Syphilis

Overview
Epidemiology
Pathophysiology
Stages of Infection
Congenital Syphilis
Diagnosis
Treatment
Complications
Prevention
Research Advances
Research Papers
PubMed Research
Connections
Featured Videos

1. Overview

Syphilis is a systemic bacterial infection caused by the spirochete Treponema pallidum. It is transmitted primarily through sexual contact — vaginal, anal, or oral — and can also pass from a pregnant mother to her baby across the placenta, causing congenital syphilis. The disease has a long, stage-based course: it can remain silent for years, quietly damaging the heart, brain, and other organs if left untreated.

The single most important thing to know about syphilis is that it is completely curable. A single injection of penicillin clears early-stage infection in most people. This is not a condition you have to live with forever. Getting tested and treated early protects you, your partners, and — if you are pregnant — your baby.

What makes syphilis particularly tricky is that its early symptoms are easy to miss or dismiss. The first sign is usually a painless sore that heals on its own without treatment — so many people never realize anything is wrong. By the time later symptoms appear, the infection has had months or years to spread. That is why regular screening for people at risk is so valuable: a simple blood test can find the infection even before any symptoms appear.

Syphilis was nearly eliminated in the United States around the year 2000, but rates have surged back dramatically since then. As of 2022, the CDC reported the highest syphilis rates in more than 30 years, making awareness and screening more important than ever.

2. Epidemiology

Syphilis is a global public health problem that had seemed close to being controlled but has returned with force. In the United States, the CDC reported over 600,000 new cases of primary, secondary, and early latent syphilis in 2022, a rate not seen since the early 1990s. Globally, the World Health Organization estimates approximately 7.1 million new syphilis infections occur among adults aged 15–49 each year.

Who is most affected? In the US, men who have sex with men (MSM) carry a disproportionate burden of syphilis, accounting for roughly half of all primary and secondary cases. However, rates among heterosexual men and women have been rising sharply, driving the resurgence in congenital cases. Women of reproductive age are now a critical focus of screening efforts.

The link with HIV is clinically significant. People living with HIV are at elevated risk of syphilis, and people with syphilis are at increased risk of acquiring or transmitting HIV. Genital ulcers from primary syphilis create easy entry and exit points for HIV, and syphilis co-infection can accelerate HIV disease progression.

Congenital syphilis — infection passed from mother to baby — has seen a catastrophic rise. The CDC recorded 3,882 cases of congenital syphilis in 2022, a more than tenfold increase from 2012, with hundreds of infant deaths and stillbirths. This is an entirely preventable tragedy: screening and treating pregnant women eliminates the risk to the baby.

The drivers of the current epidemic include gaps in routine testing, declines in condom use, stigma that keeps people from seeking care, and strained public health infrastructure. Understanding the scope of the problem is the first step toward reversing it.

3. Pathophysiology

Treponema pallidum is a gram-negative spirochete — a thin, corkscrew-shaped bacterium that cannot be grown in standard laboratory culture, which complicates research but not diagnosis or treatment. Understanding how it moves through the body explains why syphilis unfolds in such a slow, stage-by-stage way.

Entry. The spirochete penetrates the body through microscopic breaks in skin or directly through intact mucous membranes in the genitals, mouth, or rectum. This is why syphilis can transmit even without visible sores or broken skin.

Local replication and lymph spread. After entering, T. pallidum multiplies at the entry site, producing the characteristic primary sore (chancre). It simultaneously invades the local lymph nodes, which become enlarged and firm — a sign the immune system has noticed the infection.

Hematogenous dissemination. Within days to weeks of the initial infection, spirochetes enter the bloodstream and spread throughout the body. This is the critical step that transforms syphilis from a local skin infection into a systemic disease. Virtually every organ can be seeded, including the brain and spinal cord (neurosyphilis), the heart and major blood vessels (cardiovascular syphilis), bones, and skin.

Immune evasion. T. pallidum is remarkably skilled at hiding from the immune system. Its outer membrane has very few surface proteins — far fewer than most bacteria — which gives antibodies little to grab onto. The spirochete also coats itself with host proteins to blend in with normal tissue. These mechanisms allow the bacterium to persist for years in an apparently quiet (latent) phase while continuing to cause slow, cumulative damage.

