Syphilis and Treponematosis

Syphilis is a sexually-transmitted infection (STI) caused by the spirochete Treponema pallidum. Syphilis is transmissible by sexual contact with infectious lesions, from mother to fetus in utero, via blood product transfusion, and occasionally through breaks in the skin that come into contact with infectious lesions. If untreated, it progresses through four stages: primary, secondary, latent, and tertiary. 

Syphilis has a myriad of presentations and can mimic many other infections and immune-mediated processes in advanced stages. Hence, it has earned the nickname “the great impostor.” Since the discovery of penicillin in the mid-20th century, the spread of this once very common disease has been largely controlled, but efforts to eradicate the disease entirely have been unsuccessful.

Treponematosis

Treponematosis, also known as treponemiasis, traditionally refers to the group of nonvenereal diseases (including endemic syphilis [nonvenereal syphilis]) caused by Treponema species that are morphologically and serologically identical to each other and to Treponema pallidum subspecies pallidum, the cause of venereal syphilis. DNA from T pallidum subspecies pallidum is at least 99% homologous to that of T pallidum subspecies pertenue and T pallidum subspecies endemicum. However, they differ in terms of clinical manifestations.

Treponema species typically associated with nonvenereal disease are transmitted among children living in tropical, subtropical, or warm arid climates, chiefly by direct contact. In humans, the pathogenic treponemes include T pallidum pallidum (syphilis), Treponema pallidum pertenue (yaws), Treponema pallidum endemicum (bejel or endemic syphilis), and Treponema carateum (pinta). ^[1]

Yaws continues to be endemic along the tropical belt in areas characterized by hot temperatures, high humidity, and heavy rainfall. These conditions, coupled with the persistence of poverty, poor sanitation, overcrowding, and lack of public health surveillance, allow for yaws perpetuation. ^[2]

Interstitial keratitis

Interstitial keratitis (IK) is a broad, descriptive term that historically became synonymous with syphilitic disease. Although congenital syphilis remains the leading cause of interstitial keratitis, various bacterial, viral, parasitic, and autoimmune causes of interstitial keratitis are known. An example of interstitial keratitis associated with congenital syphilis is shown in the image below.

This photograph shows a child with interstitial keratitis from congenital syphilis.

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Three genera of spirochetes cause human infection:

• Treponema, which causes syphilis, yaws, and pinta

• Borrelia, which causes Lyme disease and relapsing fever

• Leptospira, which causes leptospirosis

The particular spirochete responsible for syphilis is Treponema pallidum.

T pallidum is a fragile spiral bacterium 6-15 micrometers long by 0.25 micrometers in diameter. Its small size makes it invisible on light microscopy; therefore, it must be identified by its distinctive undulating movements on darkfield microscopy. It can survive only briefly outside of the body; thus, transmission almost always requires direct contact with the infectious lesion. T pallidum is solely a human pathogen and does not naturally occur in other species.

Transmission of T pallidum occurs via penetration of the spirochetes through mucosal membranes and abrasions on epithelial surfaces. It is primarily spread through sexual contact but can be spread by exposure to blood products and transferred in utero. T pallidum is a labile organism that cannot survive drying or exposure to disinfectants; thus, fomite transmission (eg, from toilet seats) is virtually impossible.

Unprotected sex is the major risk factor for the acquisition of syphilis, especially among men who have sex with men (MSM).

Treponematosis

Transmission of yaws and bejel (endemic syphilis) typically occurs in children. Transmission typically occurs via direct skin-to-skin contact of lesions, which are infectious. Bejel is transmitted skin to skin but can also be transmitted mouth to mouth and on fomites (eg, via shared eating utensils or cups). Pinta is also transmitted by skin-to-skin contact and is more common in older children or teenagers.

Treponemes usually invade traumatized cutaneous or mucosal surfaces that come in contact with a draining open sore of the index case. A primary cutaneous lesion appears at the site of inoculation following an incubation period of a few weeks. The primary lesion could be a papule or an ulcer. Treponema may be spread from this site either topically (by scratching) or hematogenously.

