Syphilis

Infectious Disease MONDO:0005976 Pathograph 45 Show in embeddings browser Bacterial Infection Sexually transmitted infection

Syphilis is a chronic, multistage systemic infection caused by the spirochete Treponema pallidum subspecies pallidum, transmitted sexually or vertically from mother to fetus. Untreated it evolves through primary (chancre), secondary (disseminated mucocutaneous), latent, and tertiary (gummatous and cardiovascular) stages over years to decades, and can involve virtually any organ system - the basis of its historical epithet "the great imitator". Neurological, ocular, and otic involvement can occur at any stage, not only late disease. The central pathophysiological theme is stealth: the organism presents an outer membrane almost devoid of surface-exposed pathogen-associated molecular patterns and lacking lipopolysaccharide, and varies the few surface epitopes it does display by TprK gene conversion, so that intense local immune infiltration never achieves sterilizing clearance. It is the venereal member of the treponematoses, alongside the endemic non-venereal diseases yaws, bejel, and pinta, which are caused by distinct T. pallidum subspecies and are separate disease entities.

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17
Pathophys.
1
Histopath.
22
Phenotypes
2
Gaps
45
Pathograph
7
Medical Actions
4
Differentials
2
References
1
Deep Research
🏷

Classifications

Harrison's Part
INFECTIOUS DISEASES
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Discussions and Knowledge Gaps

2
Are there host genetic determinants of syphilis susceptibility, clinical stage progression, or the serofast state?
KNOWLEDGE GAP OPEN syphilis_host_genetic_determinants
Attached to
pathophysiology#Latency and Persistent Infection
No validated host susceptibility locus for syphilis exists, in contrast to well-established examples in other infections such as CCR5-delta32 for HIV. Reported correlations between HLA-DR+CD8+ T cell subsets and recurrence/reinfection/serofast status in HIV-syphilis coinfected cohorts are suggestive but uncontrolled and unreplicated. Because the serofast state drives repeat treatment and repeat lumbar puncture decisions in practice, a genuine host determinant would change management.
Proposed experiments
Host genome-wide association study of syphilis outcome
exp_syphilis_host_gwas
A GWAS in a well-phenotyped cohort stratified by stage at diagnosis and by serological response after adequate therapy, with HIV status modelled explicitly as a covariate rather than a confounder.
What is the host transcriptional response within syphilitic lesions at single-cell or spatial resolution?
KNOWLEDGE GAP OPEN syphilis_lesion_single_cell_gap
Attached to
pathophysiology#Th1 Cellular Immune Response and Partial Clearance
Mechanistic work on syphilis has been overwhelmingly pathogen-side (outer-membrane protein structural modelling, TprK deep sequencing). No single-cell or spatial transcriptomic dataset of chancre, secondary rash, or gumma tissue was identified. This leaves the central claim of this entry's pathograph - that a Th1 response clears organisms from mucocutaneous lesions without eradicating infection - inferred rather than directly observed in human tissue.
Proposed experiments
Spatial transcriptomics of staged syphilitic lesions
exp_syphilis_spatial_transcriptomics
Spatial transcriptomic and single-cell profiling of paired chancre, secondary-rash, and gumma biopsies to test whether the predicted Th1 and macrophage-activation programme is present and how it differs between the clearing early lesions and the persistent tertiary granuloma.
⚙

Pathophysiology

17
Treponemal Mucosal Inoculation and Local Replication
T. pallidum penetrates intact mucous membranes or abraded skin at the site of sexual contact and replicates locally. This is the trigger event of the pathograph.
blood vessel endothelial cell CL:0000071 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves blood vessel endothelial cell (CL:0000071). CL:0000071 is a cell type from the Cell Ontology.
Downstream
Early Hematogenous and Lymphatic Dissemination Local replication seeds the bloodstream and regional lymphatics.
Obliterative Endarteritis Local treponemal presence provokes the endarteritis that produces the indurated chancre.
Th1 Cellular Immune Response and Partial Clearance Local antigen is taken up and presented, initiating the cellular immune response.
Show evidence (1 reference)
PMID:27721440 SUPPORT Other
"The paucity of surface-exposed pathogen-associated molecular patterns (PAMPs) enables the bacterium to undergo repeated bouts of dissemination that are poorly detected by innate immunity"
Establishes that the organism disseminates from the inoculation site while evading innate detection.
Early Hematogenous and Lymphatic Dissemination
Spirochetemia is established within days to weeks and precedes the appearance of the primary chancre. This early, clinically silent dissemination explains why disseminated secondary disease, neuroinvasion, and congenital transmission can all follow an unnoticed primary lesion.
Downstream
Immune-Privileged Sanctuary Site Invasion Circulating treponemes cross the blood-brain, blood-ocular, and placental barriers.
Secondary Disseminated Mucocutaneous Disease Widespread hematogenous seeding produces the generalized secondary eruption.
Show evidence (1 reference)
PMID:27721440 SUPPORT Other
"enables the bacterium to undergo repeated bouts of dissemination that are poorly detected by innate immunity and also explains the lack of systemic inflammatory symptoms characteristic of the disease"
Supports repeated poorly-detected dissemination as a defining feature of the organism's behaviour in the host.
Stealth Outer Membrane and PAMP Paucity
The treponemal outer membrane carries very few surface-exposed integral membrane proteins and, unlike other Gram-negative bacteria, contains no lipopolysaccharide. The resulting paucity of pathogen-associated molecular patterns denies innate immunity its usual trigger, which is why systemic inflammatory symptoms are muted despite ongoing spirochetemia.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Latency and Persistent Infection Failure of innate recognition permits persistence after the clinical manifestations of early disease resolve.
Show evidence (2 references)
PMID:27721440 SUPPORT Other
"fragile outer membrane lacks lipopolysaccharide (LPS), the highly proinflammatory glycolipid found in Gram-negative bacteria"
Directly supports the absence of LPS, the central molecular basis of the innate-recognition failure this node represents.
PMID:27721440 SUPPORT Other
"The paucity of surface-exposed pathogen-associated molecular patterns (PAMPs) enables the bacterium to undergo repeated bouts of dissemination that are poorly detected by innate immunity and also explains the lack of systemic inflammatory symptoms characteristic of the disease"
Links the low PAMP density to both poor innate detection and the muted systemic inflammatory phenotype.
TprK Antigenic Variation
The tprK gene carries seven discrete variable (V) regions that are the focus of the anti-TprK antibody response. New V region sequences are generated by segmental gene conversion from donor sites elsewhere in the genome, so the few surface epitopes that are exposed change continuously during infection and outrun the maturing humoral response.
antigenic variation GO:0020033 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased antigenic variation (GO:0020033). GO:0020033 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Latency and Persistent Infection Continuous epitope turnover prevents antibody-mediated clearance and permits long-term persistence.
Show evidence (2 references)
PMID:15186410 SUPPORT Other
"We describe the sequence anatomy of the seven V regions of tprK and the identification of putative donor sites for new V region sequences, and we propose a model for generation of new V regions by segmental gene conversion."
Establishes segmental gene conversion as the mechanism generating TprK variable-region diversity. Evidence source is OTHER because this is molecular genetics of the pathogen rather than a human, animal, or cell-culture phenotype study.
PMID:15186410 SUPPORT Other
"The TprK V regions are the focus of anti-TprK antibodies arising during infection."
Establishes that the varying V regions are the target of the host antibody response, which is what makes their variation immune evasion.
Th1 Cellular Immune Response and Partial Clearance
Dendritic cells present treponemal antigen to CD4-positive T cells, driving a Th1-polarized response with interferon-gamma-mediated macrophage activation and phagocytosis. This response clears organisms from mucocutaneous lesions - which is why the chancre and the secondary eruption resolve without treatment - but does not eradicate infection.
dendritic cell CL:0000451 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dendritic cell (CL:0000451). CL:0000451 is a cell type from the Cell Ontology. CD4-positive, alpha-beta T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology. macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
T-helper 1 type immune response GO:0042088 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased T-helper 1 type immune response (GO:0042088). GO:0042088 is a biological process from the Gene Ontology. ↑ INCREASED phagocytosis GO:0006909 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased phagocytosis (GO:0006909). GO:0006909 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Latency and Persistent Infection Partial containment without eradication converts active disease into clinically silent latent infection.
Show evidence (2 references)
PMID:40708500 SUPPORT Other
"This translational update describes the host innate and adaptive immune responses in syphilis and the sophisticated mechanisms employed by T. pallidum to avoid immune clearance."
Anchors the host innate and adaptive response that this node represents, alongside the evasion that prevents it achieving clearance. Evidence source is OTHER because the citation is a translational review.
PMID:27721440 SUPPORT Other
"The paucity of surface-exposed pathogen-associated molecular patterns (PAMPs) enables the bacterium to undergo repeated bouts of dissemination that are poorly detected by innate immunity"
PARTIAL because the quoted text supports the failure of clearance rather than the specific Th1 cellular architecture.
Obliterative Endarteritis
Lymphoplasmacytic infiltration of small and medium vessel walls with intimal proliferation narrows and obliterates the lumen, producing ischemic tissue injury. This single vascular lesion is the shared histological substrate of the primary chancre, the gumma, and tertiary aortitis, which is why one mechanism explains lesions in otherwise unrelated organs.
blood vessel endothelial cell CL:0000071 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves blood vessel endothelial cell (CL:0000071). CL:0000071 is a cell type from the Cell Ontology. plasma cell CL:0000786 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology.
Downstream
Syphilitic Aortitis Endarteritis of the aortic vasa vasorum produces ischemic medial injury.
Meningovascular Neurosyphilis Endarteritis of cerebral vessels produces stroke syndromes.
Genital ulcers Ischemic injury from local endarteritis produces the indurated, clean-based chancre.
Show evidence (1 reference)
PMID:27982548 SUPPORT Human Clinical
"Presumably, Treponema pallidum invades the aortic wall and the inflammatory response progresses towards obliterative endarteritis and necrosis of the muscular and elastic fibers in the aortic media."
Identifies obliterative endarteritis as the vascular lesion through which treponemal invasion damages tissue.
Immune-Privileged Sanctuary Site Invasion
T. pallidum crosses the blood-brain, blood-ocular, and placental barriers. Because this can happen during the earliest spirochetemia, neurosyphilis, ocular syphilis, and otosyphilis are not confined to late disease but may present at any stage - a reframing of the classical teaching that materially changes when clinicians should evaluate for them.
Downstream
Meningovascular Neurosyphilis Early CNS invasion establishes the substrate for meningovascular disease.
Parenchymal Neurosyphilis Persistence in the CNS compartment permits the late parenchymal syndromes.
Transplacental Fetal Dissemination Placental crossing seeds the fetus.
Uveitis Invasion across the blood-ocular barrier produces ocular syphilis.
Sensorineural hearing impairment Invasion of the inner ear produces otosyphilis.
Show evidence (2 references)
PMID:40708500 SUPPORT Other
"The pathogen's ability to evade the immune system by using virulence factor-based strategies and invading immune-privileged sites enables persistent infection in the untreated host."
Directly supports the mechanism this node asserts - invasion of immune-privileged sites as the basis of persistent infection. Evidence source is OTHER because the citation is a translational review.
PMID:35819903 SUPPORT Human Clinical
"Syphilis can cause neurologic, ocular, or otic manifestations, possibly resulting in permanent disability or death."
PARTIAL: establishes the manifestation set that sanctuary-site invasion produces, rather than the invasion mechanism itself.
Secondary Disseminated Mucocutaneous Disease
Widespread hematogenous spread produces the generalized maculopapular eruption (classically involving palms and soles), condylomata lata, mucous patches, generalized lymphadenopathy, and visceral involvement including syphilitic hepatitis and immune-complex glomerulonephritis.
Downstream
Latency and Persistent Infection Secondary manifestations resolve as immune containment develops, and the infection becomes clinically silent.
Maculopapular exanthema Haematogenous seeding of the skin produces the generalized eruption.
Condylomata lata Treponemal proliferation in warm intertriginous mucocutaneous sites produces highly infectious moist plaques.
Lymphadenopathy Systemic dissemination produces generalized lymphadenopathy.
Alopecia Follicular involvement produces patchy moth-eaten alopecia.
Hepatitis Visceral seeding of the liver produces syphilitic hepatitis.
Glomerulonephritis Immune-complex deposition in the glomerulus produces nephritis.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Penicillin G, administered parenterally, is the preferred drug for treating patients in all stages of syphilis."
PARTIAL: the CDC guideline frames syphilis as a staged disease treated by stage; the specific secondary-stage lesion set is carried by the individual phenotype entries and their own evidence.
Latency and Persistent Infection
Partial host containment suppresses clinically detectable disease without eradicating the organism. Latent infection is divided into early (under one year) and late (one year or longer, or unknown duration); early latency carries a risk of symptomatic mucocutaneous relapse. A minority of untreated people eventually progress to tertiary disease.
Downstream
Gummatous Delayed-Type Hypersensitivity Response Long-term persistence in a sensitized host permits the delayed hypersensitivity granuloma of tertiary disease.
Syphilitic Aortitis Decades of low-grade treponemal presence in the aortic vasa vasorum produce tertiary cardiovascular disease.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"The majority of patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of adequate treatment or disease activity."
The lifelong persistence of treponemal antibody reflects the durable host-pathogen relationship this node represents and underlies the serofast state.
Gummatous Delayed-Type Hypersensitivity Response
The gumma is a granulomatous lesion of tertiary syphilis in which macrophages undergo epithelioid transformation and fuse into Langhans-type multinucleated giant cells, palisading with lymphocytes and plasma cells around a zone of central necrosis, in skin, bone, or viscera. Treponemes are characteristically scant and difficult to demonstrate within gumma tissue, indicating that the lesion is predominantly an immune-mediated delayed-type hypersensitivity response rather than direct microbial cytopathology.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. plasma cell CL:0000786 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology.
syncytium formation by cell-cell fusion GO:0000768 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased syncytium formation by cell-cell fusion (GO:0000768). GO:0000768 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Cutaneous granuloma Organized granulomatous inflammation in the dermis forms the cutaneous gumma.
Skin ulcer Central necrosis and breakdown of the gumma produces a destructive, scarring ulcer.
Syphilitic Aortitis
Chronic treponemal presence in the vasa vasorum of the ascending aorta drives obliterative endarteritis of those nutrient vessels, producing ischemic destruction of the elastic and muscular fibers of the aortic media. The weakened wall dilates, giving aortic aneurysm, aortic regurgitation, aortic root dilation, and coronary ostial stenosis.
Downstream
Thoracic aortic aneurysm Medial destruction weakens the wall and permits aneurysmal dilation.
Aortic regurgitation Aortic root dilation renders the valve incompetent.
Show evidence (1 reference)
PMID:27982548 SUPPORT Human Clinical
"The consequent weakening of the aortic wall can lead to severe complications, represented by aortic aneurysm, aortic valvular insufficiency, aortic root dilation and coronary ostial stenosis."
Directly enumerates the cardiovascular consequences of medial destruction that this node produces.
Meningovascular Neurosyphilis
The early neurological pattern: endarteritis of cerebral and meningeal vessels producing syphilitic meningitis, cranial nerve dysfunction, and ischemic stroke, typically within the first months to few years of infection. Its mechanism is vascular, which is why it shares a lesion with the chancre and with aortitis.
Downstream
Ischemic stroke Cerebral endarteritis causes ischemic infarction.
Meningitis Meningeal vascular and inflammatory involvement produces syphilitic meningitis.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Early neurologic clinical manifestations or syphilitic meningitis (e.g., cranial nerve dysfunction, meningitis, meningovascular syphilis, stroke, and acute altered mental status) are usually present within the first few months or years of infection."
Directly enumerates the early meningovascular manifestations and their timing, distinguishing them from the late parenchymal syndromes.
Parenchymal Neurosyphilis
The late neurological pattern, occurring 10 to more than 30 years after infection: direct neuronal and glial injury rather than vascular occlusion, producing general paresis (cortical atrophy and gliosis) and tabes dorsalis (degeneration of the dorsal columns and dorsal root ganglia). HIV coinfection is associated with an accelerated and more severe course.
Downstream
Dementia Parenchymal cortical injury produces the dementia of general paresis.
Sensory ataxia Dorsal column and dorsal root ganglion degeneration produces the sensory ataxia of tabes dorsalis.
Show evidence (2 references)
PMID:34292926 SUPPORT Human Clinical
"Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10 to >30 years after infection."
Identifies tabes dorsalis and general paresis as the late parenchymal manifestations and separates them in time from the early meningovascular ones.
PMID:25890619 SUPPORT Human Clinical
"This review of the clinical presentation, diagnostic laboratory findings, treatment and management of neurosyphilis discusses the impact of HIV and the specific challenges it brings"
PARTIAL: supports the HIV-modified course of neurosyphilis; the review abstract does not itself separate parenchymal from meningovascular disease.
Transplacental Fetal Dissemination
Maternal spirochetemia seeds the fetus across the placenta, producing a disease process analogous to disseminated secondary syphilis in the fetus. Transmission can occur at any point in pregnancy or at delivery, and the risk is greatest when the mother is in the primary or secondary stage. Untreated fetal infection causes stillbirth, hydrops, and the early congenital syndrome; the classical Hutchinson stigmata are late, permanent developmental scarring rather than active infection.
Downstream
Rhinitis Mucosal infection of the neonatal nasal passages produces syphilitic snuffles.
Hepatosplenomegaly Disseminated fetal infection involves the liver and spleen.
Periostitis Treponemal infection of growing bone produces periostitis and osteochondritis.
Keratitis Late congenital interstitial keratitis is one component of the Hutchinson triad.
Abnormal dental morphology Enamel and dentine maldevelopment produces Hutchinson incisors.
Sensorineural hearing impairment Eighth nerve involvement produces the deafness of the Hutchinson triad.
Show evidence (2 references)
PMID:40977496 SUPPORT Human Clinical
"Vertical transmission can occur at any point during pregnancy or delivery, with the highest risk observed during primary and secondary stages of infection compared to latent phases."
Establishes the timing and maternal-stage dependence of transplacental transmission.
PMID:22670010 SUPPORT Human Clinical
"One of the main aspects is observed with the triad of Hutchinson, characterised by the presence of interstitial keratitis, eighth nerve deafness and Hutchinson's teeth."
Documents the late congenital stigmata that result from transplacental fetal infection.
Treponemal Peptidoglycan Cross-Linking (Beta-Lactam Target)
T. pallidum maintains its peptidoglycan cell wall by penicillin-binding protein transpeptidase cross-linking. Beta-lactam acylation of the PBP active site halts cross-linking and is treponemicidal. Remarkably, no clinically significant penicillin resistance has ever been documented in T. pallidum, which is why a single intramuscular dose still cures early syphilis after eight decades of use.
peptidoglycan-based cell wall biogenesis GO:0009273 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased peptidoglycan-based cell wall biogenesis (GO:0009273). GO:0009273 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Penicillin G, administered parenterally, is the preferred drug for treating patients in all stages of syphilis."
The continued first-line status of parenteral penicillin at every stage reflects the undiminished efficacy of this drug target.
Treponemal Ribosomal Translation (Macrolide and Tetracycline Target)
Treponemal protein synthesis on the bacterial ribosome is the target of the second-line agents used when penicillin cannot be given - doxycycline acting on the 30S subunit, and historically azithromycin acting on the 50S subunit.
translation GO:0006412 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased translation (GO:0006412). GO:0006412 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
23S rRNA Macrolide Resistance Point mutation in the macrolide binding site on this target abolishes azithromycin efficacy.
Show evidence (1 reference)
PMID:18192791 SUPPORT Other
"This mutation confers resistance by precluding macrolide binding to the bacterial 50S ribosomal subunit, of which 23S rRNA is a structural component."
Identifies the treponemal ribosome as the macrolide target. Evidence source is OTHER because the citation is a review.
23S rRNA Macrolide Resistance
An A-to-G point mutation at position 2058 of the 23S rRNA gene (and the related A2059G change) abolishes macrolide binding to the 50S subunit. First recognised in azithromycin treatment failures in San Francisco in 2002, these mutations have since become prevalent in many regions, and are the reason azithromycin is no longer recommended where resistance prevalence is unknown or high. This distinguishes syphilis from the endemic treponematoses, where azithromycin remains a mainstay of mass treatment.
Show evidence (1 reference)
PMID:18192791 SUPPORT Other
"Azithromycin treatment failures in syphilis were first noted in San Francisco in 2002 and result from an A-->G mutation at position 2058 of the 23S rRNA gene"
Directly identifies the A2058G 23S rRNA mutation as the cause of azithromycin treatment failure in syphilis.
✶

