{
"id": "syphilis",
"title": "Syphilis",
"lang": "en",
"source_lang": "en",
"summary": "Syphilis is a chronic bacterial infection caused by the spirochete Treponema pallidum, usually spread through sexual contact, which can progress over years to damage the skin, nervous system, heart, and other organs if untreated.",
"category": "health",
"subcategory": "diseases",
"type": "concept",
"aliases": [
"Lues",
"lues venerea",
"morbus gallicus",
"\"the Great Pretender\" (nickname)"
],
"generated_at": "2026-10-07",
"model": "pro/claude-haiku-5-5",
"url": "https://aiwiki.page/en/syphilis/",
"translations": {
"zh-Hans": {
"url": "https://aiwiki.page/zh/syphilis/",
"json": "https://aiwiki.page/zh/syphilis.json"
}
},
"sections": [
{
"heading": "",
"text": "Syphilis is a chronic bacterial infection caused by Treponema pallidum subspecies pallidum, a spirochete that humans are the natural host for. It spreads mainly through direct contact with infectious sores during sexual activity, but it can also pass from a pregnant woman to her fetus and through transfusion of blood collected during early infection. Untreated, it runs a course of several years or decades, moving through stages that can damage the skin, the nervous system, the heart and blood vessels, and other organs. Because its symptoms can imitate many other diseases, it has long been called \"the Great Pretender.\" Early infection is curable with antibiotics, most often penicillin, and the infection is a bacterial infectious disease whose clinical picture is governed by the host's immune system as much as by the pathogen itself.\n\nSyphilis matters for several reasons. It remains a significant sexually transmitted infection in public health practice, and it is the target of a global effort to eliminate congenital infection, because untreated infection in pregnancy can cause stillbirth and severe harm to newborns. Its history is also central to modern medicine: the search for a treatment led to one of the first targeted chemical therapies, and the diagnostic tests developed for it shaped the way serological testing is still done. Its later stages, which can involve the brain, spinal cord, and blood vessels, illustrate how a chronic infection can cause lasting organ damage long after the initial symptoms have faded.\n\nThis entry first defines the pathogen and its relatives, then describes transmission and epidemiology, the clinical stages, and the special complications, including neurosyphilis and congenital infection. It then covers diagnosis, treatment and prevention, and the public-health response. It closes with the historical development of understanding and treating the disease, and with the open questions that remain, such as the absence of a vaccine."
},
{
"heading": "Causative organism and related treponemal diseases",
"text": "The organism and why it is hard to grow\n\nSyphilis is caused by Treponema pallidum subspecies pallidum, a long, spiral-shaped, motile microorganism in the order Spirochaetales. It cannot be cultured on artificial media. Because of this, the organism was for a long time harvested from infected rabbit testes, a practice that shaped research for decades (the organism is harvested from infected rabbit testes.). For more than a hundred years, scientists could not grow it reliably in a lab setting, and this limitation also blocked routine genetic manipulation (it has been very hard to use modern genetic engineering or transformation methods). Recent work on tissue-culture systems has allowed stable propagation in vitro, but this is not yet a routine diagnostic or research tool. As a result, detection relies on clinical examination, direct detection in lesion material, and serology rather than on culture.\n\nOuter membrane and immune evasion\n\nThe bacterium's outer membrane is structurally unusual. Unlike the outer membranes of typical gram-negative bacteria, it lacks the abundant immunogenic β-barrel proteins that carry out nutrient transport (In contrast, the outer membranes of gram-negative bacteria contain abundant immunogenic membrane-spanning β-barrel proteins mainly involved in nutrient transport. The absence of orthologs of gram-negative porins and outer membrane nutrient-specific transporters). The organism's outer surface therefore carries few proteins that the immune system can recognize. The highly immunogenic lipoproteins are instead kept in the periplasmic space (its denuded outer membrane, which comprises mostly nonimmunogenic transmembrane proteins, whereas the highly immunogenic lipoproteins are contained within the periplasmic space.). This is why the bacterium is often called a \"stealth pathogen.\"\n\nPersistence is reinforced by antigenic variation. The TprK protein undergoes gene conversion that draws on dozens of silent donor cassettes and alters its surface-exposed variable regions, which can abolish antibody binding (gene conversion, stochastically pulling from 53 silent donor cassettes to alter seven surface-exposed variable (V) regions. These structural shifts abrogate antibody binding and opsonophagocytosis). Because the antigenic repertoire keeps shifting, the host's antibody and cellular responses struggle to clear the infection, which allows it to persist for years.\n\nRelated treponemal diseases\n\nThree other human diseases are caused by closely related treponemes. T. pallidum subsp. pertenue, T. pallidum subsp. endemicum, and T. carateum are the agents of the endemic treponematoses yaws, bejel (or endemic syphilis), and pinta, respectively. Their geographic distribution differs: yaws is found in tropical regions of Western and Central Africa, Southeast Asia and the Pacific Islands, bejel in the Sahelian belt of Africa and Saudi Arabia, and pinta in Central and South America (Geographical distribution | Western/Central Africa, Southeast Asia, Pacific Islands | Sahelian Africa, Saudi Arabia | Central and South America). These diseases spread through close personal and skin contact rather than sexual contact (the other three are tropical neglected diseases which are spread through close personal contact.), and they mostly affect children. Their clinical features differ from venereal syphilis, yet they cannot be differentiated by morphological and serological methods.\n\nTaxonomy and genomic relationships\n\nSyphilis and yaws treponemes were once treated as separate species because their clinical pictures differed. Since 1984 they have been classified as subspecies, based on DNA hybridization. The pinta agent is handled differently: T. carateum (pinta agent), unlike T. p. pertenue or T. p. endemicum, is not currently classified as a T. pallidum subspecies since our molecular knowledge at this time is insufficient to warrant such a classification.