Syphilis
Syphilis is a chronic, systemic bacterial infection caused by the spirochete Treponema pallidum subspecies pallidum.[1][2] Transmission occurs primarily through direct mucocutaneous contact with infectious lesions during sexual activity, though it can also pass congenitally from infected mothers to fetuses.[3][4] Without intervention, the disease advances through distinct stages—primary (characterized by a painless chancre at the site of inoculation), secondary (featuring a disseminated rash and constitutional symptoms), latent (asymptomatic but infectious), and tertiary (involving destructive gummatous lesions, cardiovascular pathology, or neurosyphilis)—culminating in high morbidity or mortality from organ failure.[1][3] Penicillin remains the cornerstone of therapy, achieving cure in early infection but requiring prolonged regimens for later stages, with T. pallidum exhibiting no significant antibiotic resistance to date.[3] The pathogen's origins trace to ancient human populations, with genomic evidence from pre-Columbian European remains challenging the traditional Columbian hypothesis of New World importation via 15th-century explorers, indicating instead a deep Old World history of treponemal disease.[5] Despite curative antibiotics since the 1940s, syphilis persists as a major public health concern, with the World Health Organization estimating 8 million incident cases among adults aged 15–49 in 2022, disproportionately affecting low- and middle-income regions through inadequate screening and behavioral factors.[6] In the United States, primary and secondary syphilis diagnoses have risen sharply since 2000, driven by increases among men who have sex with men and heterosexual networks, while congenital cases approached 4,000 in 2024 amid gaps in prenatal care.[7][8] These trends underscore syphilis's potential for resurgence absent vigilant surveillance and contact tracing, even in resource-rich settings.[9]
Clinical Manifestations
Primary Stage
The primary stage of syphilis manifests after an incubation period of 10 to 90 days following inoculation with Treponema pallidum, with a median duration of 21 days.[10] This stage is defined by the development of a chancre, a typically solitary, firm, painless ulcer at the site of infection.[3] The chancre appears as a round or oval erosion with clean, sharp borders and a rubbery base, measuring 0.3 to 3 cm in diameter.[11] Common locations for the chancre include the external genitalia, anus, rectum, or oropharynx, corresponding to the portal of entry during sexual contact.[1] Although usually painless, atypical presentations can involve multiple chancres or painful lesions, particularly in cases of co-infection or trauma.[3] Regional lymphadenopathy, often nontender and discrete, frequently accompanies the chancre within 1 to 2 weeks of its appearance.[11] Untreated, the chancre resolves spontaneously within 3 to 6 weeks, leaving minimal scarring, but the underlying infection advances to the secondary stage in nearly all cases.[12] During this phase, the lesion is highly infectious due to the presence of spirochetes in the exudate, facilitating transmission through direct contact.[6] Systemic symptoms are absent in primary syphilis, distinguishing it from later stages.[10]Secondary Stage
The secondary stage of syphilis develops weeks to months after the primary chancre, typically 4 to 10 weeks following initial infection, as Treponema pallidum disseminates hematogenously.[10] This dissemination leads to widespread mucocutaneous and systemic manifestations, rendering the stage highly infectious, particularly through mucous membrane lesions.[3] Untreated, symptoms usually persist for 3 to 6 weeks before resolving spontaneously, though relapses occur in up to 25% of cases within the first year.[10] The hallmark feature is a symmetric, nonpruritic maculopapular rash that often involves the trunk, extremities, palms, and soles, appearing as copper- or red-colored spots that may progress to pustules or papules.[1][13] Mucous patches—silver-gray, painless erosions on oral, genital, or anal mucosa—and condyloma lata, broad, moist, wart-like plaques in intertriginous areas, are highly contagious due to teeming spirochetes.[14][15] Generalized lymphadenopathy, particularly nontender posterior cervical and epitrochlear nodes, accompanies the rash in most patients.[13] Systemic symptoms mimic a viral illness, including low-grade fever, malaise, anorexia, weight loss, sore throat, arthralgias, and myalgias.[1] Patchy, "moth-eaten" alopecia of the scalp, eyebrows, or beard may occur, alongside headaches from aseptic meningitis in some cases.[10] Less common manifestations include hepatitis, nephritis, or iritis, reflecting multiorgan involvement.[16] Without intervention, the stage transitions to early latent syphilis, where symptoms abate but infection persists, with potential for further dissemination.[3] Serologic titers peak during this phase, aiding diagnosis when clinical findings are subtle.Latent Stage
The latent stage of syphilis follows the resolution of secondary symptoms if untreated and is defined as a period of Treponema pallidum infection without clinical manifestations of primary, secondary, or tertiary disease, though serological evidence persists.[17] This stage is identified solely through positive treponemal and nontreponemal tests, such as the rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) assays combined with confirmatory treponemal-specific tests like the Treponema pallidum particle agglutination (TP-PA) or fluorescent treponemal antibody absorption (FTA-ABS).[17][10] Latent syphilis is subclassified into early latent and late latent based on duration since infection. Early latent syphilis occurs within one year of acquisition, often documented by recent seroconversion, a history of primary or secondary symptoms within that timeframe, or epidemiological links such as sexual exposure to an infectious partner.[18] Individuals in this phase remain potentially infectious through sexual contact or blood transfusion, with relapse to secondary syphilis possible in up to 25% of untreated cases due to incomplete immune containment of spirochetes.