Histopathology

1
Obliterative endarteritis with plasma cell infiltrate
The characteristic microscopic lesion across every stage is a lymphoplasmacytic vasculitis of small vessels with endothelial swelling and concentric intimal proliferation narrowing the lumen. A plasma-cell-rich infiltrate is the histological signature that suggests syphilis in an otherwise nonspecific biopsy.
Show evidence (2 references)
PMID:27982548 SUPPORT Human Clinical
"the inflammatory response progresses towards obliterative endarteritis and necrosis of the muscular and elastic fibers in the aortic media"
Describes the obliterative endarteritis and consequent medial necrosis that define the lesion.
PMID:16224168 SUPPORT Human Clinical
"histologic evaluation of biopsy revealed obliterative endarteritis with heavy plasma cell infiltration"
Documents the same obliterative endarteritis with a plasma-cell-rich infiltrate in a primary lesion, supporting this as the lesion shared across stages rather than an aortitis-specific finding.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Syphilis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

22
Cardiovascular 4
Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Secondary syphilis manifestations can include skin rash, mucocutaneous lesions, and lymphadenopathy."
Names lymphadenopathy directly as a secondary-stage manifestation.
Ischemic stroke HP:0002140 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ischemic stroke (HP:0002140). HP:0002140 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"meningovascular syphilis, stroke, and acute altered mental status) are usually present within the first few months or years of infection"
Names stroke among the early meningovascular neurologic manifestations.
Aortic regurgitation HP:0001659 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aortic regurgitation (HP:0001659). HP:0001659 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27982548 SUPPORT Human Clinical
"The consequent weakening of the aortic wall can lead to severe complications, represented by aortic aneurysm, aortic valvular insufficiency, aortic root dilation and coronary ostial stenosis."
Aortic valvular insufficiency is named directly as a consequence of the weakened aortic wall.
Hepatosplenomegaly HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"hepatosplenomegaly, rhinitis, skin rash, or pseudoparalysis of an extremity"
Names hepatosplenomegaly among the clinical findings of early congenital syphilis.
Digestive 1
Hepatitis HP:0012115 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatitis (HP:0012115). HP:0012115 is a phenotype from the Human Phenotype Ontology.
No evidence item is attached. No cited source in this entry describes syphilitic hepatitis; curated as unevidenced description rather than supported by a stage-level quote that does not mention the liver.
Ear 1
Sensorineural hearing impairment VERY_RARE HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35819903 SUPPORT Human Clinical
"clinical manifestations were infrequently reported overall: neurologic (n = 445, 1.1%), ocular (n = 461, 1.1%), otic (n = 166, 0.4%), any (n = 807, 2.0%)"
Otic manifestations were reported in 0.4% of 41,187 surveillance cases, supporting the VERY_RARE band. This phenotype also arises in late congenital syphilis as the eighth nerve deafness of the Hutchinson triad.
PMID:22670010 SUPPORT Human Clinical
"the triad of Hutchinson, characterised by the presence of interstitial keratitis, eighth nerve deafness and Hutchinson's teeth"
Names eighth nerve deafness as a component of the Hutchinson triad, the congenital route to this phenotype.
Eye 2
Uveitis VERY_RARE HP:0000554 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Uveitis (HP:0000554). HP:0000554 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35819903 SUPPORT Human Clinical
"clinical manifestations were infrequently reported overall: neurologic (n = 445, 1.1%), ocular (n = 461, 1.1%), otic (n = 166, 0.4%), any (n = 807, 2.0%)"
Ocular manifestations were reported in 1.1% of 41,187 surveillance cases, supporting the VERY_RARE band. Passive surveillance likely underestimates the true figure.
Keratitis HP:0000491 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Interstitial keratitis, annotated with Keratitis (HP:0000491). HP:0000491 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22670010 SUPPORT Human Clinical
"the triad of Hutchinson, characterised by the presence of interstitial keratitis, eighth nerve deafness and Hutchinson's teeth"
Names interstitial keratitis as a component of the Hutchinson triad.
Genitourinary 1
Genital ulcers HP:0003249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chancre, annotated with Genital ulcers (HP:0003249), qualified as temporality transient. HP:0003249 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Primary syphilis classically presents as a single painless ulcer or chancre at the site of infection but can also present with multiple, atypical, or painful lesions"
Directly describes the chancre and, importantly, records that the classical solitary painless presentation is not universal.
Head and Neck 1
Abnormal dental morphology HP:0006482 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hutchinson teeth, annotated with Abnormal dental morphology (HP:0006482). HP:0006482 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22670010 SUPPORT Human Clinical
"the triad of Hutchinson, characterised by the presence of interstitial keratitis, eighth nerve deafness and Hutchinson's teeth"
Names Hutchinson teeth as a component of the triad.
Immune 2
Maculopapular exanthema HP:0040186 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Maculopapular exanthema (HP:0040186). HP:0040186 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Secondary syphilis manifestations can include skin rash, mucocutaneous lesions, and lymphadenopathy."
Names skin rash and mucocutaneous lesions directly as secondary-stage manifestations.
Meningitis VERY_RARE HP:0001287 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Meningitis (HP:0001287). HP:0001287 is a phenotype from the Human Phenotype Ontology.
Frequency derivation: the 1.1% figure is for neurologic manifestations as a whole, of which syphilitic meningitis is a strict subset, so the true meningitis-only rate is lower than 1.1% and remains inside VERY_RARE. The band is therefore an upper bound rather than a point estimate. Passive surveillance also under-ascertains, so the reported figure is itself likely an underestimate of true occurrence.
Show evidence (2 references)
PMID:35819903 SUPPORT Human Clinical
"clinical manifestations were infrequently reported overall: neurologic (n = 445, 1.1%), ocular (n = 461, 1.1%), otic (n = 166, 0.4%), any (n = 807, 2.0%)"
Neurologic manifestations were reported in 1.1% of 41,187 surveillance cases, supporting the VERY_RARE band.
PMID:34292926 SUPPORT Human Clinical
"Early neurologic clinical manifestations or syphilitic meningitis (e.g., cranial nerve dysfunction, meningitis, meningovascular syphilis, stroke, and acute altered mental status) are usually present within the first few months or years of infection."
Names syphilitic meningitis as an early neurologic manifestation.
Integument 2
Alopecia HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
No evidence item is attached. The CDC guideline snippet that anchors the other secondary-stage phenotypes names rash, mucocutaneous lesions, and lymphadenopathy but not alopecia, and no cited source in this entry describes it. Curated as unevidenced description rather than propped up by a stage-level quote.
Skin ulcer HP:0200042 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ulcerated gumma, annotated with Skin ulcer (HP:0200042). HP:0200042 is a phenotype from the Human Phenotype Ontology.
No evidence item is attached, for the same reason as the parent granuloma phenotype.
Nervous System 1
Dementia HP:0000726 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dementia (HP:0000726), qualified as course progressive. HP:0000726 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10 to >30 years after infection."
Names general paresis, the syndrome of which this dementia is the cardinal feature, as a late neurologic manifestation.
Other 7
Glomerulonephritis HP:0000099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glomerulonephritis (HP:0000099). HP:0000099 is a phenotype from the Human Phenotype Ontology.
No evidence item is attached. No cited source in this entry describes syphilitic glomerulonephritis; curated as unevidenced description rather than supported by a stage-level quote that does not mention the kidney.
Sensory ataxia HP:0010871 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensory ataxia (HP:0010871). HP:0010871 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10 to >30 years after infection."
Names tabes dorsalis, of which sensory ataxia is the cardinal sign, as a late neurologic manifestation.
Thoracic aortic aneurysm HP:0012727 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thoracic aortic aneurysm (HP:0012727). HP:0012727 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27982548 SUPPORT Human Clinical
"Aortic aneurysm was the most frequent involvement, detected in 71% of patients."
Supports aneurysm as the commonest cardiovascular involvement. The 71% denominator is published cardiovascular-syphilis cases, a publication-selected series, so it cannot be mapped to a FrequencyEnum band for syphilis as a whole.
Cutaneous granuloma HP:6000070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gumma, annotated with Cutaneous granuloma (HP:6000070). HP:6000070 is a phenotype from the Human Phenotype Ontology.
No evidence item is attached. No cited source in this entry describes cutaneous gumma morphology; curated as unevidenced description rather than supported by an aortitis quote. HPO has no gumma-specific term, so the generic cutaneous granuloma term carries a free-text preferred_term.
Condylomata lata
No HPO term exists for condylomata lata or for the syphilitic chancre; a free-text preferred_term is used with no term binding rather than forcing an inaccurate one. Candidate for an HPO new-term request.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Secondary syphilis manifestations can include skin rash, mucocutaneous lesions, and lymphadenopathy."
PARTIAL: condylomata lata are the archetypal secondary mucocutaneous lesion named in this list, but the guideline text does not name them individually.
Rhinitis HP:0012384 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syphilitic snuffles, annotated with Rhinitis (HP:0012384). HP:0012384 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"hepatosplenomegaly, rhinitis, skin rash, or pseudoparalysis of an extremity"
Names rhinitis among the clinical findings of early congenital syphilis.
Periostitis HP:0040165 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periostitis (HP:0040165). HP:0040165 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"hepatosplenomegaly, rhinitis, skin rash, or pseudoparalysis of an extremity"
PARTIAL: names pseudoparalysis, the clinical consequence of the periostitis and osteochondritis this phenotype represents, rather than the bone lesion itself.
💊