Syphilis is usually classified into four stages: primary, secondary, latent, and tertiary. It can be either acquired or congenital. That is, it can be transmitted either by intimate contact with infectious lesions (most common) or via blood transfusion (if blood has been collected during early syphilis), and it can also be transmitted transplacentally from an infected mother to her fetus.

Acquired syphilis

In acquired syphilis, T pallidum rapidly penetrates intact mucous membranes or microscopic dermal abrasions and, within a few hours, enters the lymphatics and blood to produce systemic infection. Incubation time from exposure to development of primary lesions, which occur at the primary site of inoculation, averages 3 weeks but can range from 10-90 days. Studies in rabbits show that spirochetes can be found in the lymphatic system as early as 30 minutes after primary inoculation, suggesting that syphilis is a systemic disease from the outset.

The central nervous system (CNS) is invaded early in the infection; during the secondary stage, examinations demonstrate that more than 30% of patients have abnormal findings in the cerebrospinal fluid (CSF). During the first 5-10 years after the onset of untreated primary infection, the disease principally involves the meninges and blood vessels, resulting in meningovascular neurosyphilis. Later, the parenchyma of the brain and spinal cord are damaged, resulting in parenchymatous neurosyphilis. Go to Neurosyphilis for complete information on this topic.

Regardless of the stage of disease and location of lesions, histopathologic hallmarks of syphilis include endarteritis (which in some instances may be obliterative in nature) and a plasma cell–rich infiltrate. Endarteritis is caused by the binding of spirochetes to endothelial cells, mediated by host fibronectin molecules bound to the surface of the spirochetes. The resultant endarteritis can heal with scarring in some instances.

The syphilitic infiltrate reflects a delayed-type hypersensitivity response to T pallidum, and in certain individuals with tertiary syphilis, this response by sensitized T lymphocytes and macrophages results in gummatous ulcerations and necrosis. Antigens of T pallidum induce host production of treponemal antibodies and nonspecific reagin antibodies. Immunity to syphilis is incomplete.

Primary syphilis is characterized by the development of a painless chancre at the site of transmission after an incubation period of 3-6 weeks. The lesion has a punched-out base and rolled edges and is highly infectious.

Histologically, the chancre is characterized by mononuclear leukocytic infiltration, macrophages, and lymphocytes. The inflammatory reaction causes an obliterative endarteritis. In this stage, the spirochete can be isolated from the surface of the ulceration or the overlying exudate of the chancre. Whether treated or not, healing occurs within 3-12 weeks, with considerable residual fibrosis.

Secondary syphilis develops about 4-10 weeks after the appearance of the primary lesion. During this stage, the spirochetes multiply and spread throughout the body. Secondary syphilis lesions are quite variable in their manifestations. Systemic manifestations include malaise, fever, myalgias, arthralgias, lymphadenopathy, and rash.

Widespread mucocutaneous lesions are observed over the entire body and may involve the palms, soles, and oral mucosae. Most often, the lesions are macular, discrete, reddish brown, and 5 mm or smaller in diameter; however, they can be pustular, annular, or scaling. Vesicular rash is typically absent. All such lesions contain treponemes. Of these, wet mucous patches are the most contagious. Histologically, the inflammatory reaction is similar to but less intense than that of the primary chancre.

Other skin findings of secondary syphilis are condylomata lata and patchy alopecia. Condylomata lata are painless, highly infectious gray-white lesions that develop in warm, moist sites. The alopecia is characterized by patchy hair loss of the scalp and facial hair, including the eyebrows. Patients with this finding have been referred to as having a “moth-eaten” appearance. During secondary infection, the immune reaction is at its peak and antibody titers are high.

Latent syphilis is a stage at which the features of secondary syphilis have resolved, though patients remain seroreactive. Some patients experience recurrence of the infectious skin lesions of secondary syphilis during this period. About one third of untreated latent syphilis patients go on to develop tertiary syphilis, whereas the rest remain asymptomatic.