[19] Late latent syphilis, exceeding one year post-infection, carries lower relapse risk and minimal sexual transmissibility, though vertical transmission to a fetus remains possible if untreated during pregnancy.[20][17] Without intervention, the latent stage can persist indefinitely, potentially lasting decades, during which spirochetes disseminate systemically but evade symptomatic detection via immune modulation, including molecular mimicry and surface protein variation.[10] Progression to tertiary syphilis occurs in approximately 15-30% of untreated cases, manifesting years to decades later with gummatous, cardiovascular, or neurological complications, underscoring the necessity of serological screening in at-risk populations.[21] Treatment for early latent syphilis involves a single intramuscular dose of benzathine penicillin G (2.4 million units), while late latent or unknown-duration cases require three weekly doses of the same regimen to ensure sustained bactericidal levels.[17] Post-treatment serological follow-up is essential to confirm decline in nontreponemal titers, with failure indicating possible reinfection or treatment inadequacy.[17]Tertiary Stage
Tertiary syphilis manifests in 15–30% of untreated individuals, emerging 10–30 years after primary infection.[1] This stage involves destructive inflammatory processes leading to organ damage, primarily through gummatous lesions and cardiovascular involvement, distinct from neurosyphilis.[3] Gummas, the characteristic benign tertiary lesions, are focal granulomatous infiltrates that undergo necrosis, forming soft, rubbery tumors capable of eroding tissues.[10] Gummatous syphilis affects skin, bones, and internal organs such as the liver and testes, often presenting as painless nodules that ulcerate and heal with scarring.[10] Bone gummas cause periostitis or osteitis, leading to pain, pathologic fractures, or hypertrophic osteoarthropathy, typically 3–10 years post-infection.[13] Visceral gummas, though rarer, can produce hepatogummas with hepatic enlargement or testicular gummas resulting in atrophy.[10] These lesions arise from localized hypersensitivity reactions to persistent Treponema pallidum antigens rather than active bacterial proliferation.[22] Cardiovascular syphilis, comprising 80–85% of tertiary manifestations, primarily targets the ascending aorta via endarteritis obliterans, causing mesaortitis.[10] This progresses to aortic regurgitation, saccular aneurysms, or coronary ostial narrowing, with symptoms including angina, heart failure, or sudden rupture, often fatal without intervention.[23] Aortic involvement predominates in males and develops over decades in untreated cases.[24] Overall, tertiary syphilis was historically responsible for significant morbidity and mortality prior to widespread penicillin use, though cases are now exceedingly rare in treated populations.[3]Neurosyphilis
Neurosyphilis denotes the invasion of the central nervous system (CNS) by Treponema pallidum, the spirochete causative of syphilis, potentially occurring at any disease stage but with higher diagnostic frequency in latent or late phases due to cumulative bacterial dissemination via hematogenous spread and direct meningeal penetration.[25] This CNS involvement arises from the bacterium's neurotropism, enabled by its ability to traverse the blood-brain barrier, leading to inflammation, vascular damage, or parenchymal degeneration depending on the timing and extent of invasion.[26] Asymptomatic neurosyphilis, characterized solely by cerebrospinal fluid (CSF) abnormalities without clinical signs, represents the most prevalent form, often detected incidentally via lumbar puncture in untreated or inadequately treated individuals.[27] Symptomatic neurosyphilis encompasses early and late variants. Early forms include acute syphilitic meningitis, manifesting 2 weeks to 2 years post-infection with headache, photophobia, neck stiffness, and cranial nerve palsies, and meningovascular syphilis, emerging 4–7 years after primary infection, involving endarteritis that precipitates ischemic strokes, hemiparesis, or aphasia.[26] Late parenchymatous forms, rarer in the penicillin era but historically significant, comprise tabes dorsalis and general paresis of the insane. Tabes dorsalis, typically arising 15–30 years post-infection, features degeneration of the dorsal columns and roots, yielding lancinating neuralgias, sensory ataxia (worsened by visual loss or Romberg sign positivity), absent deep tendon reflexes, and Argyll Robertson pupils (accommodate but fail to react to light).[28] General paresis, involving cerebral atrophy and gliosis, presents 10–30 years after infection with progressive dementia, delusions, irritability, slurred speech, tremors, and seizures, historically mimicking psychiatric disorders and contributing to institutionalization before serological diagnostics.[29] Diagnosis hinges on clinical suspicion corroborated by CSF analysis in patients with reactive serum treponemal and nontreponemal tests (e.g., RPR or VDRL), as blood serology alone cannot distinguish neurosyphilis.[3] Lumbar puncture reveals CSF pleocytosis (white blood cells >5/μL, predominantly lymphocytes), elevated protein (>45 mg/dL), and a reactive CSF-VDRL test, which boasts >99% specificity but <50% sensitivity, necessitating supplementary CSF treponemal assays (e.g., FTA-ABS) or response to therapy for confirmation.[26] Neuroimaging via MRI may show leptomeningeal enhancement, infarcts, or atrophy, while HIV co-infection elevates risk and alters CSF profiles, with studies indicating 1–2% annual progression to symptomatic neurosyphilis in untreated HIV-syphilis cases.[30] Treatment mandates parenteral penicillin G, with aqueous crystalline penicillin G at 18–24 million units daily (divided doses) intravenously for 10–14 days as the regimen of choice, achieving bactericidal levels in CSF; alternatives like procaine penicillin with probenecid apply for outpatient management but require desensitization in penicillin-allergic patients via doxycycline or ceftriaxone, though data on latter efficacy remain limited.[30] Post-treatment CSF monitoring at 6, 12, and 24 months assesses decline in pleocytosis and serologic normalization, with persistent abnormalities signaling treatment failure or reinfection.[26] Epidemiologically, neurosyphilis incidence tracks syphilis resurgence, with U.S. cases rising alongside primary/secondary syphilis from 11.9 per 100,000 in 2019, and neurologic involvement noted in 0.6–1.0% of early syphilis diagnoses as of 2023, disproportionately affecting men who have sex with men and HIV-positive individuals due to behavioral and immunological factors.[31] In Europe, annual rates span 0.16–2.1 per 100,000 adults, underscoring the need for vigilant screening in high-risk cohorts.[32]Congenital Syphilis