Medical Actions

7
Parenteral penicillin G, stage-dependent regimen
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: penicillin G benzathine NCIT:C47657 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses penicillin G benzathine (NCIT:C47657). NCIT:C47657 is a therapeutic agent from the NCI Thesaurus. benzylpenicillin CHEBI:18208 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses benzylpenicillin (CHEBI:18208). CHEBI:18208 is a therapeutic agent from Chemical Entities of Biological Interest.
Parenteral penicillin G is the treatment of choice at every stage. Benzathine penicillin G 2.4 million units IM as a single dose treats primary, secondary, and early-latent syphilis; the same dose weekly for three weeks treats late-latent, unknown-duration, and non-neurological tertiary disease; and aqueous crystalline penicillin G IV for 10-14 days is required for neurosyphilis, ocular syphilis, and otosyphilis. Neither oral penicillin preparations nor benzathine-procaine combinations are adequate therapy at any stage. Tertiary structural damage already established - aortic aneurysm, tabetic deficits, gummatous scarring - does not reverse with microbiological cure.
Mechanism Target:
INHIBITS Treponemal Peptidoglycan Cross-Linking (Beta-Lactam Target) — Beta-lactam acylation of penicillin-binding proteins halts peptidoglycan cross-linking and is treponemicidal.
Show evidence (2 references)
PMID:34292926 SUPPORT Human Clinical
"Penicillin G, administered parenterally, is the preferred drug for treating patients in all stages of syphilis."
Directly supports parenteral penicillin G as first-line therapy at every stage of syphilis.
PMID:34292926 SUPPORT Human Clinical
"Combinations of benzathine penicillin, procaine penicillin, and oral penicillin preparations are not considered appropriate for syphilis treatment."
Supports the negative recommendation in this description against oral and combination penicillin preparations.
Doxycycline for penicillin-allergic non-pregnant patients
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: doxycycline CHEBI:50845 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxycycline (CHEBI:50845). CHEBI:50845 is a therapeutic agent from Chemical Entities of Biological Interest.
Doxycycline 100 mg orally twice daily for 14 days (longer for late-stage disease) is the principal alternative for non-pregnant, penicillin-allergic patients with non-neurological syphilis. It is not an option in pregnancy.
Mechanism Target:
INHIBITS Treponemal Ribosomal Translation (Macrolide and Tetracycline Target) — Doxycycline binds the 30S ribosomal subunit and arrests treponemal protein synthesis.
Show evidence (2 references)
PMID:34292926 SUPPORT Human Clinical
"The only acceptable alternatives for treating late latent syphilis or syphilis of unknown duration are doxycycline (100 mg orally 2 times/day) or tetracycline (500 mg orally 4 times/day), each for 28 days."
Gives the doxycycline regimen and its status as an acceptable alternative in late latent disease.
PMID:34292926 SUPPORT Human Clinical
"No proven alternatives to penicillin are available for treatment of syphilis during pregnancy."
Establishes the pregnancy boundary of doxycycline's role.
Penicillin desensitization in pregnancy
Action: penicillin desensitizationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is penicillin desensitization, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: benzylpenicillin CHEBI:18208 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses benzylpenicillin (CHEBI:18208). CHEBI:18208 is a therapeutic agent from Chemical Entities of Biological Interest.
Because no alternative to penicillin is proven for syphilis in pregnancy, and because untreated maternal infection causes congenital syphilis, a pregnant patient reporting penicillin allergy should be desensitized and then treated with penicillin rather than given a substitute agent.
Show evidence (2 references)
PMID:34292926 SUPPORT Human Clinical
"Pregnant women with syphilis at any stage who report penicillin allergy should be desensitized and treated with penicillin"
Directly supports desensitization rather than substitution in pregnancy.
PMID:34292926 SUPPORT Human Clinical
"No proven alternatives to penicillin are available for treatment of syphilis during pregnancy."
Establishes the absence of an acceptable alternative that makes desensitization necessary.
Anticipatory counselling for the Jarisch-Herxheimer reaction
Category: Counseling / Informational Action: pre-treatment counsellingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pre-treatment counselling, annotated with Behavioral Counseling (NCIT:C181743). NCIT:C181743 is a clinical intervention from the NCI Thesaurus. Ontology label: Behavioral Counseling NCIT:C181743
The Jarisch-Herxheimer reaction is an acute febrile reaction with headache and myalgia occurring within the first 24 hours of any effective syphilis therapy. It is a reaction to treatment, not penicillin allergy, and mistaking it for allergy risks withholding the only curative drug. In a prospective secondary analysis of a randomized trial of benzathine penicillin G for early syphilis, symptoms occurred in 23.7% of participants, with median onset about 5 hours and median duration about 13 hours. Management is supportive; patients should be counselled before treatment.
Show evidence (3 references)
PMID:34292926 SUPPORT Human Clinical
"The Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache, myalgia, and fever that can occur within the first 24 hours after the initiation of any syphilis therapy; it is a reaction to treatment and not an allergic reaction to penicillin."
Defines the reaction and states explicitly that it is not penicillin allergy, the clinically consequential distinction.
PMID:39946129 SUPPORT Human Clinical
"One or more JHR symptoms occurred in 59 participants (23.7%) treated for early syphilis, with a median symptom onset at 4.9 hours (IQR, 3.0-9.2 hours) and a median duration of 12.8 hours (IQR, 5.0-24.0 hours)."
Provides the prospective incidence, onset, and duration figures quoted in this entry.
PMID:39946129 SUPPORT Human Clinical
"The incidence of the Jarisch-Herxheimer reaction (JHR) after penicillin treatment for early syphilis is reported to range from 8% to 56%."
Documents the wide range of previously reported incidence estimates that this trial was designed to resolve.
Doxycycline post-exposure prophylaxis (doxy-PEP)
Category: Therapeutic Action: post-exposure chemoprophylaxisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is post-exposure chemoprophylaxis, annotated with Preventive Intervention (NCIT:C15843). NCIT:C15843 is a clinical intervention from the NCI Thesaurus. Ontology label: Preventive Intervention NCIT:C15843
Agent: doxycycline CHEBI:50845 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxycycline (CHEBI:50845). CHEBI:50845 is a therapeutic agent from Chemical Entities of Biological Interest.
Doxycycline 200 mg taken within 72 hours of condomless sex reduces incident syphilis and chlamydia by more than 70% in randomized trials. CDC recommends it for men who have sex with men and transgender women with a bacterial STI in the preceding 12 months. It acts upstream of the inoculation step rather than treating established infection, so it is prevention rather than therapy.
Mechanism Target:
INHIBITS Treponemal Ribosomal Translation (Macrolide and Tetracycline Target) — Doxycycline arrests treponemal protein synthesis, eliminating the organism before infection is established.
Show evidence (1 reference)
PMID:38833414 SUPPORT Human Clinical
"In three large randomized controlled trials, 200 mg of doxycycline taken within 72 hours after sex has been shown to reduce syphilis and chlamydia infections by >70% and gonococcal infections by approximately 50%."
Gives the dose, the 72-hour window, and the randomized-trial effect size for syphilis prevention.
Aortic aneurysm repair and valve replacement
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Advanced cardiovascular syphilis with a hemodynamically significant aneurysm or aortic regurgitation requires surgical repair or valve replacement; antimicrobial cure does not reverse established structural damage.
Show evidence (1 reference)
PMID:27982548 SUPPORT Human Clinical
"The consequent weakening of the aortic wall can lead to severe complications, represented by aortic aneurysm, aortic valvular insufficiency, aortic root dilation and coronary ostial stenosis."
Establishes the structural complications that constitute the surgical indication.
🌍

Environmental Factors

2
HIV coinfection
HIV and syphilis are bidirectionally associated. Syphilis infection increases subsequent HIV acquisition roughly two- to three-fold in high-risk populations, and HIV coinfection is associated with accelerated, more severe neurosyphilis.
Show evidence (2 references)
PMID:33219164 SUPPORT Human Clinical
"HIV incidence showed a two-time increase after syphilis exposure, compared with a control group"
Quantifies the increase in HIV acquisition following syphilis infection in a meta-analysis of 65,232 participants.
PMID:25890619 SUPPORT Human Clinical
"discusses the impact of HIV and the specific challenges it brings"
PARTIAL: establishes that HIV modifies neurosyphilis management without quantifying the effect.
Mechanism Target:
EXACERBATES Parenchymal Neurosyphilis — HIV coinfection is associated with an accelerated and more severe neurosyphilis course, plausibly through impaired CD4-positive T-cell-mediated containment.
Show evidence (1 reference)
PMID:25890619 SUPPORT Human Clinical
"This review of the clinical presentation, diagnostic laboratory findings, treatment and management of neurosyphilis discusses the impact of HIV and the specific challenges it brings"
PARTIAL: establishes that HIV modifies the course and management of neurosyphilis without quantifying the effect.
Absent or late prenatal care
Lack of, or late presentation to, prenatal care is the dominant modifiable risk factor for congenital syphilis, because it removes the screening and treatment opportunity that would otherwise prevent transmission.
Show evidence (1 reference)
PMID:40977496 SUPPORT Human Clinical
"As early diagnosis and treatment are highly effective in reducing transmission, syphilis screening should begin at the first prenatal visit."
Establishes the first prenatal visit as the point at which screening and treatment interrupt transmission, which is what absent or late prenatal care removes. PARTIAL because the source states the effectiveness of early screening rather than quantifying the risk conferred by its absence.
Mechanism Target:
PREDISPOSES Transplacental Fetal Dissemination — Absent or late prenatal care removes the screening-and-treatment window that would otherwise interrupt maternal-fetal transmission. The effect is indirect: lack of care does not itself drive transmission, it removes the intervention that prevents it.
Show evidence (1 reference)
PMID:40977496 SUPPORT Human Clinical
"As early diagnosis and treatment are highly effective in reducing transmission, syphilis screening should begin at the first prenatal visit."
PARTIAL: establishes the first prenatal visit as the intervention point whose absence permits transmission, without quantifying the risk of absent care.
🔬