\n\nWhole-genome sequencing has shown how close these organisms are. Syphilis and yaws genomes are 99.8% identical in sequence, and no major rearrangements and a nearly identical gene order was found. Within this close relationship, the divergence between subspecies is several times larger than the diversity observed within each subspecies (The whole genome nucleotide divergence (dA) between TPA and TPE subspecies was 4.7 and 4.8 times higher than the observed nucleotide diversity (π) among TPA and TPE strains). Pan-genome analyses point to a close connection among all strains of the pathogen, its clonal behaviour, while subspecies differ in genome plasticity. Some regions of sequence divergence have also been proposed as molecular markers to tell strains apart (The regions of sequence divergence could be used for the molecular detection and discrimination of syphilis, yaws, and bejel strains). The genetic differences are small, and they do not fully explain the different transmission patterns, which seem to reflect social circumstances as much as biology. Deeper evolutionary history remains uncertain; deep evolution of the complex has remained unresolved owing to limitations in the conclusions that can be drawn from the sparse palaeogenomic data, and ancient genomes from the Americas are being used to fill this gap (analyses of five pre- and peri-contact ancient treponemal genomes from the Americas that represent ancient relatives of the T. pallidum subsp.)."
},
{
"heading": "Transmission and epidemiology",
"text": "Routes of acquisition\n\nSexual contact is the dominant route. Infection needs only a small inoculum: exudate containing as few as 10 organisms has been linked to transmission. Spirochetes from an ulcer reach the skin or mucous membranes of a partner, and exposure is not limited to the genitals. Sexual transmission usually results from contact with genital mucosal membranes, but it can also occur at other sites, including the mouth, anorectal areas, and cutaneous lesions. Transmission through using the same toilet, bathroom, clothing, or cutlery as an infected person is not considered a route.\n\nVertical transmission to the fetus is the second major route. Maternal transmission predominantly occurs via transplacental passage of T. pallidum during maternal spirochetemia; less often, transmission can occur if the newborn has contact with maternal genital lesions at the time of delivery. Unlike sexual spread, which nearly always occurs in the early stages of syphilis, a mother can pass the infection to her child at any stage. The consequences of this route are described in the congenital syphilis section.\n\nBloodborne transmission is now uncommon. Transfusion was among the first recognized infectious hazards of blood donation, but reports of transfusion-transmitted syphilis have become exceedingly rare over the past 60 years as donor selection, universal serological screening, and the use of refrigerated components have spread. Donors in the early phase of infection may still test negative, which is why transfusion risk is not zero. Needle sharing among people who inject drugs is also considered infrequent.\n\nPeriod of greatest infectiousness\n\nInfectiousness follows the appearance of lesions. Communicability exists when moist mucocutaneous lesions of primary and secondary syphilis are present. The primary chancre and the mucocutaneous rash of secondary disease are therefore the most important sources of spread.\n\nEarly latent infection is less clear-cut. Early latent disease is conventionally defined as infection acquired within the previous year, and one account states that syphilis can be transmitted via sexual contact during the primary, secondary, and early latent (i.e., infection that occurred within the previous 12 months) stages. Other sources emphasise that during the first 4 years of latent syphilis, patients may exhibit mucocutaneous relapses and are considered infectious. The distinction between infectious and noninfectious early latent disease is therefore not sharp in practice.\n\nLate latent and tertiary infection are generally not sexually transmissible. It is thought that syphilis cannot be transmitted through sexual contact in this stage, though pregnant women can still pass the condition to their fetus.\n\nIncidence, prevalence and sexual networks\n\nPatterns of spread have shifted over time. Although the number of HIV cases began to decrease globally during the 2000s, the number of syphilis cases began to increase in high-income countries, including European countries and the United States. A WHO strategy target calls for a 90% reduction in global incidence over 2018–2030. In the United States, although rates of P&S syphilis are lower in women, rates have increased in recent years, increasing 21% during 2019 to 2020 and 147% during 2016 to 2020.\n\nMuch of the recent resurgence has concentrated in particular sexual networks. In high-income countries it has been associated with human immunodeficiency virus (HIV) infection and high-risk sexual behaviors among men who have sex with men. Local data show how quickly this can change: the number of MSM reported with syphilis in Florida in 2011 was 10 times the number from 2000. In a Chinese study, the greater share of men with unstable partners was thought to explain higher rates of HIV and syphilis coinfection. Prevalence estimates also depend heavily on the population studied, which is why surveillance is typically stratified by risk group.\n\nInteraction with HIV\n\nThe two infections interact in both directions. There is a bidirectional epidemiological and biological interaction between these two infections. HIV infection may increase the risk of syphilis transmission by weakening the immune system. Conversely, genital ulcers create a route for HIV entry, and syphilitic ulcers provide a portal of entry for HIV, potentially increasing the risk of HIV transmission by approximately twofold. Syphilis has also been associated with increasing infectiousness through effects on HIV shedding, HIV replication, and increases in viral diversity. In people with HIV, HIV viral load increases with incident syphilis infection, which raises the likelihood of onward HIV transmission.\n\nCoinfection also alters the course of syphilis. HIV could alter the syphilis manifestations and blur the distinction of the stages, and HIV and syphilis coinfection patients also face a higher risk of treatment failure and the emergence of neurosyphilis. Among the reported differences, in primary syphilis, chancre lesions can be multiple and larger.\n\nThe degree of overlap is substantial. In a 2004–2005 sample of men who have sex with men with early syphilis across three US cities, 47% had HIV coinfection. A 2022 meta-analysis in China estimated 19.9% overall prevalence of syphilis among PLWH. Clinical guidance accordingly holds that all patients presenting with syphilis should be offered HIV testing and all HIV-positive patients should be regularly screened for syphilis.\n\nWhether treating syphilis reduces HIV spread at population level remains debated. One line of evidence holds that detection and treatment of syphilis can, therefore, help to reduce HIV transmission. Other studies, however, found little population-level impact of treating syphilis as an HIV prevention intervention."