Congenital syphilis results from transplacental transmission of Treponema pallidum from an infected mother to the fetus during pregnancy, or less commonly via contact with infectious lesions during delivery.[4] Transmission risk exceeds 80% in untreated primary or secondary maternal syphilis but drops below 2% with adequate maternal treatment before the third trimester.[33] Untreated infection leads to adverse outcomes in up to 40% of pregnancies, including stillbirth, neonatal death, or prematurity.[34] In the United States, congenital syphilis cases reached 5,726 in 2023, yielding a rate of 77.9 per 100,000 live births, reflecting an 80% increase from 2018 to 2022 and over a 740% rise from a decade prior, though annual growth slowed slightly in 2023.[33] [35] Globally, the World Health Organization estimated 523 cases per 100,000 live births in 2022, with higher burdens in low-resource settings due to limited prenatal screening.[36] These trends stem from rising maternal syphilis incidence, inadequate screening, and treatment delays, contributing to nearly 90% of U.S. cases in 2022.[37] Early congenital syphilis manifests within the first two years of life, often in the initial weeks, with symptoms including low birth weight, hepatosplenomegaly, jaundice, hemolytic anemia, thrombocytopenia, generalized lymphadenopathy, mucocutaneous rash (maculopapular or bullous, especially on palms and soles), rhinitis ("snuffles" from bloody nasal discharge), and pseudoparalysis from painful osteochondritis or periostitis.[38] [34] Pneumonitis, meningitis, or nephrotic syndrome may also occur, while asymptomatic infants comprise up to 60% at birth but risk progression without intervention.[33] Late congenital syphilis, emerging after age two, arises from persistent inflammation or scarring and features interstitial keratitis (causing photophobia and vision loss), Hutchinson teeth (notched central incisors), sensorineural deafness from eighth nerve involvement, saber shins (anterior tibial bowing), mulberry molars, Clutton joints (symmetric knee effusions), gummatous osteitis, or neurological deficits like paresis.[33] [34] The classic Hutchinson triad—interstitial keratitis, Hutchinson teeth, and deafness—occurs in fewer than 10% of untreated cases but signifies severe prior infection.[33] Diagnosis relies on maternal history, infant clinical evaluation, and laboratory confirmation, including quantitative nontreponemal tests (e.g., RPR or VDRL) on infant serum compared to maternal titers (fourfold higher suggests infection), followed by treponemal tests (e.g., FTA-ABS) for specificity.[39] Direct detection via darkfield microscopy of lesions or placenta, radiographic evidence of metaphyseal lucencies, CSF analysis for neurosyphilis (elevated protein, pleocytosis, or positive VDRL), and long-bone X-rays support presumptive cases, especially in symptomatic or serodiscordant infants.[39] [34] Treatment involves parenteral penicillin G: aqueous crystalline for neonates with suspected neurosyphilis (50,000 units/kg IV every 12 hours for 10-14 days) or procaine penicillin for probable disease without CSF involvement, with dosages adjusted by age and weight; alternatives are unavailable due to resistance risks in non-penicillin regimens.[39] Post-treatment serologic follow-up every 2-3 months until nonreactive or stable, with Jarisch-Herxheimer reactions possible in early symptomatic cases.[39] Prevention centers on universal syphilis screening for pregnant women at the first prenatal visit, with repeat testing in the third trimester and at delivery for high-risk groups (e.g., prior positives, multiple partners), followed by prompt penicillin treatment to avert fetal infection.[39] [40] In 2022, missed third-trimester testing and inadequate maternal therapy accounted for most U.S. cases, underscoring the need for enhanced surveillance and partner notification.[37] Untreated, congenital syphilis carries 20-30% mortality in early stages, with survivors facing lifelong sequelae reducible by timely intervention.[33]Etiology and Transmission
Causative Bacterium
Syphilis is caused exclusively by the bacterium Treponema pallidum subspecies pallidum (T. pallidum subsp. pallidum), a member of the spirochete phylum. This pathogen is a motile, spiral-shaped bacterium characterized by its corkscrew morphology, with dimensions typically ranging from 6 to 20 micrometers in length and 0.1 to 0.2 micrometers in diameter.[10][41] Its helical structure enables rapid motility via endoflagella, or axial filaments, located between the inner cytoplasmic membrane and outer sheath.[42] T. pallidum subsp. pallidum is microaerophilic and Gram-negative, though it does not stain well with Gram methods due to its thin peptidoglycan layer and outer membrane rich in lipoproteins.[10] The bacterium is an obligate parasite incapable of cultivation on standard artificial media, necessitating propagation in mammalian hosts such as rabbits for experimental purposes, which has historically hindered research.[42] It exhibits a slow growth rate and fragile structure, sensitive to environmental stresses like temperature fluctuations, desiccation, and oxygen exposure, surviving outside the host for only minutes to hours.