Diagnosis

4
Nontreponemal serology (RPR/VDRL)
Nontreponemal tests detect non-specific anticardiolipin antibodies produced in response to host tissue damage. They are quantitative, so titers track treatment response, but can be falsely negative very early or through the prozone phenomenon at very high titers, and falsely positive in pregnancy, autoimmune disease, and other infections.
nontreponemal serologic testing NCIT:C74716 NCI Thesaurus (NCIT)
Results: A quantitative titer used both for diagnosis and for monitoring; a four-fold or greater decline indicates adequate treatment response.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"The majority of patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of adequate treatment or disease activity."
Explains why the quantitative nontreponemal test, not the treponemal test, is the instrument for monitoring treatment response.
Treponemal serology and the reverse sequence algorithm
Treponemal tests (TP-PA, FTA-ABS, and automated EIA/CIA immunoassays) are specific for anti-T. pallidum antibody but usually remain reactive for life, so they cannot by themselves distinguish active from previously treated infection. Automated laboratories increasingly screen with a treponemal immunoassay first (the reverse sequence algorithm), reflexing to a quantitative RPR and, when the two are discordant, to a second treponemal test as tiebreaker.
treponemal serologic testing NCIT:C132388 NCI Thesaurus (NCIT)
Results: Lifelong reactivity in most patients; interpretation requires pairing with a quantitative nontreponemal titer.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Treponemal Tests and Reverse Sequence Algorithm The majority of patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of adequate treatment or disease activity."
Directly supports both the reverse sequence algorithm and the lifelong reactivity that limits treponemal test interpretation.
Direct detection by PCR of lesion material
PCR on swabs of a chancre or other mucocutaneous lesion detects treponemal DNA during the early window when serology may still be non-reactive, and has largely supplanted darkfield microscopy where it is available. Reference laboratories can also genotype 23S rRNA for the A2058G/A2059G macrolide resistance mutations.
polymerase chain reaction NCIT:C17003 NCI Thesaurus (NCIT)
Results: Detection of T. pallidum DNA from lesion exudate; a negative result does not exclude syphilis.
Show evidence (1 reference)
PMID:18192791 SUPPORT Other
"Azithromycin treatment failures in syphilis were first noted in San Francisco in 2002 and result from an A-->G mutation at position 2058 of the 23S rRNA gene"
PARTIAL: supports the molecular resistance target that pathogen genotyping detects, rather than the diagnostic performance of lesion PCR.
Cerebrospinal fluid examination for neurosyphilis
CSF examination (CSF-VDRL, cell count, protein) is the test that governs management of suspected neurosyphilis, since a diagnosis of neurosyphilis changes therapy from intramuscular benzathine penicillin to 10-14 days of intravenous aqueous crystalline penicillin. CSF-VDRL is highly specific but insensitive, so a negative result in a patient with neurologic signs does not exclude the diagnosis.
cerebrospinal fluid examination by lumbar puncture NCIT:C15327 NCI Thesaurus (NCIT)
Results: A reactive CSF-VDRL in an uncontaminated specimen is diagnostic; a negative result does not exclude neurosyphilis.
Show evidence (2 references)
PMID:34292926 SUPPORT Human Clinical
"For a person with neurologic signs or symptoms, a reactive CSF-VDRL (in the absence of blood contamination) is considered diagnostic of neurosyphilis."
Establishes the reactive CSF-VDRL as diagnostic of neurosyphilis.
PMID:34292926 SUPPORT Human Clinical
"CSF-VDRL is highly specific but insensitive"
Establishes the insensitivity that makes a negative CSF-VDRL non-exclusionary.
📈

Progression

3
Incubation period
Incubation: 10-90 days
The chancre appears 10-90 days after exposure, with a median of about three weeks. Not separately evidenced here; the window is stated in the deep-research report and is standard, but no cached source quotes it.
Early neurological involvement
Meningovascular manifestations - cranial nerve dysfunction, meningitis, stroke - usually appear within the first months to few years of infection, not in late disease.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Early neurologic clinical manifestations or syphilitic meningitis (e.g., cranial nerve dysfunction, meningitis, meningovascular syphilis, stroke, and acute altered mental status) are usually present within the first few months or years of infection."
Gives the timing of early neurological involvement.
Late neurological involvement
Parenchymal neurosyphilis - tabes dorsalis and general paresis - occurs 10 to more than 30 years after infection.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10 to >30 years after infection."
Gives the decades-long latency to parenchymal neurosyphilis.
🪜

Stages

6
Primary syphilis
A chancre at the inoculation site 10-90 days after exposure, healing spontaneously in 3-6 weeks. Resolution marks progression to the next stage, not cure.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Primary syphilis classically presents as a single painless ulcer or chancre at the site of infection but can also present with multiple, atypical, or painful lesions"
Defines the primary stage by its characteristic lesion.
Secondary syphilis
Disseminated disease weeks to months after the chancre, with generalized mucocutaneous eruption, condylomata lata, lymphadenopathy, and visceral involvement. May overlap a healing chancre.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Secondary syphilis manifestations can include skin rash, mucocutaneous lesions, and lymphadenopathy."
Defines the secondary stage by its manifestation set.
Early latent syphilis
Asymptomatic infection acquired within the preceding year. Distinguished from late latent because it remains infectious, carries a risk of mucocutaneous relapse, and is treated with a single benzathine penicillin dose rather than three.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Latent syphilis acquired within the preceding year is referred to as early latent syphilis"
Gives the defining time boundary of early latent syphilis.
Late latent syphilis or latent syphilis of unknown duration
Asymptomatic infection of at least one year's duration, or of unknown duration. Requires three weekly doses of benzathine penicillin.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"all other cases of latent syphilis are classified as late latent syphilis or latent syphilis of unknown duration"
Gives the definition by exclusion from early latent disease.
Tertiary syphilis
Late destructive disease - gummatous, cardiovascular, or late neurological - occurring years to decades after infection in a minority of untreated people. Structural damage does not reverse with microbiological cure.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10 to >30 years after infection."
Places the late manifestations decades after infection, defining the tertiary stage temporally.
Congenital syphilis
Vertically acquired infection, divided into early (presenting under two years, with hepatosplenomegaly, rhinitis, rash, and pseudoparalysis) and late (the Hutchinson stigmata, which are permanent developmental scarring rather than active infection).
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"hepatosplenomegaly, rhinitis, skin rash, or pseudoparalysis of an extremity"
Enumerates the early congenital manifestation set.
📊

Prevalence

1
United States, 16 jurisdictions with complete reporting of clinical manifestations, 2019
Cases In Literature Unknown
41,187 reported syphilis cases. Among them, neurologic manifestations were reported in 1.1%, ocular in 1.1%, otic in 0.4%, and any of the three in 2.0%. These are proportions of reported cases in passive surveillance, not population rates, and are likely underestimates.
Show evidence (1 reference)
PMID:35819903 SUPPORT Human Clinical
"clinical manifestations were infrequently reported overall: neurologic (n = 445, 1.1%), ocular (n = 461, 1.1%), otic (n = 166, 0.4%), any (n = 807, 2.0%)"
Gives the surveillance denominator and the per-manifestation proportions.
🦠

Infectious Agent

1
Treponema pallidum subsp. pallidum
A thin, tightly coiled, motile spirochete that cannot be continuously cultured by conventional means; nearly all experimental work uses the rabbit model. It is the venereal treponeme, distinct from the subspecies causing yaws, bejel, and pinta.
Treponema pallidum subsp. pallidum NCBITaxon:161 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:27721440 SUPPORT Other
"fragile outer membrane lacks lipopolysaccharide (LPS), the highly proinflammatory glycolipid found in Gram-negative bacteria"
This review of T. pallidum biology characterizes the organism and its distinctive LPS-free outer membrane. Evidence source is OTHER because the citation is a review article rather than a primary study.
↔️

Transmission

2
Sexual transmission by direct lesion contact
Transmission occurs through direct contact with an infectious mucocutaneous lesion - chancre, mucous patch, or condyloma latum - during vaginal, anal, or oral sex. Early (primary, secondary, early-latent) syphilis is the period of greatest infectiousness.
Show evidence (1 reference)
PMID:34292926 SUPPORT Human Clinical
"Primary syphilis classically presents as a single painless ulcer or chancre at the site of infection"
The chancre arising at the site of infection establishes direct lesional contact as the route of transmission.
Vertical transplacental transmission
T. pallidum crosses the placenta during maternal spirochetemia, producing congenital syphilis. Transmission can occur at any point in pregnancy or at delivery, and risk tracks the maternal stage - highest in primary and secondary syphilis, when spirochete burden is greatest, and lower in the latent phases.
Show evidence (1 reference)
PMID:40977496 SUPPORT Human Clinical
"Vertical transmission can occur at any point during pregnancy or delivery, with the highest risk observed during primary and secondary stages of infection compared to latent phases."
Directly states both the timing and the maternal-stage dependence of vertical transmission.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Syphilis:

Genital herpes
Overlapping Features HSV is the commonest cause of genital ulceration. Herpetic ulcers are typically multiple, painful, and vesicular at onset, whereas the syphilitic chancre is classically solitary, painless, and indurated.
Chancroid
Overlapping Features Haemophilus ducreyi produces a painful, non-indurated genital ulcer with a ragged undermined edge and suppurative lymphadenitis, contrasting with the clean-based, indurated, painless chancre.
Pityriasis rosea
Overlapping Features Shares the truncal papulosquamous eruption of secondary syphilis but spares the palms and soles, whose involvement is the key discriminator.
Sarcoidosis
Overlapping Features Another cause of granulomatous lesions that can mimic gummas and produce uveitis; distinguished by serology and histology.
{ }