},
{
"heading": "Clinical stages of acquired infection",
"text": "Untreated acquired syphilis is conventionally divided into stages defined mainly by clinical findings, and these stages guide treatment and follow-up. Classification is not uniform across sources. The CDC describes four stages (primary, secondary, latent and tertiary), while some guidance treats the late stages as a single \"latent or tertiary\" category and assigns stage partly by how long ago infection was acquired. Serological history therefore matters as much as the physical examination.\n\nPrimary stage\n\nIn adults, the incubation period runs from 10 to 90 days, and the first lesion typically appears about three weeks after exposure. This lesion, the chancre, is usually a single firm, round ulcer, though multiple lesions can occur. It is often painless and tends to sit on the genitals, around the anus or rectum, or in the mouth, so it can easily go unnoticed when it forms inside a body cavity. A chancre persists for roughly two to six weeks and then heals on its own with or without treatment. The disappearance of the sore does not mean the infection has cleared, and the organism continues to multiply and spread through the body.\n\nSecondary stage\n\nSecondary syphilis generally begins two to 24 weeks after most primary lesions have healed. Its characteristic feature is a generalized mucocutaneous rash that frequently involves the trunk, palms and soles. Mucous patches in the mouth, and condylomata lata on the genitals or anal region, occur in about a quarter of patients. Lymphadenopathy, patchy hair loss, fever and occasional neurological or ocular involvement may also be present. Primary and secondary features can overlap, and this is more common in people living with HIV, whose immune response may be impaired. Secondary signs usually fade within about three months (range one to twelve months) whether or not treatment is given. In up to a quarter of untreated people, however, they recur intermittently during the first few years of infection.\n\nLatent stage\n\nLatency follows the symptomatic stages and is defined by the absence of visible signs or symptoms. Early latent syphilis refers to infection acquired within the preceding year, while infection of longer or unknown duration is classified as late latent. Because latent infection produces no clinical findings, it is identified only through serology: nontreponemal and treponemal antibody tests remain positive. Many patients are first diagnosed at this point because primary and secondary symptoms are often mild or overlooked, and routine blood testing picks up the antibodies. Without treatment, the infection can persist for years. The CDC notes that in up to two-thirds of patients, latency lasts for life and never progresses to the tertiary stage.\n\nTertiary stage\n\nTertiary syphilis is the late, destructive phase. Estimates of its frequency and timing vary between sources. One clinical reference states that about one-third of untreated people eventually develop late disease, usually years to decades after infection, while another cites 15 to 30 years of untreated infection before late manifestations typically appear. Its recognised forms include benign gummatous disease, cardiovascular syphilis and neurosyphilis, and some classifications place neurosyphilis in a separate category.\n\nGummas are soft, destructive and inflammatory masses that may occur in the skin, bones or internal organs. They are often localised, but can infiltrate a tissue diffusely, and they grow and heal slowly, leaving scars. Benign gummatous disease usually emerges within three to ten years of infection. Cardiovascular and neurological involvement, which can damage the heart, large blood vessels, brain and spinal cord, are the most serious late complications and are described in the following section."