[41] Direct visualization requires dark-field or phase-contrast microscopy, as its slender form renders it invisible under conventional light microscopy.[10] Genetically, T. pallidum subsp. pallidum possesses a small, linear chromosome of approximately 1.14 million base pairs, encoding around 1,040 protein-coding genes, with limited metabolic capabilities reflecting its parasitic lifestyle; it lacks genes for de novo synthesis of most amino acids, nucleotides, and fatty acids, relying on host nutrients.[43] The genome features high antigenic variation through mechanisms like recombination in variable loci, contributing to immune evasion.[44] Phylogenetic analyses reveal two primary global lineages, Nichols and SS14, with recent expansions linked to epidemic syphilis strains.[44] This subspecies is distinguished from related treponemes causing yaws (T. pallidum subsp. pertenue) and bejel (T. pallidum subsp. endemicum) by genetic markers and clinical manifestations, though all share over 99% sequence identity.[45]Transmission Mechanisms
Syphilis is transmitted primarily through direct contact with infectious lesions containing Treponema pallidum subsp. pallidum during sexual activity, including vaginal, anal, or oral intercourse, where the spirochetes penetrate mucous membranes or abraded skin.[1] [6] Transmission efficiency is highest during primary and secondary stages, with estimates of 51-64% per sexual partnership involving an infectious partner, though per-act probabilities range from 0.5-1.4% in studies of men who have sex with men, rising to 20-30% with direct lesion contact.[46] [47] Factors enhancing risk include multiple sexual acts, lack of condom use, and concurrent presence of genital ulcers or abrasions facilitating bacterial entry, while intact skin provides a barrier.[46] Vertical transmission occurs from infected mothers to fetuses via the placenta during pregnancy or at delivery, with near-100% infection rates in untreated primary or secondary syphilis cases, potentially leading to congenital syphilis manifestations such as stillbirth or neonatal disease.[46] [48] This route accounts for significant morbidity in regions with limited prenatal screening, though risks decline in later maternal latent stages.[6] Non-sexual transmission is rare and typically requires direct inoculation of bacteria into bloodstream or tissues, such as through contaminated blood transfusions (historically documented but minimized by modern donor screening), organ transplants, or occupational exposures like needlestick injuries in healthcare settings.[46] Isolated cases involve close, prolonged contact with open lesions via kissing, human bites, or pre-mastication of food in familial settings, but casual contact—such as sharing utensils, towels, or toilet facilities—does not transmit the bacterium, as it cannot survive outside the host or penetrate intact skin.[46] [49]Pathogenesis
Immune Evasion and Progression
Treponema pallidum enters the host through mucosal abrasions or skin breaks, initiating local replication before the innate immune response activates via pattern recognition receptors on macrophages and dendritic cells, which produce proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-12.[50] Neutrophils contribute through degranulation and reactive oxygen species, but the bacterium's outer membrane, characterized by low protein density and absence of lipopolysaccharide, restricts strong innate recognition and complement activation.[50] This sparse surface antigen profile, with few outer membrane proteins (OMPs) exposed, minimizes opsonophagocytosis and allows initial tissue invasion.[50] The pathogen employs antigenic variation primarily through the TprK protein (encoded by tp0897), featuring seven variable regions that undergo gene conversion to produce diverse variants, evading antibody-mediated clearance.[50] [51] Phase variation in OMP expression, such as tp0126 and tpr genes, further alters surface antigens.[50] Virulence factors like Tp0326 induce monocyte apoptosis via RIPK1/caspase pathways and prolong neutrophil survival through ERK/PI3K/NF-κB signaling, while Tp0574 inhibits phagocytosis by triggering autophagy and prostaglandin E2 synthesis.[51] Additionally, TpF1 (tp1038) promotes immunosuppressive cytokines IL-10 and TGF-β, fostering regulatory T cells that dampen effector responses.[50] Adaptive immunity involves early IgM production within two weeks, followed by IgG targeting lipoproteins like Tp0435 and Tp0574, alongside CD4+ Th1 cells secreting IFN-γ to activate macrophages and CD8+ T cells deploying perforin and granzymes.[50] However, T. pallidum downregulates immunogenic proteins like Tp0435 to support latency and invades immune-privileged sites such as the central nervous system and placenta, limiting access to systemic immunity.[50] [51] Disease progression hinges on the interplay between delayed-type hypersensitivity (DTH), mediated by Th1 cells for bacterial containment, and humoral responses, which opsonize but fail to eradicate due to evasion tactics.[22] In primary syphilis, localized DTH clears the chancre partially, but incomplete clearance enables hematogenous dissemination to secondary stage manifestations despite peak immune activation.[22] Latency ensues from immune tolerance, possibly via persistent low-burden infection in niches or T-cell exhaustion from high antigen loads, with ~25% progressing to tertiary stages decades later, where exaggerated DTH drives granulomatous destruction in organs like the aorta and brain.[22] This failure of sterilizing immunity permits reinfection and chronic persistence.[50]Tissue Invasion and Damage