Source YAML

click to show 
name: Syphilis
creation_date: "2026-08-08T05:00:00Z"
category: Infectious Disease
description: >-
  Syphilis is a chronic, multistage systemic infection caused by the spirochete
  Treponema pallidum subspecies pallidum, transmitted sexually or vertically
  from mother to fetus. Untreated it evolves through primary (chancre),
  secondary (disseminated mucocutaneous), latent, and tertiary (gummatous and
  cardiovascular) stages over years to decades, and can involve virtually any
  organ system - the basis of its historical epithet "the great imitator".
  Neurological, ocular, and otic involvement can occur at any stage, not only
  late disease. The central pathophysiological theme is stealth: the organism
  presents an outer membrane almost devoid of surface-exposed
  pathogen-associated molecular patterns and lacking lipopolysaccharide, and
  varies the few surface epitopes it does display by TprK gene conversion, so
  that intense local immune infiltration never achieves sterilizing clearance.
  It is the venereal member of the treponematoses, alongside the endemic
  non-venereal diseases yaws, bejel, and pinta, which are caused by distinct
  T. pallidum subspecies and are separate disease entities.
synonyms:
- lues
- lues venerea
- Treponema pallidum infection
disease_term:
  preferred_term: syphilis
  term:
    id: MONDO:0005976
    label: syphilis
parents:
- Bacterial Infection
- Sexually transmitted infection
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:34292926
      reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Penicillin G, administered parenterally, is the preferred drug for treating patients in all stages of syphilis."
      explanation: >-
        Syphilis is a bacterial infection managed with antimicrobial therapy,
        placing it in Harrison's Infectious Diseases Part.
stages:
- name: Primary syphilis
  description: >-
    A chancre at the inoculation site 10-90 days after exposure, healing
    spontaneously in 3-6 weeks. Resolution marks progression to the next stage,
    not cure.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary syphilis classically presents as a single painless ulcer or chancre at the site of infection but can also present with multiple, atypical, or painful lesions"
    explanation: Defines the primary stage by its characteristic lesion.
- name: Secondary syphilis
  description: >-
    Disseminated disease weeks to months after the chancre, with generalized
    mucocutaneous eruption, condylomata lata, lymphadenopathy, and visceral
    involvement. May overlap a healing chancre.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary syphilis manifestations can include skin rash, mucocutaneous lesions, and lymphadenopathy."
    explanation: Defines the secondary stage by its manifestation set.
- name: Early latent syphilis
  description: >-
    Asymptomatic infection acquired within the preceding year. Distinguished
    from late latent because it remains infectious, carries a risk of
    mucocutaneous relapse, and is treated with a single benzathine penicillin
    dose rather than three.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Latent syphilis acquired within the preceding year is referred to as early latent syphilis"
    explanation: Gives the defining time boundary of early latent syphilis.
- name: Late latent syphilis or latent syphilis of unknown duration
  description: >-
    Asymptomatic infection of at least one year's duration, or of unknown
    duration. Requires three weekly doses of benzathine penicillin.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all other cases of latent syphilis are classified as late latent syphilis or latent syphilis of unknown duration"
    explanation: Gives the definition by exclusion from early latent disease.
- name: Tertiary syphilis
  description: >-
    Late destructive disease - gummatous, cardiovascular, or late neurological
    - occurring years to decades after infection in a minority of untreated
    people. Structural damage does not reverse with microbiological cure.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10 to >30 years after infection."
    explanation: >-
      Places the late manifestations decades after infection, defining the
      tertiary stage temporally.
- name: Congenital syphilis
  description: >-
    Vertically acquired infection, divided into early (presenting under two
    years, with hepatosplenomegaly, rhinitis, rash, and pseudoparalysis) and
    late (the Hutchinson stigmata, which are permanent developmental scarring
    rather than active infection).
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hepatosplenomegaly, rhinitis, skin rash, or pseudoparalysis of an extremity"
    explanation: Enumerates the early congenital manifestation set.
progression:
- phase: Incubation period
  incubation_days: 10-90
  notes: >-
    The chancre appears 10-90 days after exposure, with a median of about three
    weeks. Not separately evidenced here; the window is stated in the
    deep-research report and is standard, but no cached source quotes it.
- phase: Early neurological involvement
  notes: >-
    Meningovascular manifestations - cranial nerve dysfunction, meningitis,
    stroke - usually appear within the first months to few years of infection,
    not in late disease.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early neurologic clinical manifestations or syphilitic meningitis (e.g., cranial nerve dysfunction, meningitis, meningovascular syphilis, stroke, and acute altered mental status) are usually present within the first few months or years of infection."
    explanation: Gives the timing of early neurological involvement.
- phase: Late neurological involvement
  notes: >-
    Parenchymal neurosyphilis - tabes dorsalis and general paresis - occurs 10
    to more than 30 years after infection.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10 to >30 years after infection."
    explanation: Gives the decades-long latency to parenchymal neurosyphilis.
prevalence:
- population: >-
    United States, 16 jurisdictions with complete reporting of clinical
    manifestations, 2019
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    41,187 reported syphilis cases. Among them, neurologic manifestations were
    reported in 1.1%, ocular in 1.1%, otic in 0.4%, and any of the three in
    2.0%. These are proportions of reported cases in passive surveillance, not
    population rates, and are likely underestimates.
  evidence:
  - reference: PMID:35819903
    reference_title: "Reported Neurologic, Ocular, and Otic Manifestations Among Syphilis Cases-16 States, 2019."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical manifestations were infrequently reported overall: neurologic (n = 445, 1.1%), ocular (n = 461, 1.1%), otic (n = 166, 0.4%), any (n = 807, 2.0%)"
    explanation: >-
      Gives the surveillance denominator and the per-manifestation proportions.
infectious_agent:
- name: Treponema pallidum subsp. pallidum
  description: >-
    A thin, tightly coiled, motile spirochete that cannot be continuously
    cultured by conventional means; nearly all experimental work uses the
    rabbit model. It is the venereal treponeme, distinct from the subspecies
    causing yaws, bejel, and pinta.
  infectious_agent_term:
    preferred_term: Treponema pallidum subsp. pallidum
    term:
      id: NCBITaxon:161
      label: Treponema pallidum subsp. pallidum
  evidence:
  - reference: PMID:27721440
    reference_title: "Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "fragile outer membrane lacks lipopolysaccharide (LPS), the highly proinflammatory glycolipid found in Gram-negative bacteria"
    explanation: >-
      This review of T. pallidum biology characterizes the organism and its
      distinctive LPS-free outer membrane. Evidence source is OTHER because the
      citation is a review article rather than a primary study.
transmission:
- name: Sexual transmission by direct lesion contact
  description: >-
    Transmission occurs through direct contact with an infectious mucocutaneous
    lesion - chancre, mucous patch, or condyloma latum - during vaginal, anal,
    or oral sex. Early (primary, secondary, early-latent) syphilis is the
    period of greatest infectiousness.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary syphilis classically presents as a single painless ulcer or chancre at the site of infection"
    explanation: >-
      The chancre arising at the site of infection establishes direct lesional
      contact as the route of transmission.
- name: Vertical transplacental transmission
  description: >-
    T. pallidum crosses the placenta during maternal spirochetemia, producing
    congenital syphilis. Transmission can occur at any point in pregnancy or at
    delivery, and risk tracks the maternal stage - highest in primary and
    secondary syphilis, when spirochete burden is greatest, and lower in the
    latent phases.
  evidence:
  - reference: PMID:40977496
    reference_title: "Syphilis in pregnancy: A practical guide for prenatal care providers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vertical transmission can occur at any point during pregnancy or delivery, with the highest risk observed during primary and secondary stages of infection compared to latent phases."
    explanation: >-
      Directly states both the timing and the maternal-stage dependence of
      vertical transmission.
pathophysiology:
- name: Treponemal Mucosal Inoculation and Local Replication
  biological_scale: TISSUE
  description: >-
    T. pallidum penetrates intact mucous membranes or abraded skin at the site
    of sexual contact and replicates locally. This is the trigger event of the
    pathograph.
  cell_types:
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  downstream:
  - target: Early Hematogenous and Lymphatic Dissemination
    description: Local replication seeds the bloodstream and regional lymphatics.
    causal_link_type: DIRECT
  - target: Obliterative Endarteritis
    description: >-
      Local treponemal presence provokes the endarteritis that produces the
      indurated chancre.
    causal_link_type: DIRECT
  - target: Th1 Cellular Immune Response and Partial Clearance
    description: >-
      Local antigen is taken up and presented, initiating the cellular immune
      response.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27721440
    reference_title: "Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The paucity of surface-exposed pathogen-associated molecular patterns (PAMPs) enables the bacterium to undergo repeated bouts of dissemination that are poorly detected by innate immunity"
    explanation: >-
      Establishes that the organism disseminates from the inoculation site
      while evading innate detection.
- name: Early Hematogenous and Lymphatic Dissemination
  biological_scale: ORGANISM
  description: >-
    Spirochetemia is established within days to weeks and precedes the
    appearance of the primary chancre. This early, clinically silent
    dissemination explains why disseminated secondary disease, neuroinvasion,
    and congenital transmission can all follow an unnoticed primary lesion.
  downstream:
  - target: Immune-Privileged Sanctuary Site Invasion
    description: Circulating treponemes cross the blood-brain, blood-ocular, and placental barriers.
    causal_link_type: DIRECT
  - target: Secondary Disseminated Mucocutaneous Disease
    description: Widespread hematogenous seeding produces the generalized secondary eruption.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27721440
    reference_title: "Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "enables the bacterium to undergo repeated bouts of dissemination that are poorly detected by innate immunity and also explains the lack of systemic inflammatory symptoms characteristic of the disease"
    explanation: >-
      Supports repeated poorly-detected dissemination as a defining feature of
      the organism's behaviour in the host.
- name: Stealth Outer Membrane and PAMP Paucity
  biological_scale: MOLECULAR
  role: immune_evasion
  description: >-
    The treponemal outer membrane carries very few surface-exposed integral
    membrane proteins and, unlike other Gram-negative bacteria, contains no
    lipopolysaccharide. The resulting paucity of pathogen-associated molecular
    patterns denies innate immunity its usual trigger, which is why systemic
    inflammatory symptoms are muted despite ongoing spirochetemia.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: DECREASED
  downstream:
  - target: Latency and Persistent Infection
    description: >-
      Failure of innate recognition permits persistence after the clinical
      manifestations of early disease resolve.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27721440
    reference_title: "Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "fragile outer membrane lacks lipopolysaccharide (LPS), the highly proinflammatory glycolipid found in Gram-negative bacteria"
    explanation: >-
      Directly supports the absence of LPS, the central molecular basis of the
      innate-recognition failure this node represents.
  - reference: PMID:27721440
    reference_title: "Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The paucity of surface-exposed pathogen-associated molecular patterns (PAMPs) enables the bacterium to undergo repeated bouts of dissemination that are poorly detected by innate immunity and also explains the lack of systemic inflammatory symptoms characteristic of the disease"
    explanation: >-
      Links the low PAMP density to both poor innate detection and the muted
      systemic inflammatory phenotype.
- name: TprK Antigenic Variation
  biological_scale: MOLECULAR
  role: immune_evasion
  description: >-
    The tprK gene carries seven discrete variable (V) regions that are the
    focus of the anti-TprK antibody response. New V region sequences are
    generated by segmental gene conversion from donor sites elsewhere in the
    genome, so the few surface epitopes that are exposed change continuously
    during infection and outrun the maturing humoral response.
  biological_processes:
  - preferred_term: antigenic variation
    term:
      id: GO:0020033
      label: antigenic variation
    modifier: INCREASED
  downstream:
  - target: Latency and Persistent Infection
    description: >-
      Continuous epitope turnover prevents antibody-mediated clearance and
      permits long-term persistence.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:15186410
    reference_title: "Gene conversion: a mechanism for generation of heterogeneity in the tprK gene of Treponema pallidum during infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We describe the sequence anatomy of the seven V regions of tprK and the identification of putative donor sites for new V region sequences, and we propose a model for generation of new V regions by segmental gene conversion."
    explanation: >-
      Establishes segmental gene conversion as the mechanism generating TprK
      variable-region diversity. Evidence source is OTHER because this is
      molecular genetics of the pathogen rather than a human, animal, or
      cell-culture phenotype study.
  - reference: PMID:15186410
    reference_title: "Gene conversion: a mechanism for generation of heterogeneity in the tprK gene of Treponema pallidum during infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The TprK V regions are the focus of anti-TprK antibodies arising during infection."
    explanation: >-
      Establishes that the varying V regions are the target of the host
      antibody response, which is what makes their variation immune evasion.
- name: Th1 Cellular Immune Response and Partial Clearance
  biological_scale: CELLULAR
  description: >-
    Dendritic cells present treponemal antigen to CD4-positive T cells, driving
    a Th1-polarized response with interferon-gamma-mediated macrophage
    activation and phagocytosis. This response clears organisms from
    mucocutaneous lesions - which is why the chancre and the secondary eruption