},
{
"heading": "Neurosyphilis, cardiovascular and ocular complications",
"text": "Neurosyphilis\n\nNeurosyphilis is infection of the central nervous system by T. pallidum. Historically, neurosyphilis was often described as a form of \"tertiary syphilis,\" but it is now established that neurosyphilis can occur at any stage of infection. Early involvement mainly affects the cerebrospinal fluid, the meninges and blood vessels. Before antibiotics, asymptomatic neurosyphilis was seen in between 25% and 35% of patients with early syphilis and 13.5% of those with late forms. Today it is the most common form, though it is more commonly associated with HIV-positive individuals, particularly those with low CD4+ counts.\n\nSymptomatic early disease usually takes the form of meningitis. Meningeal symptoms include headache, photophobia, neck stiffness, and cranial nerve palsies. Meningovascular disease follows when inflamed arteries are involved. Vascular involvement manifests as infectious arteritis that can affect any vessel from the aorta to those within the subarachnoid space, and this can cause infarction. The middle cerebral artery is most often affected, causing a variety of symptoms including weakness, sensory loss, eye deviation, and hemineglect syndrome. Onset is reported variably: one source places meningovascular disease typically between five and 12 years post-infection, while another gives 5–12 years for meningovascular and 18–25 years for parenchymatous disease in untreated patients (progress to meningovascular syphilis about 5-12 years after the primary stage, or to the parenchymatous form of neurosyphilis (tabes dorsalis, paralytic neurosyphilis) after 18-25 years). A rare chronic granulomatous lesion, the syphilitic gumma, may also form within the meninges. It develops years after the primary infection and is seen as a poorly vascularized, meninges-based enhancing mass.\n\nParenchymatous disease is the classic late form. Its two main presentations are general paresis and tabes dorsalis. General paresis is a progressive dementing illness initially characterized by forgetfulness and personality changes, which progressively worsen to severe dementia. Less frequently, affected patients can present with depression, mania, or psychosis. Tabes dorsalis affects the sensory pathways of the spinal cord. It presents as sensory ataxia and neuropathic pain and less commonly as paresthesia and gastrointestinal disturbance. Typical features include pains in the arms and legs or abdomen, lack of muscle coordination, burning or tingling sensations, and bladder control and sexual function problems. Eye issues, such as pupil abnormalities (Argyll Robertson pupils) and ocular palsies, and neuropathic arthropathy (Charcot joint) can also occur. Both syndromes have become uncommon: general paresis and tabes dorsalis are less common than the other forms due to medical advancements in the prevention, screening and treatment of syphilis. Penicillin remains the mainstay of treatment and can improve or resolve spinal cord lesions, though one reported case progressed despite a course accepted as adequate by the World Health Organisation.\n\nCardiovascular syphilis\n\nThe characteristic cardiovascular lesion is aortitis. The typical lesion of cardiovascular syphilis is aortitis affecting the ascending aorta and appearing 10–30 years after infection. Pathologically, the organism invades the aortic wall and evolves to obliterative endarteritis of the vasa vasorum and results in necrosis of the elastic fibres and connective tissue in the aortic media. The ascending segment is the most frequently involved, followed by the arch and the descending aorta. Syphilitic aortitis is reported in 70–80% of untreated cases after the primary infection, and in 10% of these patients, significant cardiovascular complications will occur.\n\nMany of these lesions are silent. The aortitis may be asymptomatic and detected as dilatation of the ascending aorta on chest radiography, often accompanied by linear calcification of the aortic wall, or it may lead to stretching and incompetence of the aortic valve, to left ventricular failure or to aneurysm formation. Aneurysms may be associated with a variety of syndromes caused by pressure on adjacent structures in the mediastinum, and they may cause sudden death from rupture. Coronary involvement can produce angina. In many cases the lesion is found late: it can enlarge asymptomatically until incidental finding in a chest X-ray or a catastrophic and often fatal aneurysmal rupture. Diagnosis is also complicated because serological tests for syphilis are often negative in patients with cardiovascular manifestations, making histological analysis mandatory in open aortic surgery. Aortic lesions are now uncommon in many developed settings, a change attributed to penicillin and improved screening. For the same reason, syphilitic aortitis should be considered when an unexplained aneurysm appears in a younger patient.\n\nOcular and otic involvement\n\nEye involvement can occur at any stage. Reported ocular forms include unspecific anterior uveitis, acute syphilitic posterior placoid chorioretinitis, panuveitis, and optic atrophy, which is listed among the manifestations of neurosyphilis. Visual loss may therefore reflect either inflammation of the eye itself or damage to the optic nerve and central nervous system.\n\nEar involvement (otosyphilis) affects the inner ear and can cause hearing loss and vertigo. It may appear at any stage, including early infection, and it can be difficult to separate from other causes of hearing loss without serological and clinical correlation. Because both ocular and otic signs may be the first presentation, clinicians are advised to consider syphilis when unexplained vision or hearing changes occur in a patient at risk."