Tissue damage. The body's immune response to the bacterium — an inflammatory reaction involving T cells and macrophages — is responsible for much of the tissue damage in syphilis. In late-stage disease, this produces gummas, granulomatous (inflammatory) nodules that can destroy bone, skin, and organs. In neurosyphilis, inflammation of blood vessels in the brain and spinal cord (meningovascular disease) can cause strokes. In cardiovascular syphilis, arteritis of the vasa vasorum (the tiny blood vessels that feed the aortic wall) weakens and stretches the aorta.

4. Stages of Infection

Syphilis moves through distinct stages that each look and behave differently. Knowing what to watch for at each stage is essential because early stages are curable with a single dose of antibiotics, while untreated infection can progress to serious, harder-to-reverse damage.

Primary Syphilis

The first sign of syphilis is a chancre — a firm, painless ulcer at the site where the spirochete entered the body. The incubation period is 10 to 90 days after exposure, with an average of about 21 days. Chancres most commonly appear on the genitals, anus, lips, or inside the mouth, depending on the type of sexual contact. Because the sore is painless, it is frequently overlooked. Without any treatment, the chancre heals on its own in 3 to 6 weeks — but this does not mean the infection is gone. It has simply moved deeper into the body.

Secondary Syphilis

About 6 to 8 weeks after the chancre appears (sometimes while it is still healing), hematogenous spread produces the characteristic secondary syphilis syndrome. The hallmark is a diffuse maculopapular rash that often involves the palms of the hands and soles of the feet — a distribution so distinctive that it is considered a classic teaching sign. The rash is usually non-itchy and may be subtle enough to ignore.

Other features of secondary syphilis include:

Condyloma lata — moist, flat, wart-like plaques that appear in warm skin folds (groin, perineum, under the breasts). They are highly infectious.
Mucous patches — painless gray-white erosions on mucous membranes inside the mouth or genitals, also highly contagious.
Patchy alopecia — a moth-eaten pattern of hair loss that can affect the scalp, eyebrows, and eyelashes.
Systemic symptoms — fever, malaise, fatigue, headache, and widespread lymph node enlargement, giving an overall flu-like feeling.

Like the primary chancre, secondary syphilis resolves on its own without treatment. This makes it dangerously easy to dismiss. The infection then enters a silent latent phase.

Latent Syphilis

Latent syphilis has no symptoms at all. It is defined entirely by a positive blood test for syphilis antibodies in someone with no active signs of disease. Latent syphilis is divided into two sub-stages based on timing:

Early latent (within the first year after infection): the person may still be infectious to sexual partners.
Late latent (more than one year after infection): sexual transmission is unlikely, but a pregnant woman with late latent syphilis can still pass the infection to her baby.

Without treatment, about one-third of people with latent syphilis will eventually develop tertiary syphilis, which can occur years to decades later.

Tertiary Syphilis

Tertiary syphilis is uncommon today because most people are diagnosed and treated before reaching this stage, but it represents the most destructive phase of untreated infection. Three major forms occur:

Gummatous syphilis — soft, rubbery granulomatous lesions (gummas) that can form in skin, bone, or internal organs. They are locally destructive but respond well to treatment.
Cardiovascular syphilis — typically appears 10–30 years after initial infection. Arteritis of the aorta leads to aortic aneurysm (often involving the ascending aorta, unlike atherosclerotic aneurysms) and aortic regurgitation (a leaky aortic valve). These are serious, life-threatening cardiovascular complications.
Neurosyphilis — while neurosyphilis can appear at any stage, its late manifestations are especially severe and include tabes dorsalis (degeneration of the dorsal columns of the spinal cord, causing shooting pains, loss of coordination, and bladder dysfunction) and general paresis (progressive dementia, personality change, and psychiatric symptoms from brain infection).

Neurosyphilis

T. pallidum can invade the central nervous system at any stage of infection, not only in the late tertiary phase. Early neurosyphilis (weeks to months after infection) may present as meningitis with headache, stiff neck, and sensitivity to light. Meningovascular syphilis can cause a stroke in a young person, weeks to months after initial infection. The Argyll Robertson pupil — a small, irregular pupil that reacts to near objects (accommodation) but not to light — is a classic but rare finding of neurosyphilis. Diagnosis requires lumbar puncture (spinal tap) to examine cerebrospinal fluid. The CSF-VDRL test is highly specific for neurosyphilis but insensitive; pleocytosis (elevated white blood cells) and elevated protein are supportive findings.