Currently, tertiary syphilis disease is rare. When it does occur, it mainly affects the cardiovascular system (80-85%) and the CNS (5-10%), developing over months to years and involving slow inflammatory damage to tissues. The three general categories of tertiary syphilis are gummatous syphilis (also called late benign), cardiovascular syphilis, and neurosyphilis.

Gummatous syphilis is characterized by granulomatous lesions, called gummas, which are characterized by a center of necrotic tissue with a rubbery texture. Gummas principally form in the liver, bones, and testes but may affect any organ. Histological examination shows palisaded macrophages and fibroblasts, as well as plasma cells surrounding the margins. Gummas may break down and form ulcers, eventually becoming fibrotic. Treponemes are rarely visualized or recovered from these lesions.

Cardiovascular syphilis occurs at least 10 years after primary infection. The most common manifestation is aneurysm formation in the ascending aorta, caused by chronic inflammatory destruction of the vasa vasorum, the penetrating vessels that nourish the walls of large arteries. Aortic valve insufficiency may result.

Neurosyphilis has several forms. If the spirochete invades the CNS, syphilitic meningitis results. Syphilitic meningitis is an early manifestation, usually occurring within 6 months of the primary infection. CSF shows high protein, low glucose, high lymphocyte count, and positive syphilis serology.

Meningovascular syphilis occurs as a result of damage to the blood vessels of the meninges, brain, and spinal cord, leading to infarctions causing a wide spectrum of neurologic impairments.

Parenchymal neurosyphilis includes tabes dorsalis and general paresis. Tabes dorsalis develops as the posterior columns and dorsal roots of the spinal cord are damaged. Posterior column impairment results in impaired vibration and proprioceptive sensation, leading to a wide-based gait.

Disruption of the dorsal roots leads to loss of pain and temperature sensation and areflexia. Damage to the cortical regions of the brain leads to general paresis, formerly called “general paresis of the insane,” which mimics other forms of dementia. Impairment of memory and speech, personality changes, irritability, and psychotic symptoms develop and may advance to progressive dementia.

The Argyll-Robertson pupil, a pupil that does not react to light but does constrict during accommodation, may be seen in tabes dorsalis and general paresis. The precise location of the lesion causing this phenomenon is unknown.

Congenital syphilis

Congenital syphilis, discussed briefly here, is a veritable potpourri of antiquated medical terminology. The treponemes readily cross the placental barrier and infect the fetus, causing a high rate of spontaneous abortion and stillbirth. Within the first 2 years of life, symptoms are similar to severe adult secondary syphilis with widespread condylomata lata and rash. “Snuffles” describes the mucopurulent rhinitis caused by involvement of the nasal mucosae.

Later manifestations of congenital syphilis include bone and teeth deformities, such as “saddle nose” (due to destruction of the nasal septum), “saber shins” (due to inflammation and bowing of the tibia), “Clutton’s joints” (due to inflammation of the knee joints), “Hutchinson’s teeth” (in which the upper incisors are widely spaced and notched), and “mulberry molars” (in which the molars have too many cusps).

Tabes dorsalis and general paresis may develop as in adults, with cranial nerve XIII deafness and optic nerve atrophy as well as a variety of other ophthalmologic involvement leading to blindness being additional features.

Go to Pediatric Syphilis for complete information on this topic.

Treponematosis

Lesions from treponemes often heal spontaneously. Treponematosis can remain latent or it may recur.

The secondary stage of any of these diseases follows the dissemination of the treponemes. It may begin while the primary lesion is still present or after a variable latent period. It may also resolve spontaneously, recur, or persist. The long-term effects of these infections include multiple cutaneous lesions and destruction of bones or cartilage.

Yaws, like syphilis, has been classified into the following four stages:

1. Primary stage, in which the initial yaws lesion develops at the inoculation site

2. Secondary stage, in which widespread dissemination of treponemes results in multiple skin lesions that are similar to the primary yaws lesion

3. Latent stage, in which symptoms are usually absent but skin lesions can relapse

4. Tertiary stage, in which bone, joint, and soft tissue deformities may occur

Cutaneous lesions characterize the primary and secondary stages of yaws. The tertiary stage of yaws may involve the skin, bones, and joints.