},
{
"heading": "Congenital syphilis",
"text": "Congenital syphilis develops when the bacterium passes from an infected mother to her fetus. Usually this happens across the placenta, and the transplacental transmission can occur during any time of pregnancy, and, rarely, during childbirth. The in-utero route typically depends on a disseminated bloodstream infection in the mother. The bacterium invades the placenta during this maternal bacteremia, and then crosses the placental barrier. Transmission during delivery requires active genital lesions in the birth canal, and it is much less common than in-utero spread.\n\nThe maternal stage of infection strongly influences the risk. Untreated primary or secondary syphilis in the mother usually passes to the fetus, whereas latent or tertiary infection is transmitted in roughly 7 to 40% of cases. Gestational timing also matters. Neonatal mortality and morbidity are higher when transplacental transmission occurs during the first and second trimesters. Untreated infection in pregnancy has effects beyond the fetus, and it increases the risk of spontaneous abortion, preterm delivery, and adverse neonatal outcomes including low birth weight and neonatal death.\n\nThe range of outcomes is wide. Clinical manifestations range from asymptomatic infection, seen in up to 70% of cases, to severe outcomes such as stillbirth, which occurs in up to 40% of untreated pregnancies, hydrops fetalis, and preterm birth. Symptomatic newborns may show pneumonia, nasal discharge, hepatosplenomegaly, lymphadenopathy, cholestasis, hyperbilirubinemia, a maculopapular or desquamating rash often involving the palms and soles, meningitis, and seizures. Infants who survive the neonatal period may later show congenital deformities of the neurological, bone, and organ systems. Sensory impairment, such as hearing and vision loss, is also a recognised late sequela. Infection that becomes apparent after the age of two is classed as late congenital syphilis, indicating long-term or delayed complications.\n\nThe global burden is large. In 2022, WHO estimated 700 000 congenital syphilis cases and 390 000 adverse birth outcomes globally. In the United States, there were 3,882 cases of congenital syphilis reported in 2023, which included a total of 252 congenital syphilis-related stillbirths and 27 infant deaths.\n\nAntenatal screening and treatment are the main preventive measures, and unlike many neonatal infections, congenital syphilis is preventable through effective antenatal screening and treatment of infected pregnant women. WHO's breakdown of adverse outcomes shows where prevention fails. Of these adverse birth outcomes, 21% occurred in pregnant women who did not attend antenatal care; 53% in women who attended antenatal care but were not screened for syphilis; 16% in women who tested positive for syphilis but were not treated or received inadequate treatment; and 9% in women who tested positive and were adequately treated. Treatment works best when it starts early. The risk of adverse outcomes to the fetus is minimal if the mother receives adequate treatment with benzathine penicillin during early pregnancy, ideally before the second trimester.\n\nPenicillin is the only treatment recommended for pregnant women, and the reasons are pharmacological as well as clinical. Benzathine penicillin G is the only recommended treatment for syphilis in pregnant women to prevent mother-to-child transmission, as other drugs are contraindicated, do not cross the placenta to treat the fetus, or are less effective. The same drug is also the recommended treatment for infants born with congenital syphilis. Treatment of syphilis-infected pregnant women with 2.4 million international units of intramuscular benzathine penicillin G given at least 28 days before delivery can result in an 82% reduced risk of stillbirth and an 80% reduction in neonatal mortality.\n\nWhen treatment is delayed or unavailable, the consequences are predictable. Because penicillin G is the only evidence-based therapy for syphilis during pregnancy, delays in access have translated directly into preventable cases of congenital syphilis. Supply is a recurring problem. Shortages of injectable penicillin, the only recommended treatment for pregnant women and infants with syphilis, have been reported by high-morbidity countries. In the United States, a shortage of the benzathine product Bicillin L-A has continued and is projected to last through the end of 2027, according to a Nevada public health summary. Penicillin allergy is another barrier. Allergy labels are often inaccurate, and for patients with a confirmed severe allergy, desensitization followed by penicillin treatment is recommended."
},
{
"heading": "Diagnosis and laboratory testing",
"text": "Direct detection of the organism\n\nBecause it is difficult to culture T. pallidum in vitro, and microbiological examination of the organism is therefore not usable for diagnosing neurosyphilis. Direct methods therefore remain the only way to see the organism itself, and they are no longer the mainstay. The historic use of darkfield microscopy for diagnosis has been eclipsed by algorithms that combine nontreponemal and treponemal antibody tests.\n\nDarkfield microscopy examines fluid from anogenital ulcers for motile spirochetes. Specimens from the mouth are unsuitable, since oral lesions contain oral spirochetes that can be confused with the pathogen. The method is also time-bound: it requires a darkfield microscope and trained personnel, and the sample must be examined within 20 minutes of collection. Its yield depends on operator skill, so dark-field examination is either not done or often performed incorrectly. Reported sensitivity falls from 75–100% in primary syphilis to 58–71% in secondary syphilis, and a negative result cannot exclude infection.\n\nDNA amplification assays are more sensitive. Darkfield microscopy and immunofluorescence have been largely replaced by the more sensitive method of PCR. In one early-infection study, real-time PCR of ulcer samples reached 100% sensitivity and 97.14% specificity. Limits remain: PCR detection for secondary or latent syphilis is not satisfactory. Antigen-detection methods are still largely investigational and are not yet routine in clinical practice.\n\nNontreponemal tests\n\nNontreponemal tests such as RPR and VDRL are the usual screening tools. They are based on the reactivity of a patient's serum to a cardiolipin-cholesterol-lecithin antigen, rather than detecting antibodies specific to syphilis. Results are reported as titres (for example 1:2, 1:4, 1:8), and a reduction in the nontreponemal antibody titer relative to baseline usually signals successful therapy. Sensitivity is imperfect: nontreponemal screening tests have a sensitivity of 70–90% in primary syphilis. Later in infection, the reactivity of the nontreponemal tests decreases with the increasing duration of latency, and in approximately 30% of patients with late latent or late syphilis the VDRL/RPR test is negative. A prozone reaction, where antibody concentration is so high that the test antigen becomes saturated, can produce false-negative results.