5. Congenital Syphilis

Congenital syphilis occurs when T. pallidum crosses the placenta from an infected mother to her baby during pregnancy. It can cause miscarriage, stillbirth, or a range of serious health problems in a live-born infant. This tragedy is entirely preventable with routine prenatal screening and timely treatment.

Early congenital syphilis presents within the first two years of life and may include:

Snuffles — a profuse, bloody nasal discharge that is one of the earliest and most distinctive signs
A diffuse maculopapular or vesicular skin rash, similar in distribution to secondary syphilis in adults
Hepatosplenomegaly (enlarged liver and spleen) with jaundice
Periostitis — inflammation of the bone coverings, causing pain and swelling in the long bones (Wimberger sign on X-ray)
Generalized lymph node enlargement
Meningitis and neurological involvement

Late congenital syphilis appears after age 2 and includes the classic stigmata:

Hutchinson teeth — notched, peg-shaped permanent incisors, a hallmark of congenital syphilis
Interstitial keratitis — inflammation of the cornea that can cause blindness
Saber shins — anterior bowing of the tibia from periostitis
Clutton joints — painless joint effusions, typically in the knees
Saddle-nose deformity from destruction of the nasal cartilage
Sensorineural hearing loss

Hutchinson teeth, interstitial keratitis, and sensorineural hearing loss together form the Hutchinson triad of late congenital syphilis. Screening all pregnant women for syphilis at the first prenatal visit — and again in the third trimester for high-risk women — is mandatory in most US states precisely because treatment during pregnancy protects the baby completely.

6. Diagnosis

Diagnosing syphilis relies on blood tests rather than clinical findings alone, because the symptoms at each stage are non-specific and easily confused with other conditions. The testing approach uses a two-tier strategy to balance sensitivity (catching true infections) with specificity (avoiding false positives).

Standard (Classic) Two-Step Testing

The traditional approach starts with a nontreponemal test — either the RPR (Rapid Plasma Reagin) or the VDRL (Venereal Disease Research Laboratory) test. These tests detect antibodies to host tissue damaged by the infection, not antibodies to T. pallidum itself. They are reported as a titer (e.g., 1:16 or 1:128), which is crucial: a falling titer after treatment confirms the infection is responding. A positive nontreponemal test is then confirmed with a treponemal test (FTA-ABS, TPPA, or EIA), which detects antibodies to the spirochete directly. Treponemal tests stay positive for life even after successful treatment, so they cannot be used to track treatment response.

Reverse Algorithm

Many laboratories now use a reverse algorithm: they run the treponemal test first (often an automated EIA or CIA), then confirm positives with an RPR titer. This catches people with very early or very late infection whose RPR might be negative, but it also flags people with old, treated infections. When treponemal and nontreponemal results disagree, additional treponemal testing (TPPA) helps clarify.

Diagnosing Neurosyphilis

When neurosyphilis is suspected — neurological symptoms in any stage of syphilis, or late syphilis in general — a lumbar puncture (spinal tap) is needed. The CSF-VDRL is highly specific for neurosyphilis (a positive result is almost certain evidence) but is insensitive (a negative result does not rule it out). Elevated white blood cells and protein in the CSF support the diagnosis. The treponema-specific FTA-ABS on CSF has higher sensitivity.

Primary Lesion Testing

When a suspected chancre is present, dark-field microscopy of material from the sore can directly visualize the characteristic corkscrew motility of live T. pallidum spirochetes. This is highly specific but requires specialized equipment and expertise.

Screening Recommendations

The CDC recommends annual syphilis screening for MSM and more frequent screening (every 3–6 months) for those with multiple partners or other risk factors. All pregnant women should be screened at the first prenatal visit. People living with HIV should be screened at least annually. Other sexually active adults should discuss screening with their clinician based on their individual risk factors.

7. Treatment

Treponema pallidum has remained exquisitely sensitive to penicillin for over 70 years. Unlike many other bacteria, it has never developed penicillin resistance. This makes treatment reliably effective when given correctly.