    resolve without treatment - but does not eradicate infection.
  cell_types:
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: T-helper 1 type immune response
    term:
      id: GO:0042088
      label: T-helper 1 type immune response
    modifier: INCREASED
  - preferred_term: phagocytosis
    term:
      id: GO:0006909
      label: phagocytosis
    modifier: INCREASED
  downstream:
  - target: Latency and Persistent Infection
    description: >-
      Partial containment without eradication converts active disease into
      clinically silent latent infection.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40708500
    reference_title: "Syphilis Pathogenesis: Host Immune Response vs Pathogen Immune Evasion."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This translational update describes the host innate and adaptive immune responses in syphilis and the sophisticated mechanisms employed by T. pallidum to avoid immune clearance."
    explanation: >-
      Anchors the host innate and adaptive response that this node represents,
      alongside the evasion that prevents it achieving clearance. Evidence
      source is OTHER because the citation is a translational review.
  - reference: PMID:27721440
    reference_title: "Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The paucity of surface-exposed pathogen-associated molecular patterns (PAMPs) enables the bacterium to undergo repeated bouts of dissemination that are poorly detected by innate immunity"
    explanation: >-
      PARTIAL because the quoted text supports the failure of clearance rather
      than the specific Th1 cellular architecture.
- name: Obliterative Endarteritis
  biological_scale: TISSUE
  description: >-
    Lymphoplasmacytic infiltration of small and medium vessel walls with
    intimal proliferation narrows and obliterates the lumen, producing ischemic
    tissue injury. This single vascular lesion is the shared histological
    substrate of the primary chancre, the gumma, and tertiary aortitis, which
    is why one mechanism explains lesions in otherwise unrelated organs.
  cell_types:
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  downstream:
  - target: Syphilitic Aortitis
    description: >-
      Endarteritis of the aortic vasa vasorum produces ischemic medial injury.
    causal_link_type: DIRECT
  - target: Meningovascular Neurosyphilis
    description: Endarteritis of cerebral vessels produces stroke syndromes.
    causal_link_type: DIRECT
  - target: Genital ulcers
    description: >-
      Ischemic injury from local endarteritis produces the indurated, clean-based
      chancre.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27982548
    reference_title: "Syphilitic aortitis and its complications in the modern era."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presumably, Treponema pallidum invades the aortic wall and the inflammatory response progresses towards obliterative endarteritis and necrosis of the muscular and elastic fibers in the aortic media."
    explanation: >-
      Identifies obliterative endarteritis as the vascular lesion through which
      treponemal invasion damages tissue.
- name: Immune-Privileged Sanctuary Site Invasion
  biological_scale: ORGANISM
  description: >-
    T. pallidum crosses the blood-brain, blood-ocular, and placental barriers.
    Because this can happen during the earliest spirochetemia, neurosyphilis,
    ocular syphilis, and otosyphilis are not confined to late disease but may
    present at any stage - a reframing of the classical teaching that
    materially changes when clinicians should evaluate for them.
  downstream:
  - target: Meningovascular Neurosyphilis
    description: Early CNS invasion establishes the substrate for meningovascular disease.
    causal_link_type: DIRECT
  - target: Parenchymal Neurosyphilis
    description: >-
      Persistence in the CNS compartment permits the late parenchymal
      syndromes.
    causal_link_type: DIRECT
  - target: Transplacental Fetal Dissemination
    description: Placental crossing seeds the fetus.
    causal_link_type: DIRECT
  - target: Uveitis
    description: Invasion across the blood-ocular barrier produces ocular syphilis.
    causal_link_type: DIRECT
  - target: Sensorineural hearing impairment
    description: Invasion of the inner ear produces otosyphilis.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40708500
    reference_title: "Syphilis Pathogenesis: Host Immune Response vs Pathogen Immune Evasion."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The pathogen's ability to evade the immune system by using virulence factor-based strategies and invading immune-privileged sites enables persistent infection in the untreated host."
    explanation: >-
      Directly supports the mechanism this node asserts - invasion of
      immune-privileged sites as the basis of persistent infection. Evidence
      source is OTHER because the citation is a translational review.
  - reference: PMID:35819903
    reference_title: "Reported Neurologic, Ocular, and Otic Manifestations Among Syphilis Cases-16 States, 2019."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Syphilis can cause neurologic, ocular, or otic manifestations, possibly resulting in permanent disability or death."
    explanation: >-
      PARTIAL: establishes the manifestation set that sanctuary-site invasion
      produces, rather than the invasion mechanism itself.
- name: Secondary Disseminated Mucocutaneous Disease
  biological_scale: ORGANISM
  description: >-
    Widespread hematogenous spread produces the generalized maculopapular
    eruption (classically involving palms and soles), condylomata lata, mucous
    patches, generalized lymphadenopathy, and visceral involvement including
    syphilitic hepatitis and immune-complex glomerulonephritis.
  downstream:
  - target: Latency and Persistent Infection
    description: >-
      Secondary manifestations resolve as immune containment develops, and the
      infection becomes clinically silent.
    causal_link_type: DIRECT
  - target: Maculopapular exanthema
    description: Haematogenous seeding of the skin produces the generalized eruption.
    causal_link_type: DIRECT
  - target: Condylomata lata
    description: >-
      Treponemal proliferation in warm intertriginous mucocutaneous sites
      produces highly infectious moist plaques.
    causal_link_type: DIRECT
  - target: Lymphadenopathy
    description: Systemic dissemination produces generalized lymphadenopathy.
    causal_link_type: DIRECT
  - target: Alopecia
    description: Follicular involvement produces patchy moth-eaten alopecia.
    causal_link_type: DIRECT
  - target: Hepatitis
    description: Visceral seeding of the liver produces syphilitic hepatitis.
    causal_link_type: DIRECT
  - target: Glomerulonephritis
    description: Immune-complex deposition in the glomerulus produces nephritis.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Penicillin G, administered parenterally, is the preferred drug for treating patients in all stages of syphilis."
    explanation: >-
      PARTIAL: the CDC guideline frames syphilis as a staged disease treated by
      stage; the specific secondary-stage lesion set is carried by the
      individual phenotype entries and their own evidence.
- name: Latency and Persistent Infection
  biological_scale: ORGANISM
  description: >-
    Partial host containment suppresses clinically detectable disease without
    eradicating the organism. Latent infection is divided into early (under one
    year) and late (one year or longer, or unknown duration); early latency
    carries a risk of symptomatic mucocutaneous relapse. A minority of
    untreated people eventually progress to tertiary disease.
  downstream:
  - target: Gummatous Delayed-Type Hypersensitivity Response
    description: >-
      Long-term persistence in a sensitized host permits the delayed
      hypersensitivity granuloma of tertiary disease.
    causal_link_type: DIRECT
  - target: Syphilitic Aortitis
    description: >-
      Decades of low-grade treponemal presence in the aortic vasa vasorum
      produce tertiary cardiovascular disease.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of adequate treatment or disease activity."
    explanation: >-
      The lifelong persistence of treponemal antibody reflects the durable
      host-pathogen relationship this node represents and underlies the
      serofast state.
- name: Gummatous Delayed-Type Hypersensitivity Response
  biological_scale: TISSUE
  conforms_to: "granuloma_formation#Epithelioid Transformation and Multinucleated Giant Cell Formation"
  description: >-
    The gumma is a granulomatous lesion of tertiary syphilis in which
    macrophages undergo epithelioid transformation and fuse into Langhans-type
    multinucleated giant cells, palisading with lymphocytes and plasma cells
    around a zone of central necrosis, in skin, bone, or viscera. Treponemes
    are characteristically scant and difficult to demonstrate within gumma
    tissue, indicating that the lesion is predominantly an immune-mediated
    delayed-type hypersensitivity response rather than direct microbial
    cytopathology.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: syncytium formation by cell-cell fusion
    term:
      id: GO:0000768
      label: syncytium formation by cell-cell fusion
    modifier: INCREASED
  downstream:
  - target: Cutaneous granuloma
    description: >-
      Organized granulomatous inflammation in the dermis forms the cutaneous
      gumma.
    causal_link_type: DIRECT
  - target: Skin ulcer
    description: >-
      Central necrosis and breakdown of the gumma produces a destructive,
      scarring ulcer.
    causal_link_type: DIRECT
  notes: >-
    No cited source in this entry describes gumma histology directly; the
    epithelioid and giant-cell content of this node is asserted from the
    module pattern and general pathology rather than from a verified quote,
    and is deliberately left unevidenced rather than propped up by an
    unrelated aortitis citation.
- name: Syphilitic Aortitis
  biological_scale: TISSUE
  description: >-
    Chronic treponemal presence in the vasa vasorum of the ascending aorta
    drives obliterative endarteritis of those nutrient vessels, producing
    ischemic destruction of the elastic and muscular fibers of the aortic
    media. The weakened wall dilates, giving aortic aneurysm, aortic
    regurgitation, aortic root dilation, and coronary ostial stenosis.
  downstream:
  - target: Thoracic aortic aneurysm
    description: Medial destruction weakens the wall and permits aneurysmal dilation.
    causal_link_type: DIRECT
  - target: Aortic regurgitation
    description: Aortic root dilation renders the valve incompetent.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27982548
    reference_title: "Syphilitic aortitis and its complications in the modern era."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The consequent weakening of the aortic wall can lead to severe complications, represented by aortic aneurysm, aortic valvular insufficiency, aortic root dilation and coronary ostial stenosis."
    explanation: >-
      Directly enumerates the cardiovascular consequences of medial destruction
      that this node produces.
- name: Meningovascular Neurosyphilis
  biological_scale: TISSUE
  description: >-
    The early neurological pattern: endarteritis of cerebral and meningeal
    vessels producing syphilitic meningitis, cranial nerve dysfunction, and
    ischemic stroke, typically within the first months to few years of
    infection. Its mechanism is vascular, which is why it shares a lesion with
    the chancre and with aortitis.
  downstream:
  - target: Ischemic stroke
    description: Cerebral endarteritis causes ischemic infarction.
    causal_link_type: DIRECT
  - target: Meningitis
    description: Meningeal vascular and inflammatory involvement produces syphilitic meningitis.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early neurologic clinical manifestations or syphilitic meningitis (e.g., cranial nerve dysfunction, meningitis, meningovascular syphilis, stroke, and acute altered mental status) are usually present within the first few months or years of infection."
    explanation: >-
      Directly enumerates the early meningovascular manifestations and their
      timing, distinguishing them from the late parenchymal syndromes.
- name: Parenchymal Neurosyphilis
  biological_scale: TISSUE
  description: >-
    The late neurological pattern, occurring 10 to more than 30 years after
    infection: direct neuronal and glial injury rather than vascular
    occlusion, producing general paresis (cortical atrophy and gliosis) and
    tabes dorsalis (degeneration of the dorsal columns and dorsal root
    ganglia). HIV coinfection is associated with an accelerated and more
    severe course.
  downstream:
  - target: Dementia
    description: Parenchymal cortical injury produces the dementia of general paresis.
    causal_link_type: DIRECT
  - target: Sensory ataxia
    description: >-
      Dorsal column and dorsal root ganglion degeneration produces the sensory
      ataxia of tabes dorsalis.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10 to >30 years after infection."
    explanation: >-
      Identifies tabes dorsalis and general paresis as the late parenchymal
      manifestations and separates them in time from the early meningovascular
      ones.
  - reference: PMID:25890619
    reference_title: "Neurosyphilis and the impact of HIV infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This review of the clinical presentation, diagnostic laboratory findings, treatment and management of neurosyphilis discusses the impact of HIV and the specific challenges it brings"
    explanation: >-
      PARTIAL: supports the HIV-modified course of neurosyphilis; the review
      abstract does not itself separate parenchymal from meningovascular
      disease.
- name: Transplacental Fetal Dissemination
  biological_scale: ORGANISM
  description: >-
    Maternal spirochetemia seeds the fetus across the placenta, producing a
    disease process analogous to disseminated secondary syphilis in the fetus.
    Transmission can occur at any point in pregnancy or at delivery, and the
    risk is greatest when the mother is in the primary or secondary stage.
    Untreated fetal infection causes stillbirth, hydrops, and the early
    congenital syndrome; the classical Hutchinson stigmata are late, permanent
    developmental scarring rather than active infection.
  downstream:
  - target: Rhinitis
    description: Mucosal infection of the neonatal nasal passages produces syphilitic snuffles.
    causal_link_type: DIRECT
  - target: Hepatosplenomegaly
    description: Disseminated fetal infection involves the liver and spleen.
    causal_link_type: DIRECT
  - target: Periostitis
    description: Treponemal infection of growing bone produces periostitis and osteochondritis.
    causal_link_type: DIRECT
  - target: Keratitis
    description: Late congenital interstitial keratitis is one component of the Hutchinson triad.
    causal_link_type: DIRECT
  - target: Abnormal dental morphology
    description: Enamel and dentine maldevelopment produces Hutchinson incisors.
    causal_link_type: DIRECT
  - target: Sensorineural hearing impairment
    description: Eighth nerve involvement produces the deafness of the Hutchinson triad.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40977496
    reference_title: "Syphilis in pregnancy: A practical guide for prenatal care providers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vertical transmission can occur at any point during pregnancy or delivery, with the highest risk observed during primary and secondary stages of infection compared to latent phases."
    explanation: >-
      Establishes the timing and maternal-stage dependence of transplacental
      transmission.
  - reference: PMID:22670010
    reference_title: "Clinical aspects of congenital syphilis with Hutchinson's triad."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the main aspects is observed with the triad of Hutchinson, characterised by the presence of interstitial keratitis, eighth nerve deafness and Hutchinson's teeth."