\n\nBecause the antigen is not unique to the bacterium, many non-syphilitic states produce reactive results. These include other infections such as HIV, autoimmune conditions, vaccinations, injecting drug use, pregnancy, and older age. In one surveillance dataset, biological false positives made up 14 to 40% of reactive nontreponemal tests, depending on the prevalence of syphilis.\n\nTreponemal tests and combined algorithms\n\nTreponemal tests are more specific. They detect IgM and IgG antibodies against proteins specific to T. pallidum. Methods such as TP-PA and EIA detect antibodies specific to syphilis and are therefore called confirmatory tests. Their drawback is persistence: approximately 85% of patients remain positive for life for treponemal antibody even with successful therapy. For this reason they cannot by themselves show whether an infection is current.\n\nLaboratories combine the two families in different orders. In the traditional sequence, persons with a reactive nontreponemal test should always receive a treponemal test to confirm the diagnosis. The reverse sequence starts with a treponemal assay. If it is reactive, a nontreponemal test is performed, and when that is non-reactive, a second treponemal test checks whether the first result was a false positive. Under either sequence, a reactive RPR must also have a reactive treponemal test to be considered a case of syphilis.\n\nDiscordant results and serofast states\n\nDiscordance has several sources. A reactive nontreponemal test with a nonreactive treponemal test is classed as a biological false positive. False negatives can also occur with the nontreponemal test, most often during early acute infection. Another pattern is the serofast state: serofast patients fail to fully resolve serologically and perpetually exhibit low nontreponemal titers, whereas re-infected patients have persistently higher antibody titers. Quantitative follow-up therefore helps separate persistent low-level reactivity from new infection.\n\nNeurosyphilis and cerebrospinal fluid analysis\n\nNeurosyphilis is hard to confirm. There is no commonly accepted gold standard test for neurosyphilis, and the algorithms used vary between countries. Laboratory evaluation relies on cerebrospinal fluid (CSF) findings: CSF pleocytosis, which may decline over time, and mildly elevated CSF protein. CSF nontreponemal testing is weak, and the CSF-RPR test is not recommended due to even lower sensitivity. A nested PCR on CSF showed an overall sensitivity of 42.5%, a specificity of 97%, a positive predictive value of 77%, and a negative predictive value of 86%. Interpretation of CSF treponemal results also requires care: a negative treponemal test in the cerebrospinal fluid excludes neurosyphilis, while a positive test is highly sensitive but lacks specificity, usually due to blood contamination. Lumbar puncture is therefore recommended in all patients with late latent syphilis to exclude neurosyphilis."
},
{
"heading": "Treatment, follow-up and prevention",
"text": "First-line therapy and dosing\n\nBenzathine penicillin G is the preferred treatment at every stage of syphilis, and the 2021 CDC guidelines treat penicillin as the backbone of care. The main variable is duration. Because Treponema pallidum divides slowly, later infections need a longer period of drug exposure. For primary, secondary and early latent infection (acquired within the past year), a single intramuscular dose of 2.4 million units is standard. Late latent infection, or infection of unknown duration, is treated with three weekly intramuscular doses of 2.4 million units, for a total of 7.2 million units. Neurosyphilis is handled differently. It is treated with intravenous aqueous crystalline penicillin G for 10 to 14 days, and a follow-on course of benzathine penicillin is often added to match total treatment time. Clinicians must also use the correct long-acting formulation. A shorter-acting preparation given in error does not adequately treat syphilis.\n\nAlternatives for penicillin allergy\n\nPenicillin is the only regimen recommended for syphilis in pregnancy, which is why pregnant patients with a reported allergy are usually referred for penicillin desensitization rather than given a substitute. Outside pregnancy, doxycycline is the main alternative for patients who cannot take penicillin. Its evidence base is limited, and it requires a longer course than the single-dose penicillin regimen. Ceftriaxone is used in some situations, but it is less well validated than penicillin. Macrolides, including azithromycin, are not recommended. Macrolide efficacy has been undermined by treponemal strains carrying mutations in the 23S ribosomal RNA gene, a problem that has been documented in several countries. The guideline stance against macrolides is therefore tied directly to antibiotic resistance surveillance and the wider problem of antibiotic misuse.\n\nJarisch–Herxheimer reaction\n\nWithin hours of the first dose, many patients develop a transient febrile reaction with chills, headache, myalgia and tachycardia. This is the Jarisch–Herxheimer reaction. It is thought to reflect a rapid inflammatory response to the release of bacterial components as the organisms die, and it is most common in early syphilis with a high organism load. It usually resolves within about a day. It is generally managed with antipyretics, rest and fluids, and it is not in itself a reason to stop treatment. Clinicians should still be alert to the rare patient in whom it is severe, particularly those with neurological or cardiovascular involvement, because the reaction can strain a compromised system.\n\nFollow-up serology\n\nResponse to treatment is monitored with nontreponemal tests such as RPR and VDRL, because their titres fall over time. Titres are usually checked at about six, twelve and twenty-four months after treatment, and a fourfold decline is generally taken as evidence of cure. Treponemal tests stay positive for life, so they cannot be used to judge response. Some patients show a \"serofast\" pattern, in which the titre stops falling and remains low, and this must be separated from treatment failure or reinfection. Repeat testing is also needed because infection does not confer lasting protective immunity: a person can be reinfected after recovery, and the antibodies produced during infection do not reliably prevent it.\n\nPartner management and prevention\n\nPublic-health practice treats syphilis as a partnership problem. Recent sex partners are notified, tested and, when appropriate, treated presumptively, with the look-back window depending on the stage at diagnosis. Patients are advised to abstain from sex until any lesions have healed and treatment is complete. Condoms reduce risk but do not cover all skin contact with lesions. No vaccine is available. Chemoprophylaxis is a newer option: in three large randomized trials, a 200 mg dose of doxycycline taken within 72 hours of sex reduced syphilis and chlamydia infection by more than 70 percent. The 2024 CDC recommendation for doxycycline postexposure prophylaxis is limited to gay, bisexual and other men who have sex with men, and transgender women, who have had a bacterial STI in the past year. It is intended as part of a broader sexual health programme that includes regular testing and evidence-based care, not as a replacement for them."