Treponema pallidum invades host tissues primarily through initial attachment to extracellular matrix components and endothelial cells at the site of entry, facilitated by adhesins such as Tp0136, which mediates binding to fibronectin and other host proteins.[52] Following local multiplication in the primary chancre, the spirochete disseminates rapidly via the bloodstream and lymphatic system, reaching distant organs including the spleen, liver, and kidneys within hours to days of infection.[53] This hematogenous spread enables T. pallidum to breach endothelial barriers, such as those in blood vessels, by disrupting intercellular junctions like VE-cadherin and exploiting cholesterol-rich lipid rafts for endocytosis-mediated traversal.[54] The bacterium's corkscrew motility and rare outer-membrane proteins further aid penetration of tight epithelial and endothelial connections, allowing systemic dissemination without immediate clearance.[55] Tissue damage in syphilis arises predominantly from the host's inflammatory response rather than direct cytolytic effects of T. pallidum, which possesses few classical virulence factors or toxins.[56] Upon tissue invasion, spirochetes trigger perivascular accumulation of plasma cells, lymphocytes, and macrophages, leading to endarteritis obliterans—a obliterative vasculitis that compromises vascular integrity and causes downstream ischemia, ulceration, and necrosis.[57] Pro-inflammatory cytokines induced by T. pallidum, including IL-6 and TNF-α, exacerbate endothelial dysfunction and amplify local inflammation, contributing to tissue destruction observed in secondary and tertiary lesions.[58] In late-stage gummatous syphilis, granulomatous reactions form with central caseous necrosis surrounded by fibrotic tissue, resulting from persistent antigenic stimulation and failed immune containment.[41] Certain T. pallidum proteins, such as Tp0750 (pallilysin) and Tp0751, contribute to localized damage by proteolytically degrading host basement membrane components like laminin and fibrinogen, potentially facilitating further invasion and impairing tissue repair.[59] Necrotic damage in infected tissues has been linked to excessive host cell pyroptosis and inflammasome activation triggered by spirochetal lipoproteins, underscoring the interplay between bacterial persistence and dysregulated immunity.[60] Overall, while T. pallidum's invasive prowess enables multi-organ tropism, the resultant pathology reflects a maladaptive host response that, in untreated cases, culminates in chronic fibrosis, aneurysms, and organ failure across cardiovascular, skeletal, and neural systems.[61]Diagnosis
Clinical Assessment
Clinical assessment of syphilis relies on a thorough patient history and physical examination to identify characteristic lesions, systemic symptoms, and stage-specific findings, which guide diagnostic suspicion prior to confirmatory testing.[3] History should elicit details of sexual exposure, including unprotected intercourse or multiple partners, incubation period typically 10 to 90 days for primary manifestations, and any prior treatment for sexually transmitted infections.[10] Risk factors such as men who have sex with men, HIV co-infection, or residence in high-prevalence areas further heighten suspicion.[13] In the primary stage, a painless, indurated chancre appears at the inoculation site, most commonly on the genitals, anus, or oropharynx, measuring 0.3 to 3 cm in diameter with clean base and rolled edges; regional lymphadenopathy may accompany it, and the lesion typically resolves spontaneously in 3 to 6 weeks without scarring.[21] [10] Multiple chancres occur in up to 30% of cases, often mistaken for trauma or herpes simplex.[13] Secondary syphilis, emerging 4 to 10 weeks after primary infection, features a symmetric, non-pruritic maculopapular rash often involving palms and soles, alongside mucous patches, condyloma lata in intertriginous areas, generalized lymphadenopathy, and constitutional symptoms like low-grade fever, malaise, sore throat, and alopecia.[3] [11] These findings, present in over 80% of untreated cases, can mimic viral exanthems or drug reactions, necessitating differentiation via serology.[10] During the latent phase, clinical findings are absent, complicating assessment without historical or serologic context; early latent syphilis (within one year of infection) may relapse to secondary symptoms in 25% of cases.[13] Tertiary manifestations, occurring in 15 to 30% of untreated individuals after years, include gummatous skin or mucosal nodules, cardiovascular lesions like aortitis, and neurologic signs such as Argyll Robertson pupils or tabes dorsalis, requiring targeted neurologic and cardiac evaluation.[11] [10] Neurosyphilis, assessable via cranial nerve exam, fundoscopy for ocular involvement, and mental status testing, can manifest at any stage but peaks in secondary or tertiary phases, with symptoms ranging from asymptomatic to meningovascular events or general paresis.[3] Physical exam must include darkfield microscopy of lesions if present for direct visualization of Treponema pallidum, though this is operator-dependent and less reliable for oral sites.[62] Differential diagnosis encompasses chancroid, lymphogranuloma venereum, psoriasis for rashes, and malignancy for gummas, underscoring the need for integrated clinical judgment.[13]Serologic Tests
Serologic testing forms the cornerstone of syphilis diagnosis due to the inability to culture Treponema pallidum in routine laboratories. These tests detect host antibodies elicited by the infection, categorized into nontreponemal and treponemal assays, which must be used in combination for accurate interpretation.[48] Nontreponemal tests measure reagin antibodies against lipoidal antigens derived from host cell damage, while treponemal tests target T. pallidum-specific proteins.[48] Sensitivity varies by disease stage, with both test types potentially negative in very early primary syphilis before seroconversion, which typically occurs 1–4 weeks post-infection.[48] [62] Nontreponemal tests, such as the rapid plasma reagin (RPR) and Venereal Disease Research Laboratory (VDRL) assays, employ a cardiolipin-cholesterol-lecithin antigen to detect nonspecific antibodies. They serve primarily for screening, establishing baseline titers, and monitoring treatment response, as titers decline fourfold within 3–6 months post-therapy in early syphilis.[48] Specificities range from 98.5%–100%, but biologic false positives occur in 0.2%–0.8% of the general population, often linked to autoimmune conditions (e.g., systemic lupus erythematosus), acute viral infections (e.g., hepatitis, HIV), malaria, pregnancy, or recent vaccinations.