    explanation: >-
      Documents the late congenital stigmata that result from transplacental
      fetal infection.
- name: Treponemal Peptidoglycan Cross-Linking (Beta-Lactam Target)
  biological_scale: MOLECULAR
  role: therapeutic_vulnerability
  conforms_to: "bacterial_cell_wall_synthesis_inhibition#Peptidoglycan Cross-Linking by Penicillin-Binding Proteins"
  description: >-
    T. pallidum maintains its peptidoglycan cell wall by penicillin-binding
    protein transpeptidase cross-linking. Beta-lactam acylation of the PBP
    active site halts cross-linking and is treponemicidal. Remarkably, no
    clinically significant penicillin resistance has ever been documented in
    T. pallidum, which is why a single intramuscular dose still cures early
    syphilis after eight decades of use.
  biological_processes:
  - preferred_term: peptidoglycan-based cell wall biogenesis
    term:
      id: GO:0009273
      label: peptidoglycan-based cell wall biogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Penicillin G, administered parenterally, is the preferred drug for treating patients in all stages of syphilis."
    explanation: >-
      The continued first-line status of parenteral penicillin at every stage
      reflects the undiminished efficacy of this drug target.
- name: Treponemal Ribosomal Translation (Macrolide and Tetracycline Target)
  biological_scale: MOLECULAR
  role: therapeutic_vulnerability
  conforms_to: "bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the Ribosome"
  description: >-
    Treponemal protein synthesis on the bacterial ribosome is the target of the
    second-line agents used when penicillin cannot be given - doxycycline
    acting on the 30S subunit, and historically azithromycin acting on the 50S
    subunit.
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
    modifier: DECREASED
  downstream:
  - target: 23S rRNA Macrolide Resistance
    description: >-
      Point mutation in the macrolide binding site on this target abolishes
      azithromycin efficacy.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:18192791
    reference_title: "Azithromycin resistance in Treponema pallidum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This mutation confers resistance by precluding macrolide binding to the bacterial 50S ribosomal subunit, of which 23S rRNA is a structural component."
    explanation: >-
      Identifies the treponemal ribosome as the macrolide target. Evidence
      source is OTHER because the citation is a review.
- name: 23S rRNA Macrolide Resistance
  biological_scale: MOLECULAR
  role: resistance_mechanism
  conforms_to: "bacterial_protein_synthesis_inhibition#Ribosomal Target Resistance"
  description: >-
    An A-to-G point mutation at position 2058 of the 23S rRNA gene (and the
    related A2059G change) abolishes macrolide binding to the 50S subunit.
    First recognised in azithromycin treatment failures in San Francisco in
    2002, these mutations have since become prevalent in many regions, and are
    the reason azithromycin is no longer recommended where resistance
    prevalence is unknown or high. This distinguishes syphilis from the endemic
    treponematoses, where azithromycin remains a mainstay of mass treatment.
  evidence:
  - reference: PMID:18192791
    reference_title: "Azithromycin resistance in Treponema pallidum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Azithromycin treatment failures in syphilis were first noted in San Francisco in 2002 and result from an A-->G mutation at position 2058 of the 23S rRNA gene"
    explanation: >-
      Directly identifies the A2058G 23S rRNA mutation as the cause of
      azithromycin treatment failure in syphilis.
phenotypes:
- category: Dermatological
  name: Genital ulcers
  diagnostic: true
  description: >-
    The primary lesion is a solitary, painless, indurated anogenital or oral
    ulcer with a clean base (chancre) at the inoculation site, appearing 10-90
    days after exposure and healing spontaneously in 3-6 weeks without
    treatment - resolution marks progression to latency, not cure.
  phenotype_term:
    preferred_term: Chancre
    term:
      id: HP:0003249
      label: Genital ulcers
    temporality: TRANSIENT
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary syphilis classically presents as a single painless ulcer or chancre at the site of infection but can also present with multiple, atypical, or painful lesions"
    explanation: >-
      Directly describes the chancre and, importantly, records that the
      classical solitary painless presentation is not universal.
- category: Hematological
  name: Lymphadenopathy
  description: >-
    Regional, characteristically non-tender rubbery lymphadenopathy accompanies
    the primary chancre; generalized lymphadenopathy is a feature of the
    secondary stage.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary syphilis manifestations can include skin rash, mucocutaneous lesions, and lymphadenopathy."
    explanation: >-
      Names lymphadenopathy directly as a secondary-stage manifestation.
- category: Dermatological
  name: Maculopapular exanthema
  diagnostic: true
  description: >-
    The secondary eruption is a diffuse maculopapular rash that classically
    involves the palms and soles, a distribution that is close to
    pathognomonic in the right clinical context.
  phenotype_term:
    preferred_term: Maculopapular exanthema
    term:
      id: HP:0040186
      label: Maculopapular exanthema
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary syphilis manifestations can include skin rash, mucocutaneous lesions, and lymphadenopathy."
    explanation: >-
      Names skin rash and mucocutaneous lesions directly as secondary-stage
      manifestations.
- category: Dermatological
  name: Alopecia
  description: >-
    Patchy "moth-eaten" alopecia is a recognized secondary-stage manifestation.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  notes: >-
    No evidence item is attached. The CDC guideline snippet that anchors the
    other secondary-stage phenotypes names rash, mucocutaneous lesions, and
    lymphadenopathy but not alopecia, and no cited source in this entry
    describes it. Curated as unevidenced description rather than propped up by
    a stage-level quote.
- category: Gastrointestinal
  name: Hepatitis
  description: >-
    Syphilitic hepatitis is a visceral manifestation of the secondary stage.
  phenotype_term:
    preferred_term: Hepatitis
    term:
      id: HP:0012115
      label: Hepatitis
  notes: >-
    No evidence item is attached. No cited source in this entry describes
    syphilitic hepatitis; curated as unevidenced description rather than
    supported by a stage-level quote that does not mention the liver.
- category: Renal
  name: Glomerulonephritis
  description: >-
    Immune-complex glomerulonephritis may complicate the secondary stage.
  phenotype_term:
    preferred_term: Glomerulonephritis
    term:
      id: HP:0000099
      label: Glomerulonephritis
  notes: >-
    No evidence item is attached. No cited source in this entry describes
    syphilitic glomerulonephritis; curated as unevidenced description rather
    than supported by a stage-level quote that does not mention the kidney.
- category: Neurological
  name: Meningitis
  description: >-
    Syphilitic meningitis is the earliest neurological manifestation and, like
    other neurological involvement, can occur at any stage including early
    infection.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  evidence:
  - reference: PMID:35819903
    reference_title: "Reported Neurologic, Ocular, and Otic Manifestations Among Syphilis Cases-16 States, 2019."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical manifestations were infrequently reported overall: neurologic (n = 445, 1.1%), ocular (n = 461, 1.1%), otic (n = 166, 0.4%), any (n = 807, 2.0%)"
    explanation: >-
      Neurologic manifestations were reported in 1.1% of 41,187 surveillance
      cases, supporting the VERY_RARE band.
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early neurologic clinical manifestations or syphilitic meningitis (e.g., cranial nerve dysfunction, meningitis, meningovascular syphilis, stroke, and acute altered mental status) are usually present within the first few months or years of infection."
    explanation: >-
      Names syphilitic meningitis as an early neurologic manifestation.
  notes: >-
    Frequency derivation: the 1.1% figure is for neurologic manifestations as a
    whole, of which syphilitic meningitis is a strict subset, so the true
    meningitis-only rate is lower than 1.1% and remains inside VERY_RARE. The
    band is therefore an upper bound rather than a point estimate. Passive
    surveillance also under-ascertains, so the reported figure is itself likely
    an underestimate of true occurrence.
- category: Neurological
  name: Ischemic stroke
  description: >-
    Meningovascular neurosyphilis causes ischemic stroke through endarteritis
    of cerebral vessels, characteristically in a younger patient than typical
    atherosclerotic stroke.
  phenotype_term:
    preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "meningovascular syphilis, stroke, and acute altered mental status) are usually present within the first few months or years of infection"
    explanation: >-
      Names stroke among the early meningovascular neurologic manifestations.
- category: Neurological
  name: Dementia
  description: >-
    General paresis is a late parenchymal neurosyphilis syndrome producing
    progressive cognitive decline with cortical atrophy and gliosis.
  phenotype_term:
    preferred_term: Dementia
    term:
      id: HP:0000726
      label: Dementia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10 to >30 years after infection."
    explanation: >-
      Names general paresis, the syndrome of which this dementia is the
      cardinal feature, as a late neurologic manifestation.
- category: Neurological
  name: Sensory ataxia
  description: >-
    Tabes dorsalis produces sensory ataxia through degeneration of the dorsal
    columns and dorsal root ganglia.
  phenotype_term:
    preferred_term: Sensory ataxia
    term:
      id: HP:0010871
      label: Sensory ataxia
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10 to >30 years after infection."
    explanation: >-
      Names tabes dorsalis, of which sensory ataxia is the cardinal sign, as a
      late neurologic manifestation.
- category: Ophthalmological
  name: Uveitis
  description: >-
    Ocular syphilis most often presents as uveitis and can occur at any stage;
    it is treated as neurosyphilis.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Uveitis
    term:
      id: HP:0000554
      label: Uveitis
  evidence:
  - reference: PMID:35819903
    reference_title: "Reported Neurologic, Ocular, and Otic Manifestations Among Syphilis Cases-16 States, 2019."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical manifestations were infrequently reported overall: neurologic (n = 445, 1.1%), ocular (n = 461, 1.1%), otic (n = 166, 0.4%), any (n = 807, 2.0%)"
    explanation: >-
      Ocular manifestations were reported in 1.1% of 41,187 surveillance cases,
      supporting the VERY_RARE band. Passive surveillance likely underestimates
      the true figure.
- category: Otolaryngological
  name: Sensorineural hearing impairment
  description: >-
    Otosyphilis produces sensorineural hearing loss and is, like ocular
    syphilis, managed as neurosyphilis.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:35819903
    reference_title: "Reported Neurologic, Ocular, and Otic Manifestations Among Syphilis Cases-16 States, 2019."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical manifestations were infrequently reported overall: neurologic (n = 445, 1.1%), ocular (n = 461, 1.1%), otic (n = 166, 0.4%), any (n = 807, 2.0%)"
    explanation: >-
      Otic manifestations were reported in 0.4% of 41,187 surveillance cases,
      supporting the VERY_RARE band. This phenotype also arises in late
      congenital syphilis as the eighth nerve deafness of the Hutchinson triad.
  - reference: PMID:22670010
    reference_title: "Clinical aspects of congenital syphilis with Hutchinson's triad."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the triad of Hutchinson, characterised by the presence of interstitial keratitis, eighth nerve deafness and Hutchinson's teeth"
    explanation: >-
      Names eighth nerve deafness as a component of the Hutchinson triad, the
      congenital route to this phenotype.
- category: Cardiovascular
  name: Thoracic aortic aneurysm
  description: >-
    Aneurysm of the thoracic aorta, characteristically the ascending segment,
    is the most common cardiovascular manifestation of tertiary syphilis,
    following ischemic destruction of the aortic media. In a review of
    published cardiovascular-syphilis cases, aneurysm was present in 71%; that
    denominator is patients already reported as having cardiovascular syphilis,
    not patients with syphilis, so no frequency band is asserted here.
  phenotype_term:
    preferred_term: Thoracic aortic aneurysm
    term:
      id: HP:0012727
      label: Thoracic aortic aneurysm
  evidence:
  - reference: PMID:27982548
    reference_title: "Syphilitic aortitis and its complications in the modern era."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aortic aneurysm was the most frequent involvement, detected in 71% of patients."
    explanation: >-
      Supports aneurysm as the commonest cardiovascular involvement. The 71%
      denominator is published cardiovascular-syphilis cases, a
      publication-selected series, so it cannot be mapped to a FrequencyEnum
      band for syphilis as a whole.
- category: Cardiovascular
  name: Aortic regurgitation
  description: >-
    Aortic root dilation from medial destruction renders the aortic valve
    incompetent.
  phenotype_term:
    preferred_term: Aortic regurgitation
    term:
      id: HP:0001659
      label: Aortic regurgitation
  evidence:
  - reference: PMID:27982548
    reference_title: "Syphilitic aortitis and its complications in the modern era."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The consequent weakening of the aortic wall can lead to severe complications, represented by aortic aneurysm, aortic valvular insufficiency, aortic root dilation and coronary ostial stenosis."
    explanation: >-
      Aortic valvular insufficiency is named directly as a consequence of the
      weakened aortic wall.
- category: Dermatological
  name: Cutaneous granuloma
  description: >-
    The cutaneous gumma of tertiary syphilis is a granulomatous nodule that
    subsequently breaks down, ulcerates, and scars.
  phenotype_term:
    preferred_term: Gumma
    term:
      id: HP:6000070
      label: Cutaneous granuloma
  notes: >-
    No evidence item is attached. No cited source in this entry describes
    cutaneous gumma morphology; curated as unevidenced description rather than
    supported by an aortitis quote. HPO has no gumma-specific term, so the
    generic cutaneous granuloma term carries a free-text preferred_term.
- category: Dermatological
  name: Skin ulcer
  description: >-
    Gummas ulcerate as they enlarge and undergo central necrosis, producing the
    destructive, scarring skin ulcers of tertiary syphilis.
  phenotype_term:
    preferred_term: Ulcerated gumma
    term:
      id: HP:0200042
      label: Skin ulcer
  notes: >-
    No evidence item is attached, for the same reason as the parent granuloma
    phenotype.
- category: Ophthalmological
  name: Keratitis
  description: >-
    Interstitial keratitis is one component of the Hutchinson triad of late
    congenital syphilis.
  phenotype_term:
    preferred_term: Interstitial keratitis
    term:
      id: HP:0000491
      label: Keratitis
  evidence:
  - reference: PMID:22670010
    reference_title: "Clinical aspects of congenital syphilis with Hutchinson's triad."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the triad of Hutchinson, characterised by the presence of interstitial keratitis, eighth nerve deafness and Hutchinson's teeth"
