, although studies show 15%–25% of patients treated during the primary stage are serologically nonreactive after 2–3 years.Multiple treponemal tests exist:8

  • Enzyme-linked immunosorbent assays (EIAs): Automated tests that allow for screening large numbers of people, confer lower costs. Examples: IgG-ELISA, IgM-EIA, and immune-capture EIA

  • Immunochemoluminescence assays (CLIA): Automated, but less widely available

  • Fluorescent treponemal antibody absorption assays (FTA-ABS)

  • Microhemagglutination assay for T.pallidum (MHA-TP)

  • T. pallidum particle agglutination (TPPA)

  • T. pallidum hemagglutination assay (TPHA)


The most sensitive tests in primary disease are the IgG-ELISA (100%) and the CLIA (98%).8Other than the IgM-EIA, the treponemal tests generally have similar performance characteristics in secondary and latent disease (94-100%), and similar specificities (96-99%).8

Non-treponemal tests: The two most widely used non-treponemal tests are the rapid plasma reagin (RPR) and the Venereal Disease Research Laboratory test (VDRL), both of which take 3-6 weeks to turn positive. They are 78-86% sensitive in primary disease, 100% sensitive in secondary disease, and 71-98% sensitive in latent disease; they are 98-99% specific.6,8 False positives can occur (rate of 1-2%) due to viral infections, malignancy, pregnancy, autoimmune diseases, age, etc.3,6,8

Unlike the treponemal tests, the non-treponemal tests report titers. The tests are repeated 6 months and 12 months after treatment; if the titers don’t fall four-fold by 12 months, it may indicate treatment failure, although 15-20% of persons may not achieve this decline.3It is unclear how to manage these persons; they should at least be evaluated for HIV infection and have close follow up. Retreatment can also be considered. In addition, as treatment failure can occur due to previously unrecognized neurosyphilis a CSF evaluation may be performed.

Other tests: Direct visualization of the spirochete via darkfield microscopy of genital secretions in primary/secondary syphilis provides a definitive diagnosis. However, this requires expertise and special equipment. PCRs exist but are not widely available.5  There are also more than 20 rapid tests available world-wide, but only one, called the “Syphilis Health Check” has been FDA approved. This test detects antibodies to T. pallidum on whole blood, serum, or plasma; the manufacturer reports 98% agreement with other treponemal tests. A positive result should be followed by a non-treponemal test.9


How do I utilize syphilis diagnostics? 


Traditionally, screening began with a non-treponemal test, and if positive, a treponemal test was performed for confirmation (given non-treponemal tests have higher false positive rates). However, the automation of EIA tests has now made EIAs less expensive for large-volume laboratories to perform. Therefore, many laboratories have implemented a “reverse sequence” algorithm in which a treponemal test is performed first. If this is positive, a non-treponemal test is obtained to distinguish between latent versus active disease.3

How do I interpret syphilis diagnostics? If a treponemal test is positive but a follow-up non-treponemal test is negative, a different treponemal test should be obtained as a “tie breaker.” If positive, the first positive treponemal test is confirmed.3 If one starts with the non-treponemal test and it is negative, no further testing is obtained unless there is high suspicion for the disease (active or latent).


Treponemal test

Non-treponemal test




Active syphilis infection 


Previously treated syphilis


Very early primary syphilis


False positive non-treponemal test






False positive treponemal test


Lab error


Early primary syphilis


Prozone reaction


Late untreated syphilis with seroreversion


Treated syphilis


Special Considerations:

Neurosyphilis: To diagnose neurosyphilis, a lumbar puncture must be performed. No test is definitive; a combination of the cell count, protein, and a VDRL are usually used. If there is high suspicion and a CSF VDRL is negative a FTA-ABS can be obtained, as the CSF VDRL is highly specific but only 30-70% sensitive.3 Conversely, a CSF FTA-ABS is highly sensitive but not specific.

Ocular Syphilis: Recently, there has been an increase in reported cases of ocular syphilis in the US, with more than 200 cases reported during the past 2 years. As a result, in October 2015 the CDC released a clinical advisory warning providers to screen for visual complaints in any patient at risk for syphilis.10 Ocular syphilis is considered a subset of neurosyphilis and should be managed as such. Ocular syphilis can occur at any stage of syphilis infection and can involve any portion of the eye. Given the recent rise in reported cases, clinicians should be careful to ask about eye symptoms in evaluating any patient suspected to have syphilis. They should also note that a CSF examination can be negative in ocular syphilis.


Bottom Line:  Syphilis continues to be an important health problem globally. Use treponemal and non-treponemal tests for diagnosis.

This ID Clinical Minute was written with Susan Tuddenham, MD, MPH. Additionally, we thank Dr. Khalil Ghanem for his thoughtful review.



  1. World Health Organization.  Accessed 2016-06-22.

  2. World Health Organization.

  3. Centers for Disease Control and Prevention. Accessed 2016-06-22.

  4. Bowen V, Su J, Torrone E, Kidd S, Weinstock H. Increase in incidence of congenital syphilis - United States, 2012-2014. MMWR Morb Mortal Wkly Rep. 2015;64(44):1241-5. PMID 26562206

  5. French P. Syphilis. BMJ. 2007;334(7585):143-7. PMID 17235095

  6. Golden MR1, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA. 2003;290(11):1510-4. PMID 13129993

  7. Huber TW, Storms S, Young P, Phillips LE, Rogers TE, Moore DG, Williams RP. Reactivity of microhemagglutination, fluorescent treponemal antibody absorption, Venereal Disease Research Laboratory, and rapid plasma reagin tests in primary syphilis. J Clin Microbiol. 1983;17(3):405-9. PMID 6341398

  8. Seña AC1, White BL, Sparling PF. Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century. Clin Infect Dis. 2010;51(6):700-8. PMID 20687840

  9. Peterman TA, Fakile YF. What Is the Use of Rapid Syphilis Tests in the United States? Sex Transm Dis. 2016;43(3):201-3. PMID 26859809

  10. Tuddenham S, Ghanem KG. Ocular syphilis: opportunities to address important unanswered questions. Sex Transm Infect. 2016. pii: sextrans-2016-052570. PMID 27116973.



The Johns Hopkins Center for Clinical Global Health Education is a clinical research, education, and leadership development center in the Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine. We conduct clinical research, and we train, support, and empower healthcare providers and researchers working in resource-limited communities who share our commitment to improve health outcomes.