[48] Sensitivities by stage include 48.7%–92.7% in primary syphilis, 91%–100% in secondary, 82.1%–100% in early latent, 63%–66% in late latent, and 47%–64% in tertiary syphilis.[48] Limitations encompass subjective microscopic interpretation, prozone effects causing false negatives at high titers (resolved by dilution), and non-interchangeability between assays (e.g., RPR titers may not correlate directly with VDRL).[48] Treponemal tests, including the T. pallidum particle agglutination (TP-PA), fluorescent treponemal antibody absorption (FTA-ABS), enzyme immunoassay (EIA), and chemiluminescence immunoassay (CIA), detect immunoglobulin G (IgG) and IgM antibodies to treponemal antigens like Tp47 or Tp15/17. These assays confirm reactive nontreponemal results or screen in reverse algorithms, with TP-PA preferred over FTA-ABS for its objectivity and lack of prozone phenomenon.[48] Sensitivities are 53%–100% in primary syphilis, 90%–100% in secondary, 84.5%–100% in latent stages, and 70.6%–100% in tertiary, with specificities of 87%–100%; antibodies persist lifelong in most treated cases, precluding their use for treatment monitoring or distinguishing active from past infection.[48] False positives are rare but can arise from cross-reactivity with other spirochetes (e.g., Borrelia burgdorferi) or in low-prevalence settings using automated EIAs/CIAs.[48] [62] The U.S. Centers for Disease Control and Prevention (CDC) endorses two serologic algorithms as of 2024: the traditional approach, initiating with a nontreponemal test followed by treponemal confirmation of reactives; and the reverse sequence, starting with an automated treponemal assay (e.g., EIA/CIA) reflexed to nontreponemal testing, with discordant results resolved by a different treponemal test (e.g., TP-PA).[48] The reverse algorithm enhances detection of early or past infections but may yield more discordant results requiring adjudication (e.g., 10%–20% in some studies), while the traditional method better assesses disease activity via titers.[48] Quantitative nontreponemal titers must be reported as exact endpoints (e.g., 1:16) without qualifiers like "greater than," using the same assay type for follow-up to ensure comparability.[48] Interpretation integrates clinical findings, as serology alone cannot stage infection precisely or rule out coinfections; for instance, a reactive treponemal with nonreactive nontreponemal suggests treated or late latent syphilis, but titers guide reinfection assessment (e.g., fourfold rise).[48] In high-risk groups like pregnant individuals or those with HIV, false positives may increase due to immune dysregulation, necessitating confirmatory testing and direct detection (e.g., darkfield microscopy) when lesions are present.[48] Overall, no single test suffices, and laboratories should report the algorithm employed to aid clinical decision-making.[48]Direct Detection
Direct detection methods identify Treponema pallidum subsp. pallidum in clinical specimens, enabling definitive diagnosis without reliance on host antibody response, which is crucial for early primary syphilis where serologic tests exhibit low sensitivity (50–70%). These approaches include microscopic examination, antigen detection, and molecular amplification, applied to lesion exudates, tissue biopsies, cerebrospinal fluid (CSF), or amniotic fluid.[48][63] Dark-field microscopy (DFM) visualizes motile spirochetes in fresh chancre exudate or secondary lesions, offering rapid point-of-care results with sensitivity of 75–100% for primary syphilis and specificity of 94–100%. Specimens must be examined within 20 minutes to preserve motility, requiring trained personnel to differentiate T. pallidum from commensal treponemes; it is ineffective for oral, rectal, or healed lesions. The Centers for Disease Control and Prevention (CDC) endorses DFM in high-incidence sexually transmitted disease clinics for immediate diagnosis.[48][63] Direct fluorescent antibody (DFA-TP) assays employ fluorescence-labeled monoclonal or polyclonal antibodies to detect T. pallidum in lesion smears, achieving sensitivity of 73–100% and specificity of 91–100%, outperforming DFM by not requiring viable organisms and allowing deferred processing. Availability is restricted by the absence of U.S. Food and Drug Administration (FDA)-cleared commercial tests, confining use to specialized laboratories.[63][48] Immunohistochemistry (IHC) targets T. pallidum antigens in formalin-fixed paraffin-embedded (FFPE) tissue from skin or mucosal biopsies, with sensitivity ranging 64–94% and specificity of 100%, surpassing silver staining methods that yield only 0–41% sensitivity due to staining artifacts. IHC facilitates diagnosis of secondary syphilis rashes or tertiary gummas where treponemes persist in tissues.[48][63] Nucleic acid amplification tests (NAATs), primarily polymerase chain reaction (PCR) assays targeting genes such as polA or tpp47, detect T. pallidum DNA in lesion swabs with sensitivity of 72–95% for primary syphilis and specificity of 98–100%. These molecular methods excel in seronegative early infections, congenital cases (e.g., 67–94% in neonatal blood), and neurosyphilis CSF evaluation, though performance varies by site (lower in pharyngeal/rectal swabs) and lacks FDA clearance, necessitating laboratory-developed validation. Dual-target NAATs mitigate false negatives from genetic variation.[48][63] Despite their specificity, direct detection tests face barriers including specimen viability, expertise demands, and limited accessibility, often supplementing rather than replacing serology in routine practice. CDC guidelines urge expanded NAAT implementation for outbreak control amid rising syphilis incidence.[48]Prevention
Behavioral and Barrier Methods