Another classification distinguishes early yaws from late yaws. Early yaws includes the primary and secondary stages and is characterized by the presence of contagious skin lesions. Late yaws includes the tertiary stage, when lesions are not contagious.

Interstitial Keratitis

Acute interstitial keratitis may be triggered by ocular surface inflammation and following intraocular surgery. Corneal inflammation most often affects the deep stromal layers, either as multifocal infiltrates or as a diffuse process. Corneal stromal edema may result from the inflammation, resulting in the ground-glass cornea.

Inflammation may be either the direct result of an infectious process or, more commonly, secondary to an immunologic response to a specific foreign antigen. This immunologic response may take the form of antigen-antibody complex deposition, complement-mediated disease, or a delayed-type hypersensitivity reaction.

Variability of the extent of corneal stromal neovascularization depends on the severity of the inflammation that has been present. Typically, the neovascularization begins at the corneal limbus and may occur at any level, although it most commonly is seen in the deeper stromal layers. Stromal inflammation overlying the vessel often causes a salmon-colored patch due to the pinkish color imparted by the stromal vessels. Intrastromal hemorrhage also may occur.

Interstitial keratitis may progress to the regression phase, during which scarring of the corneal stromal and collagen remodeling occur. The superficial vessels resorb, and the deeper vessels may constrict, resulting in the ghost vessels that are seen as a late finding of syphilitic interstitial keratitis.

United States statistics

Provision data shows that, in 2024, there were 190,242 syphilis cases reported in the US. From 2018 to 2022, syphilis cases in the US increased nearly 80%, outpacing the increase in cases of other STIs. ^[3]  However, since 2023, cases of primary and secondary syphilis have declined by 22%. Congenital syphilis cases continue to increase, and, as of 2025, have risen nearly seven-fold since 2015. ^[4]

Although treponematosis does not occur in the United States, imported cases have been documented. It may be found in children immigrating from areas of endemicity. 

International statistics

The global incidence of syphilis climbed during 2015-2025, with significant new outbreaks identified in Asia, Europe, and North America. Men who have sex with men (MSM) have carried a disproportionate amount of the disease burden. Many low- and middle-income nations face a sustained, high burden, particularly among women of childbearing age, which is often intensified by insufficient screening and tracking systems. Furthermore, the COVID-19 pandemic hampered timely diagnosis and treatment by disrupting essential services and increasing underreporting. ^[5]

During the period from 2001 to 2024, there was also a concerning rise in global congenital syphilis prevalence, especially in low- and middle-income nations. ^[6]

Neurosyphilis cases increased considerably from 2010-2024. Between 2020 and 2021 alone, the number of neurosyphilis cases increased by 32%. ^[7]

Age distribution of syphilis

In the US, syphilis was most common among those aged 25-29 years from 2018 to 2022. ^[3]

Sex distribution of syphilis

Syphilis affects men at a greater rate than women. ^[4]

Prevalence of syphilis by race or ethnicity

As of 2022, Native American/Alaskan Natives had the greatest syphilis burden, followed by Black individuals. Native Hawaiians/Pacific Islanders were third. Those of Asian descent had the lowest syphilis rates in the US. ^[3]

HIV and syphilis co-infection

Syphilis acquisition increases the risk of HIV acquisition by 2- to 5-fold and makes transmission of HIV more efficient via various methods. First, primary syphilis infection causes a genital ulcer, which disrupts the mucous membrane, making it more vulnerable to penetration by the HIV virus. Second, genital ulcers bleed easily during sex, increasing the risk of viral transmission. Third, genital ulcers attract CD4 cells to the ulcer surface, increasing targets for the HIV virus to infect. Fourth, the risk behaviors associated with acquiring syphilis also increase the likelihood of acquiring HIV. ^[8]

The rate of HIV and syphilis co-infection is high. More than 50% of MSM with syphilis are also infected with HIV, and this number increases with each recurrence. ^{[8, 9]}

The morbidity of syphilis ranges from the relatively minor symptoms of the primary stages of infection to the more significant constitutional systemic symptoms of secondary syphilis and the significant neurological and cardiovascular consequences of tertiary disease. Since latent syphilis can persist for years or decades, the manifestations of tertiary syphilis often occur much later in life, causing significant morbidity and even death if not identified and treated.