},
{
"heading": "Public-health control and global response",
"text": "Control of syphilis depends on national surveillance systems that record cases, follow up people who test positive, and trace the partners they may have infected so that those partners can be tested and treated. Because latent infection produces no symptoms, most cases are found only through serological screening, so notification counts understate the true burden. A 2026 regional review of Latin America argues that strengthening integrated services, supply chains, data systems, and partner management is needed to improve outcomes.\n\nElimination of congenital syphilis\n\nEfforts to eliminate congenital syphilis are the most visible part of the global response. The WHO global initiative for the elimination of congenital syphilis is run together with efforts to eliminate mother-to-child transmission of HIV and hepatitis B. Its benchmarks are concrete: at least 95% coverage of antenatal care, syphilis testing, and treatment with at least one dose of intramuscular benzathine benzylpenicillin, sustained for two years, with the aim of keeping congenital syphilis at or below 50 cases per 100,000 live births. Cuba was the first country officially validated by WHO for eliminating congenital syphilis, in 2015, and about ten more countries and territories were validated by the end of 2018. Most of these gains came from folding syphilis into existing programmes for HIV, and in Brazil rapid tests for HIV, syphilis, and hepatitis B and C were incorporated into routine prenatal care. Progress has not been uniform. In Latin America, congenital syphilis incidence continues to rise despite available diagnosis and treatment, and in New York State a community-led planning group was convened after a 410% increase in congenital syphilis cases from 2012 to 2022. In 2026, Denmark became the first European Union country to eliminate mother-to-child transmission of HIV and syphilis.\n\nShortages of benzathine penicillin\n\nBenzathine penicillin G (BPG) is the only recommended treatment for syphilis in pregnancy, so shortages of this drug have direct consequences for newborns. In the United States, Pfizer issued a voluntary recall of identified Bicillin L-A lots in July 2025 because of particulate matter contamination, and supply has been constrained since then. In April 2026 the manufacturer extended the next delivery to October 2026 and moved the anticipated recovery date to the fourth quarter of 2027. Health authorities have responded by rationing. The CDC continues to advise jurisdictions to strongly consider preserving BPG for pregnant patients. Some states have prioritised supply for pregnant people, infants, and their sexual partners, and Canadian guidance has limited the drug to pregnant patients and their contacts. Non-pregnant patients may be given doxycycline, for 14 days in primary, secondary, and early latent syphilis and for 28 days in late latent syphilis or infection of unknown duration. Temporary importation of an equivalent product, Lentocilin, has also been permitted in the US. The substitution has costs: in one Dallas hospital during a 2023 shortage, only 61 of 84 doxycycline prescriptions (73%) were confirmed as dispensed. Shortages also fall unevenly on particular communities. In Australia, BPG is the most effective treatment for syphilis, and its supply matters most for Aboriginal and Torres Strait Islander people, who are disproportionately affected by both syphilis and rheumatic heart disease.\n\nEthical and social dimensions\n\nTesting, reporting, and partner notification all involve trade-offs between public health and individual privacy, and stigma can deter people from being tested or treated. Access to treatment is also a matter of equity, as the shortages above show. The historical reference point is the US Public Health Service Untreated Syphilis Study at Tuskegee, conducted between 1932 and 1972. There is no evidence that researchers obtained informed consent from participants. Researchers also withheld treatment even after it had become easily available. The study ended in 1972 on the recommendation of an Ad Hoc Advisory Panel, after press reports drew public attention to it. The case shaped later research ethics. The 1974 National Research Act and the Belmont Report that followed it framed consent around information, comprehension, and voluntariness, and the institutional review board system was built on those principles."