Abstinence from all forms of sexual contact, including vaginal, anal, and oral sex, provides complete protection against syphilis transmission, as the bacterium Treponema pallidum requires direct contact with infectious lesions or mucous membranes for spread.[64] Mutual monogamy with a partner confirmed free of syphilis through testing eliminates risk within the relationship, assuming no extrarelational exposure occurs.[65] Limiting the number of sexual partners proportionally decreases exposure probability, with epidemiological data indicating higher partner counts correlate with elevated syphilis incidence rates.[64] Consistent and correct use of latex condoms during sexual intercourse reduces syphilis transmission risk by 50-71%, primarily by blocking contact with infectious chancres on covered genital areas, though protection is incomplete due to potential lesions on uncovered skin such as the scrotum, perineum, or pubic region.[66] Typical condom use, accounting for inconsistent application or breakage, lowers risk by approximately 29%.[66] Laboratory evidence confirms latex condoms form an impermeable barrier to T. pallidum-sized particles in fluids, but real-world efficacy varies with proper usage, including avoiding oil-based lubricants that degrade latex.[67] [68] For oral-genital contact, dental dams—latex or polyurethane sheets—offer analogous barrier protection against mucosal exposure to syphilitic sores, though adherence is lower and direct studies on syphilis prevention are limited.[67] Female condoms provide comparable mechanical barriers but face similar coverage limitations.[69] Combining behavioral strategies, such as partner reduction with barrier use, yields synergistic risk mitigation beyond either method alone.[70]Screening and Contact Tracing
Screening for syphilis typically involves serologic testing using a combination of nontreponemal tests (such as rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL]) and treponemal tests (such as Treponema pallidum particle agglutination [TP-PA] or enzyme immunoassay [EIA]) to detect infection in asymptomatic individuals.[48] The U.S. Centers for Disease Control and Prevention (CDC) recommends universal screening for all pregnant women at the first prenatal visit, with repeat testing in the third trimester and at delivery for those at high risk, such as women residing in communities with high syphilis prevalence or those with partners known to be at risk for sexually transmitted infections (STIs).[3] For nonpregnant adults and adolescents, the U.S. Preventive Services Task Force (USPSTF) advises screening only for those at increased risk, including men who have sex with men (MSM), persons with HIV infection, individuals engaging in commercial sex work, and those with multiple or anonymous sexual partners; routine screening is not recommended for the general asymptomatic population due to limited evidence of benefit in low-prevalence groups.[71] High-risk groups like MSM and HIV-positive individuals should undergo screening at least annually, or every 3–6 months if engaging in high-risk behaviors, as syphilis rates have surged in these populations, with CDC data showing over 200,000 cases reported in the U.S. in 2022 alone.[3] In response to rising congenital syphilis cases, which exceeded 2,200 in the U.S. in 2022, some jurisdictions have expanded recommendations to test all sexually active individuals aged 15–44 years.[72] Contact tracing, also known as partner notification or partner services, is a core public health intervention for syphilis, mandated in all U.S. states as a reportable disease, whereby diagnosed individuals (index patients) are interviewed confidentially by health department personnel to identify recent sexual partners for testing and presumptive treatment.[3] The process emphasizes anonymity and confidentiality to encourage disclosure, with strategies including patient referral (where the index patient notifies partners), provider referral (health workers contact partners without revealing the index patient's identity), or contract referral (a hybrid approach with time-limited patient responsibility).[73] For early syphilis (primary, secondary, or early latent stages), partners exposed within the preceding 90 days are evaluated, tested serologically, and treated presumptively with benzathine penicillin G if serologic results are pending or negative but exposure is recent, as untreated early infections are highly infectious; if no partners are identified within 90 days, evaluation extends to 1 year prior.[3] In late latent syphilis, routine partner notification is not pursued due to low transmissibility, though lifetime partners may be assessed in select cases like congenital syphilis investigations.[3] Partner services have demonstrated effectiveness in detecting additional cases, with studies showing that 20–30% of traced partners test positive for syphilis or other STIs, contributing to reduced community transmission when integrated with expedited partner therapy where legally permitted, though syphilis-specific presumptive treatment avoids legal barriers seen in bacterial STIs like chlamydia.[74] Challenges include incomplete partner disclosure due to stigma or fear, but digital tools and anonymous apps are increasingly piloted to enhance reach, as outlined in CDC toolkits for technology-based services.[75]Congenital Prevention
Prevention of congenital syphilis centers on the routine screening of pregnant women for syphilis infection, followed by prompt treatment of those who test positive to interrupt vertical transmission from mother to fetus. The Centers for Disease Control and Prevention (CDC) recommends universal serologic screening at the first prenatal visit, with repeat screening in the third trimester for all women and at delivery for those in high-risk categories, such as individuals living in areas with elevated syphilis rates or those with risk factors like incarceration or substance use.[76][77] The World Health Organization (WHO) endorses universal antenatal screening as a core strategy, emphasizing integration with other reproductive health services to facilitate early detection.