Standard Treatment by Stage

Primary, secondary, or early latent syphilis: Benzathine penicillin G 2.4 million units, given as a single intramuscular injection. This one shot cures early syphilis in the vast majority of people. It is one of the most effective single-dose antibiotic treatments in medicine.
Late latent syphilis or tertiary syphilis (without neurosyphilis): Three weekly injections of benzathine penicillin G 2.4 million units IM (total 7.2 million units over 3 weeks) to address deeper tissue infection.
Neurosyphilis: Because benzathine penicillin does not reliably penetrate the cerebrospinal fluid, neurosyphilis requires aqueous crystalline penicillin G 18–24 million units per day by continuous intravenous infusion for 10 to 14 days. This means hospitalization or a peripherally inserted central catheter (PICC) line for outpatient IV therapy.

Penicillin Allergy

For people who report penicillin allergy, doxycycline 100 mg twice daily for 14 days is an alternative for primary, secondary, or early latent syphilis, though evidence for its efficacy is less robust than for penicillin. Doxycycline cannot be used in pregnancy. For pregnant women with documented penicillin allergy, the CDC recommends penicillin desensitization — a medically supervised process to temporarily overcome the allergy — followed by treatment with benzathine penicillin. Penicillin is the only reliably effective treatment for neurosyphilis and congenital syphilis.

Jarisch-Herxheimer Reaction

Within 2 to 8 hours of the first antibiotic dose, many patients experience the Jarisch-Herxheimer reaction: an acute onset of fever, chills, sweating, headache, myalgias, and a temporary worsening of syphilitic rashes. This reaction is caused by the sudden release of bacterial products when large numbers of spirochetes are killed all at once. It is not a drug allergy.

Key points for patients:

Warn the patient in advance so they are not alarmed.
Manage with oral antipyretics (acetaminophen or ibuprofen) and rest.
The reaction typically resolves within 12–24 hours.
Pregnant women are at higher risk for preterm labor from the Jarisch-Herxheimer reaction and should receive their first dose in a monitored medical setting where fetal heart rate can be watched.

Test-of-Cure and Follow-Up

Treatment success is monitored by checking RPR or VDRL titers at 6, 12, and 24 months after treatment. A fourfold fall in titer (e.g., from 1:32 to 1:8) is considered treatment success. Titers that fail to fall or that rise fourfold may indicate treatment failure or reinfection and require re-evaluation — possibly including lumbar puncture to rule out neurosyphilis. All sexual partners from the relevant exposure period should be tested and treated.

8. Complications

Untreated or late-diagnosed syphilis can cause severe and sometimes irreversible harm. Most of these complications are preventable with early detection and treatment.

Neurosyphilis spectrum. Ranges from asymptomatic meningeal inflammation to devastating stroke (meningovascular), dementia (general paresis), and loss of coordination and bladder control (tabes dorsalis). Some neurological damage, particularly from tabes dorsalis, may not fully reverse even after successful antibiotic treatment.
Cardiovascular syphilis. Aortic aneurysm (especially of the ascending aorta or aortic arch) and aortic regurgitation are the major cardiac complications. Aortic aneurysm carries risk of rupture; aortic regurgitation can progress to heart failure. These typically appear 10–30 years after initial infection.
Ocular syphilis. Uveitis (inflammation inside the eye) and other ocular manifestations can occur at any stage of syphilis and may lead to permanent vision loss or blindness if not recognized and treated promptly. Ocular syphilis should be treated as neurosyphilis.
Otic syphilis. Sensorineural hearing loss and tinnitus (ringing in the ears) can occur, also treated as neurosyphilis. Hearing loss from syphilis may improve with treatment, unlike most other causes of sensorineural deafness.
Congenital transmission. As detailed in the congenital syphilis section, untreated maternal infection leads to miscarriage, stillbirth, and multi-organ disease in the newborn.
Increased HIV susceptibility. The genital ulcer of primary syphilis and the mucosal inflammation of secondary syphilis create a dramatically easier entry route for HIV. Syphilis infection is associated with a two- to fivefold increase in the risk of HIV acquisition per sexual act.
Gummatous destruction. Gummas — the granulomatous nodules of tertiary syphilis — can destroy bone (causing the saddle-nose deformity characteristic of congenital syphilis), perforate the palate, and damage visceral organs. They respond well to antibiotic treatment, though structural damage may be permanent.