These figures have continued to increase since the emergence of the AIDS epidemic, since genital ulcer diseases (including syphilis) are cofactors for the sexual transmission of HIV. Additionally, untreated patients who are HIV seropositive have an increased risk for rapid progression to neurosyphilis. In addition, patients with HIV are at greater risk for development or relapse of early symptomatic neurosyphilis for up to 2 years after treatment with intramuscular or intravenous penicillin.

The morbidity and mortality of untreated syphilis must be estimated from the limited data available regarding its natural course. These data are largely from one retrospective study of autopsies and two prospective studies, most notably the infamous Tuskegee Study of Untreated Syphilis in the Negro Male, which fell under serious ethical scrutiny in later years for exploiting a vulnerable patient population and not offering treatment for the disease when it became available after the study was underway.

These data indicate that approximately one third of patients left untreated will develop late complications, with 10% of the total developing cardiovascular syphilis; 6%, neurosyphilis; and 16%, gummatous syphilis. Mortality rates in general are greater among those affected, and late complications appear to occur more commonly in men than in women. ^{[10, 11]}

For patients diagnosed with either primary or secondary syphilis (without auditory/neurologic/ocular involvement), the prognosis is good following appropriate treatment. T pallidum remains highly responsive to the penicillins, and cure is likely. Among patients diagnosed with tertiary syphilis, the prognosis is less sanguine. Twenty percent of untreated patients with tertiary syphilis die of the disease, making syphilis one of the few sexually transmitted diseases (SDTs) capable of killing its host. However, with adequate treatment, 90% of patients with neurosyphilis have a clinical response.

Overall prognosis for tertiary syphilis depends on the extent of scarring and tissue damage, as treatment arrests further damage and inflammation but cannot reverse previous tissue damage. For example, the prognosis or advanced symptomatic disease in cardiovascular syphilis is poor. In contrast, syphilitic gummas typically resolve promptly with high-dose penicillin.

Congenital syphilis is the most serious outcome of syphilis in women. It has been shown that a higher proportion of infants are affected if the mother has untreated secondary syphilis, compared to untreated early latent syphilis. Since T pallidum does not invade the placental tissue or the fetus until the fifth month of gestation, syphilis causes late abortion, stillbirth, or death soon after delivery in more than 40% of untreated maternal infections. ^{[12, 13]}  Neonatal mortality usually results from pulmonary hemorrhage, bacterial superinfection, or fulminant hepatitis.

For patients who are pregnant and have early syphilis, it is likely that the mother will deliver a child not infected by syphilis (assuming the mother was treated appropriately).

Treponematosis

Untreated treponematosis may cause disfiguring cutaneous lesions and deformities of bone, cartilage (particularly the nose), and skin, potentially leading to significant disfigurement, pain, and disability. Affected children can become socially ostracized and often miss school. Thickening and cracking of the soles may make walking difficult. Treponematosis can extract a significant economic toll on already-disadvantaged populations. Fortunately, with penicillin or azithromycin therapy, cure rates of 95-97% are possible.

Unless treated, yaws can become a chronic, relapsing disease after 5-15 years, with skin, bone, and joint involvement. In most patients, yaws remains limited to the skin, but early bone and joint involvement can occur. Although yaws lesions disappear spontaneously, secondary bacterial infections and scarring are common complications.

In 10% of yaws cases, patients enter a late stage (tertiary stage) characterized by destructive cutaneous lesions and severely deforming bone and joint lesions. Tissue damage occurring in late yaws is irreversible. Neurologic and ophthalmologic involvement may also occur. Relapses may occur at intervals of up to 5 years after infection.

Because the disease rarely manifests clinically significant cardiovascular and neurologic symptoms, mortality is uncommon unless the disease state is highly exaggerated, through either a large inoculum or a devastating immune reaction.