[78] Treatment of maternal syphilis with penicillin G benzathine is the cornerstone of prevention, as it effectively crosses the placenta and eradicates Treponema pallidum in the fetus when administered prior to the development of fetal infection. A single intramuscular dose of 2.4 million units is standard for early syphilis in pregnancy, while later stages require three weekly doses; this regimen has been shown to prevent congenital infection in over 98% of cases when given early in gestation.[76] Treatment timing is critical: administration before 16 weeks' gestation nearly eliminates transmission risk, though interventions even in the third trimester can avert adverse outcomes if followed by fetal assessment via ultrasound or serology.[39] Partners of infected women should receive expedited treatment and testing to prevent reinfection, as untreated sexual contacts contribute to recurrent maternal syphilis and ongoing transmission risk.[37] Prenatal screening and treatment have demonstrated high effectiveness in reducing congenital syphilis incidence; retrospective analyses indicate that early and third-trimester screening prevents a substantial proportion of cases, with CDC data showing that 88% of reported congenital syphilis cases in 2022 could have been averted through timely maternal screening and intervention.[77] In resource-limited settings, decentralized point-of-care testing with same-day treatment has further enhanced outcomes by minimizing loss to follow-up.[79] Despite these measures, challenges persist, including gaps in prenatal care access and screening adherence, which have driven a 740% increase in U.S. congenital syphilis cases from 2012 to 2022, underscoring the need for enhanced public health infrastructure.[37] Ongoing efforts focus on integrating syphilis screening with HIV and hepatitis testing during routine prenatal visits to maximize coverage.[80]Vaccine Development Efforts
Efforts to develop a vaccine against Treponema pallidum, the causative agent of syphilis, have been ongoing for decades but remain in the preclinical stage as of 2025, with no candidates advancing to human clinical trials.[81][82] The resurgence of syphilis cases globally, including over 2 million incident infections annually and rising congenital syphilis rates, has intensified research priorities, driven by concerns over treatment failures from T. pallidum strains exhibiting reduced penicillin susceptibility.[83][84] Major challenges include the bacterium's inability to be cultured in vitro until 2018, which historically limited antigen identification and testing; antigenic variation, particularly in the TprK protein due to gene conversion mechanisms; and the pathogen's stealth adaptations that evade host immunity, such as sparse outer membrane proteins and mimicry of host tissues.[85][86] Vaccine candidates must elicit sterilizing immunity or at least block dissemination to prevent neurosyphilis and congenital transmission, requiring broad coverage against diverse strains identified through genomic sequencing from over 700 global isolates.[87][88] Promising preclinical candidates target outer membrane proteins (OMPs), which are surface-exposed and immunogenic. Tp0136 and Tp0663, adhesins facilitating tissue invasion, induced antibodies in rabbits that inhibited bacterial motility and dissemination in infection models, reducing bacterial loads by up to 90% in distant tissues.[89] A tri-antigen formulation combining TprC, TprK variable regions, and Tp0751 (a rare outer membrane protein) protected rabbits from syphilitic lesions upon challenge, with immunized animals showing 80-100% lesion resolution compared to controls.[90] Full-length TprC variants have also generated cross-reactive antibodies against heterologous strains, addressing variability concerns.[91] Genomic analyses confirm low overall diversity in key OMPs like Tp0136 across strains, supporting their viability as universal targets. Recent initiatives include $1.6 million in U.S. funding awarded in November 2024 to expand genomic surveillance in low- and middle-income countries, aiding strain diversity mapping for vaccine design.[82] Pre-meeting symposia, such as one preceding the 2024 International Society for STD Research conference, highlighted progress in OMP characterization and adjuvant optimization.[92] Barriers to trials include historical mistrust from events like the Tuskegee study, particularly among high-risk groups such as men who have sex with men and sex workers, alongside needs for equitable manufacturing and distribution in resource-limited settings.[93][94] Experts emphasize pairing OMP-based vaccines with novel adjuvants to enhance T-cell responses, as antibody alone may insufficiently clear infection.[95] Despite optimism from animal models, human efficacy trials face ethical hurdles in challenge studies, necessitating surrogate endpoints like reduced transmission.[96]Treatment
Standard Antibiotic Regimens
Penicillin G, administered parenterally, remains the preferred antibiotic for treating all stages of syphilis due to its proven efficacy in eradicating Treponema pallidum and the absence of documented resistance.[3][97] The standard regimens vary by disease stage, with benzathine penicillin G used for non-neurologic stages and aqueous crystalline penicillin G for neurosyphilis.[3] These recommendations, established by the U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), emphasize single-dose or multi-dose intramuscular injections for early and late syphilis, respectively, to achieve sustained bactericidal levels.[3][98]| Stage of Syphilis | Recommended Regimen |
|---|---|
| Primary, Secondary, or Early Latent (<1 year duration) | Benzathine penicillin G 2.4 million units intramuscularly in a single dose.[3][98] |
| Late Latent or Unknown Duration (>1 year) | Benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 weeks (total 7.2 million units).[3][98] |
| Tertiary (without neurologic involvement) | Benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 weeks.[3] |
| Neurosyphilis, Ocular Syphilis, or Otic Syphilis | Aqueous crystalline penicillin G 18–24 million units per day, administered as 3–4 million units intravenously every 4 hours or continuous infusion, for 10–14 days.[3] |