9. Prevention

Syphilis is preventable, and the tools available to reduce transmission are practical and widely accessible.

Condoms reduce the risk of syphilis transmission but do not eliminate it entirely, because the spirochete can shed from skin surfaces not covered by a condom. Consistent condom use is an important but incomplete protection strategy.
Regular screening. Because syphilis can be asymptomatic for extended periods, routine screening of people at risk is the most powerful prevention tool. Knowing your status allows early treatment, which prevents onward transmission and protects your own health.
Partner notification (contact tracing). When syphilis is diagnosed, health departments and clinicians work to notify and test recent sexual partners. This interrupts transmission chains. Many jurisdictions offer confidential partner notification services.
Doxycycline post-exposure prophylaxis (doxy-PEP). Emerging evidence from clinical trials (including the DoxyPEP trial) shows that taking doxycycline 200 mg within 72 hours of unprotected sexual exposure significantly reduces the risk of syphilis, gonorrhea, and chlamydia. The CDC issued guidance in 2023 supporting doxy-PEP as an option for MSM and transgender women at high risk. Discuss this option with your clinician.
Prenatal screening. All pregnant women should be screened for syphilis at their first prenatal visit. Treating infected women during pregnancy prevents congenital syphilis completely. In high-prevalence areas, repeat testing in the third trimester is recommended.
HIV prevention linkage. Because syphilis and HIV are epidemiologically linked, syphilis prevention efforts are most effective when integrated with HIV testing, pre-exposure prophylaxis (PrEP) for HIV, and access to condoms.
Reducing stigma. Fear of judgment deters people from getting tested and treated. Syphilis is not a consequence of moral failure; it is an infection. Non-judgmental healthcare access and open community communication are essential to controlling the epidemic.

10. Research Advances

Despite being caused by a bacterium discovered over a century ago, syphilis research remains highly active, driven by the resurgent epidemic and several scientific challenges unique to this organism.

Whole-genome sequencing of T. pallidum strains is providing unprecedented insight into the genetics of this pathogen, which cannot be cultured in a standard laboratory dish. Genomic surveillance has identified distinct lineages circulating in different geographic regions and has tracked the spread of strains with macrolide resistance (azithromycin, once used as a penicillin alternative, is now unreliable in many settings due to widespread resistance mutations). This highlights the critical importance of benzathine penicillin as the treatment backbone.

Doxycycline post-exposure prophylaxis (doxy-PEP) has emerged as one of the most important developments in STI prevention in decades. The DoxyPEP randomized trial (Luetkemeyer et al., 2023) demonstrated that doxycycline taken within 72 hours of unprotected sex reduced syphilis incidence by 87% among MSM and transgender women on HIV PrEP or living with HIV. Implementation research is now focused on how to deliver doxy-PEP equitably and monitor for doxycycline resistance in other organisms.

Point-of-care treponemal rapid tests — accurate diagnostic tests that give results in 15–20 minutes from a finger-stick blood sample — are expanding the reach of syphilis diagnosis into settings without laboratory infrastructure. These tools are particularly valuable in low-resource settings and in emergency departments, where patients may not return for follow-up results.

Understanding the global re-emergence of syphilis is an active area of social epidemiology. Research points to intersecting factors: declining condom use partly related to effective HIV treatment (removing fear of HIV as a motivator for safer sex), reduced public health funding for STI programs, and social app-mediated sexual networks that connect more partners more efficiently. These insights inform the public health response.

Vaccine development for syphilis has been elusive because T. pallidum cannot be grown in culture, making it difficult to study its surface antigens. However, advances in genomic technology are identifying candidate proteins that could serve as vaccine targets, and animal model work is progressing.

11. Key Research Papers

Confirmed Citations

PubMed Search Links

12. PubMed Research Papers

The following links run live searches on PubMed, the U.S. National Library of Medicine’s database of biomedical literature. Use them to find the most current studies on syphilis biology, diagnosis, treatment, and prevention.

Connections

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