},
{
"heading": "Historical discovery and treatment",
"text": "The origin of syphilis in Europe remains a contested question. The most widely discussed explanation is the Columbian hypothesis, which holds that sailors from Columbus's voyages, who reached the Americas in 1492, carried the infection back to Europe. The timing fits the first well-documented epidemic, which broke out in 1495 among French troops during the campaign against Naples. Critics of this view argue that the disease already existed in the Old World but had not yet been separated from leprosy and other chronic skin and bone conditions. Later work has shifted the balance. A 2024 study of ancient DNA from South American skeletal remains, published in Nature, favoured an American origin and linked the global spread of the disease to transatlantic trade and European colonial expansion. Phylogenetic analyses of Treponema pallidum strains point the same way, suggesting that the venereal form emerged relatively recently in human history, while the non-venereal treponemal infections are older.\n\nThe epidemic's name shows how quickly it became a political matter. Italians called it the \"French disease\", because the French army had brought it, while the French called it the \"Neapolitan disease\". Across Europe, populations tended to name the disease after a neighbour or rival rather than admit that it had begun at home. England and Ireland used both \"French\" and \"Spanish\" labels, Poland was linked to Germany, and Russia linked it to Poland. The modern name comes from the Latin poem Syphilis, sive morbus Gallicus by the Italian physician and poet Girolamo Fracastoro, published in 1530. The poem's title keeps the older French association, but the name \"syphilis\" was not in general use until the early nineteenth century; before that the disease was usually called the French pox, the Spanish pox, or simply \"the pox\".\n\nThe identity of the causative agent was not known until 1905. On 3 March of that year, the zoologist Fritz Schaudinn and the dermatologist Erich Hoffmann, working at the Charité hospital in Berlin, examined material from a syphilitic lesion under dark-field microscopy and observed slender spiral-shaped organisms. They first named the organism Spirochaeta pallida, which is now called Treponema pallidum. The discovery was preceded by a disputed claim that a protozoan was responsible, and it prompted systematic follow-up work that confirmed the organism's causal role. In 1906, August von Wassermann and his colleagues introduced a complement-fixation test that detected antibodies reacting to the spirochete. This was the first serological test for the disease. It made it possible to measure the disease's prevalence more accurately and to link laboratory findings with clinical stages.\n\nTreatment before the twentieth century relied largely on mercury and other toxic compounds, which offered limited benefit. The first systematic chemotherapeutic approach came from Paul Ehrlich, who developed the arsenical compound arsphenamine, marketed as Salvarsan (compound 606). It was introduced in 1910 and was regarded as an effective and less toxic anti-syphilitic agent than earlier remedies, though it still required long and sometimes painful courses of injection and carried risks. Its success established the principle that a chemical agent could be designed to target a specific pathogen. Penicillin, discovered by Alexander Fleming in 1928, was tested against syphilis in the early 1940s, when trials showed that it cured the infection reliably and with few side effects. By the mid-1940s penicillin had replaced arsenicals as the standard treatment, a shift that rapidly changed the course of the disease in many countries."
},
{
"heading": "Current research and unresolved questions",
"text": "Vaccine development\n\nA vaccine remains the most significant unmet need in syphilis control. The organism cannot be grown continuously in laboratory culture, which slows research and makes it hard to produce large amounts of vaccine material. Its outer membrane carries only a limited number of outer membrane proteins (OMPs), which are the usual vaccine targets in other bacterial infections, and many of them are highly variable, allowing the bacterium to evade the human immune system. Animal work offers some encouragement: gamma-irradiated organisms gave complete protection in rabbit models, but that immunization schedule is not practical for people .\n\nSeveral vaccine platforms are under study, including subunit, virus-like particle, mRNA and outer membrane vesicle formats, each with trade-offs in manufacturing and efficacy . Researchers also face a demanding efficacy bar. A candidate would have to provide full protection, because partial protection could allow infection to persist unnoticed as latent disease . The immune correlates of protection in humans are still not firmly defined, although an animal model has helped clarify them . Current candidate antigens include TprC, Tp92 and TprK, and whether certain lipoproteins reach the cell surface remains disputed . Public acceptance is a further concern, as skepticism linked to the Tuskegee experiments persists among some communities .\n\nSurveillance of antibiotic resistance\n\nMacrolide antibiotics such as azithromycin have been used as oral alternatives to benzathine penicillin, and resistance to them has spread. In a French study of 146 patients with early syphilis, the A2058G mutation in the 23S rRNA gene was found in 85% of the population tested . That study detected no doxycycline-associated mutations . In North America, nearly all strains with a determinable genotype carried macrolide resistance, with 584 of 599 resistant strains carrying the A2058G change . Southern African surveillance has recorded a significant rise in macrolide-resistant symptomatic primary cases in South Africa over the study period . Phylogenetic work indicates that resistance arose independently in several circulating lineages rather than spreading from a single source . The same analysis raised a concern that mass campaigns against yaws could select for resistance in the closely related subspecies pertenue . Based on such data, a study in Hunan, China concluded that macrolides such as azithromycin should be avoided as a treatment option for syphilis in that setting, which bears directly on guidelines that still list them as alternatives. Because the organism is genetically stable, genomic surveillance of doxycycline resistance can focus on specific 16S rRNA positions that could serve as early warning signs .\n\nGenomics and the origin of the pathogen\n\nSequencing of historical and modern strains has revealed considerable diversity in the genes encoding outer membrane proteins . This has implications for vaccine design and makes the case for high-quality genomes from a wider range of regions. Phylogenetic analyses of large genome collections have separated strains into the Nichols-like and SS14-like lineages . Such work has also shown that sequencing is feasible from clinical material. One Hunan study found that whole blood could be used to determine molecular subtypes and monitor resistance, especially when chancres are absent . Continuing this approach, DNA sequencing of historical and contemporary genomes is the main route to resolving the disease's evolutionary history and its geographic origins, although the evidence remains incomplete.\n\nPoint-of-care and multiplex diagnostics\n\nTreponemal point-of-care tests yield results in 10–15 minutes, allowing diagnosis and treatment in a single visit without a laboratory or intensive technical training. In 2023, Health Canada approved a multiplex point-of-care assay that detects both syphilis and HIV antibodies in under five minutes . Its sensitivity in community settings, especially in people with low RPR titres, still needs real-world evaluation . A systematic review found that treponemal point-of-care testing in low-resource antenatal settings increased testing and treatment rates and prevented more adverse pregnancy outcomes than laboratory screening . By contrast, laboratory-based molecular platforms need continuous power, clean water and climate control, which limits their reach in remote areas . Whether dual treponemal and nontreponemal rapid tests offer additional benefit remains an open question ."
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"license": "https://creativecommons.org/licenses/by/4.0/"
}