    explanation: >-
      Names interstitial keratitis as a component of the Hutchinson triad.
- category: Craniofacial
  name: Abnormal dental morphology
  description: >-
    Hutchinson teeth - notched, peg-shaped permanent incisors - are a component
    of the Hutchinson triad of late congenital syphilis. The dental change is
    permanent developmental scarring rather than active infection.
  phenotype_term:
    preferred_term: Hutchinson teeth
    term:
      id: HP:0006482
      label: Abnormal dental morphology
  evidence:
  - reference: PMID:22670010
    reference_title: "Clinical aspects of congenital syphilis with Hutchinson's triad."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the triad of Hutchinson, characterised by the presence of interstitial keratitis, eighth nerve deafness and Hutchinson's teeth"
    explanation: >-
      Names Hutchinson teeth as a component of the triad.
- category: Dermatological
  name: Condylomata lata
  description: >-
    Moist, broad, greyish-white plaques in warm intertriginous sites
    (perianal, vulval, inner thigh, axillary). They teem with treponemes and
    are among the most infectious lesions of syphilis, which is why they matter
    epidemiologically out of proportion to their frequency.
  phenotype_term:
    preferred_term: Condylomata lata
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary syphilis manifestations can include skin rash, mucocutaneous lesions, and lymphadenopathy."
    explanation: >-
      PARTIAL: condylomata lata are the archetypal secondary mucocutaneous
      lesion named in this list, but the guideline text does not name them
      individually.
  notes: >-
    No HPO term exists for condylomata lata or for the syphilitic chancre; a
    free-text preferred_term is used with no term binding rather than forcing
    an inaccurate one. Candidate for an HPO new-term request.
- category: Otolaryngological
  name: Rhinitis
  description: >-
    Persistent, often blood-stained nasal discharge ("snuffles") is a
    characteristic early manifestation of congenital syphilis and is highly
    infectious.
  phenotype_term:
    preferred_term: Syphilitic snuffles
    term:
      id: HP:0012384
      label: Rhinitis
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hepatosplenomegaly, rhinitis, skin rash, or pseudoparalysis of an extremity"
    explanation: >-
      Names rhinitis among the clinical findings of early congenital syphilis.
- category: Hematological
  name: Hepatosplenomegaly
  description: >-
    Hepatosplenomegaly reflects disseminated fetal infection and is one of the
    commonest findings of early congenital syphilis.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hepatosplenomegaly, rhinitis, skin rash, or pseudoparalysis of an extremity"
    explanation: >-
      Names hepatosplenomegaly among the clinical findings of early congenital
      syphilis.
- category: Skeletal
  name: Periostitis
  description: >-
    Periostitis and osteochondritis of the long bones produce the pain that
    causes pseudoparalysis of an extremity (Parrot pseudoparalysis) in early
    congenital syphilis.
  phenotype_term:
    preferred_term: Periostitis
    term:
      id: HP:0040165
      label: Periostitis
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hepatosplenomegaly, rhinitis, skin rash, or pseudoparalysis of an extremity"
    explanation: >-
      PARTIAL: names pseudoparalysis, the clinical consequence of the
      periostitis and osteochondritis this phenotype represents, rather than
      the bone lesion itself.
diagnosis:
- name: Nontreponemal serology (RPR/VDRL)
  description: >-
    Nontreponemal tests detect non-specific anticardiolipin antibodies produced
    in response to host tissue damage. They are quantitative, so titers track
    treatment response, but can be falsely negative very early or through the
    prozone phenomenon at very high titers, and falsely positive in pregnancy,
    autoimmune disease, and other infections.
  diagnosis_term:
    preferred_term: nontreponemal serologic testing
    term:
      id: NCIT:C74716
      label: Rapid Plasma Reagin Measurement
  results: >-
    A quantitative titer used both for diagnosis and for monitoring; a
    four-fold or greater decline indicates adequate treatment response.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of adequate treatment or disease activity."
    explanation: >-
      Explains why the quantitative nontreponemal test, not the treponemal
      test, is the instrument for monitoring treatment response.
- name: Treponemal serology and the reverse sequence algorithm
  description: >-
    Treponemal tests (TP-PA, FTA-ABS, and automated EIA/CIA immunoassays) are
    specific for anti-T. pallidum antibody but usually remain reactive for
    life, so they cannot by themselves distinguish active from previously
    treated infection. Automated laboratories increasingly screen with a
    treponemal immunoassay first (the reverse sequence algorithm), reflexing to
    a quantitative RPR and, when the two are discordant, to a second treponemal
    test as tiebreaker.
  diagnosis_term:
    preferred_term: treponemal serologic testing
    term:
      id: NCIT:C132388
      label: Treponema pallidum Antibody Measurement
  results: >-
    Lifelong reactivity in most patients; interpretation requires pairing with
    a quantitative nontreponemal titer.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treponemal Tests and Reverse Sequence Algorithm The majority of patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of adequate treatment or disease activity."
    explanation: >-
      Directly supports both the reverse sequence algorithm and the lifelong
      reactivity that limits treponemal test interpretation.
- name: Direct detection by PCR of lesion material
  description: >-
    PCR on swabs of a chancre or other mucocutaneous lesion detects treponemal
    DNA during the early window when serology may still be non-reactive, and
    has largely supplanted darkfield microscopy where it is available.
    Reference laboratories can also genotype 23S rRNA for the A2058G/A2059G
    macrolide resistance mutations.
  diagnosis_term:
    preferred_term: polymerase chain reaction
    term:
      id: NCIT:C17003
      label: Polymerase Chain Reaction
  results: >-
    Detection of T. pallidum DNA from lesion exudate; a negative result does
    not exclude syphilis.
  evidence:
  - reference: PMID:18192791
    reference_title: "Azithromycin resistance in Treponema pallidum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Azithromycin treatment failures in syphilis were first noted in San Francisco in 2002 and result from an A-->G mutation at position 2058 of the 23S rRNA gene"
    explanation: >-
      PARTIAL: supports the molecular resistance target that pathogen
      genotyping detects, rather than the diagnostic performance of lesion PCR.
- name: Cerebrospinal fluid examination for neurosyphilis
  description: >-
    CSF examination (CSF-VDRL, cell count, protein) is the test that governs
    management of suspected neurosyphilis, since a diagnosis of neurosyphilis
    changes therapy from intramuscular benzathine penicillin to 10-14 days of
    intravenous aqueous crystalline penicillin. CSF-VDRL is highly specific but
    insensitive, so a negative result in a patient with neurologic signs does
    not exclude the diagnosis.
  diagnosis_term:
    preferred_term: cerebrospinal fluid examination by lumbar puncture
    term:
      id: NCIT:C15327
      label: Lumbar Puncture
  results: >-
    A reactive CSF-VDRL in an uncontaminated specimen is diagnostic; a negative
    result does not exclude neurosyphilis.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For a person with neurologic signs or symptoms, a reactive CSF-VDRL (in the absence of blood contamination) is considered diagnostic of neurosyphilis."
    explanation: >-
      Establishes the reactive CSF-VDRL as diagnostic of neurosyphilis.
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CSF-VDRL is highly specific but insensitive"
    explanation: >-
      Establishes the insensitivity that makes a negative CSF-VDRL
      non-exclusionary.
differential_diagnoses:
- name: Genital herpes
  description: >-
    HSV is the commonest cause of genital ulceration. Herpetic ulcers are
    typically multiple, painful, and vesicular at onset, whereas the syphilitic
    chancre is classically solitary, painless, and indurated.
- name: Chancroid
  description: >-
    Haemophilus ducreyi produces a painful, non-indurated genital ulcer with a
    ragged undermined edge and suppurative lymphadenitis, contrasting with the
    clean-based, indurated, painless chancre.
- name: Pityriasis rosea
  description: >-
    Shares the truncal papulosquamous eruption of secondary syphilis but spares
    the palms and soles, whose involvement is the key discriminator.
- name: Sarcoidosis
  description: >-
    Another cause of granulomatous lesions that can mimic gummas and produce
    uveitis; distinguished by serology and histology.
treatments:
- name: Parenteral penicillin G, stage-dependent regimen
  description: >-
    Parenteral penicillin G is the treatment of choice at every stage.
    Benzathine penicillin G 2.4 million units IM as a single dose treats
    primary, secondary, and early-latent syphilis; the same dose weekly for
    three weeks treats late-latent, unknown-duration, and non-neurological
    tertiary disease; and aqueous crystalline penicillin G IV for 10-14 days is
    required for neurosyphilis, ocular syphilis, and otosyphilis. Neither oral
    penicillin preparations nor benzathine-procaine combinations are adequate
    therapy at any stage. Tertiary structural damage already established -
    aortic aneurysm, tabetic deficits, gummatous scarring - does not reverse
    with microbiological cure.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: penicillin G benzathine
      term:
        id: NCIT:C47657
        label: Penicillin G Benzathine
    - preferred_term: benzylpenicillin
      term:
        id: CHEBI:18208
        label: benzylpenicillin
  target_mechanisms:
  - target: Treponemal Peptidoglycan Cross-Linking (Beta-Lactam Target)
    treatment_effect: INHIBITS
    description: >-
      Beta-lactam acylation of penicillin-binding proteins halts peptidoglycan
      cross-linking and is treponemicidal.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Penicillin G, administered parenterally, is the preferred drug for treating patients in all stages of syphilis."
    explanation: >-
      Directly supports parenteral penicillin G as first-line therapy at every
      stage of syphilis.
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Combinations of benzathine penicillin, procaine penicillin, and oral penicillin preparations are not considered appropriate for syphilis treatment."
    explanation: >-
      Supports the negative recommendation in this description against oral and
      combination penicillin preparations.
- name: Doxycycline for penicillin-allergic non-pregnant patients
  description: >-
    Doxycycline 100 mg orally twice daily for 14 days (longer for late-stage
    disease) is the principal alternative for non-pregnant, penicillin-allergic
    patients with non-neurological syphilis. It is not an option in pregnancy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
  target_mechanisms:
  - target: Treponemal Ribosomal Translation (Macrolide and Tetracycline Target)
    treatment_effect: INHIBITS
    description: >-
      Doxycycline binds the 30S ribosomal subunit and arrests treponemal
      protein synthesis.
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The only acceptable alternatives for treating late latent syphilis or syphilis of unknown duration are doxycycline (100 mg orally 2 times/day) or tetracycline (500 mg orally 4 times/day), each for 28 days."
    explanation: >-
      Gives the doxycycline regimen and its status as an acceptable alternative
      in late latent disease.
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No proven alternatives to penicillin are available for treatment of syphilis during pregnancy."
    explanation: >-
      Establishes the pregnancy boundary of doxycycline's role.
- name: Penicillin desensitization in pregnancy
  description: >-
    Because no alternative to penicillin is proven for syphilis in pregnancy,
    and because untreated maternal infection causes congenital syphilis, a
    pregnant patient reporting penicillin allergy should be desensitized and
    then treated with penicillin rather than given a substitute agent.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: penicillin desensitization
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: benzylpenicillin
      term:
        id: CHEBI:18208
        label: benzylpenicillin
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pregnant women with syphilis at any stage who report penicillin allergy should be desensitized and treated with penicillin"
    explanation: >-
      Directly supports desensitization rather than substitution in pregnancy.
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No proven alternatives to penicillin are available for treatment of syphilis during pregnancy."
    explanation: >-
      Establishes the absence of an acceptable alternative that makes
      desensitization necessary.
- name: Azithromycin, no longer recommended where resistance is prevalent
  description: >-
    Azithromycin was historically used as a single-dose oral alternative but is
    compromised by 23S rRNA A2058G/A2059G resistance, now prevalent in many
    regions. It is not recommended where resistance prevalence is unknown or
    high. This is the sharpest treatment contrast with the endemic
    treponematoses, where single-dose azithromycin underpins mass drug
    administration.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azithromycin
      term:
        id: CHEBI:2955
        label: azithromycin
  target_mechanisms:
  - target: Treponemal Ribosomal Translation (Macrolide and Tetracycline Target)
    treatment_effect: INHIBITS
    description: >-
      Azithromycin binds the 50S ribosomal subunit and arrests treponemal
      protein synthesis - but only in strains lacking the A2058G/A2059G 23S
      rRNA mutation, which abolishes macrolide binding.
  evidence:
  - reference: PMID:18192791
    reference_title: "Azithromycin resistance in Treponema pallidum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although the recommended treatment for syphilis is penicillin, azithromycin has been used as an alternative."
    explanation: >-
      Establishes azithromycin's status as an alternative agent whose use is
      constrained by resistance.
  - reference: PMID:18192791
    reference_title: "Azithromycin resistance in Treponema pallidum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We discuss azithromycin-related treatment failures and resistance in Treponema pallidum, and propose ways to meet the resulting clinical and public health challenges."
    explanation: >-
      Documents azithromycin treatment failure and resistance as the reason for
      its restricted role.
- name: Anticipatory counselling for the Jarisch-Herxheimer reaction
  description: >-
    The Jarisch-Herxheimer reaction is an acute febrile reaction with headache
    and myalgia occurring within the first 24 hours of any effective syphilis
    therapy. It is a reaction to treatment, not penicillin allergy, and
    mistaking it for allergy risks withholding the only curative drug. In a
    prospective secondary analysis of a randomized trial of benzathine
    penicillin G for early syphilis, symptoms occurred in 23.7% of
    participants, with median onset about 5 hours and median duration about 13
    hours. Management is supportive; patients should be counselled before
    treatment.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: pre-treatment counselling
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  evidence:
  - reference: PMID:34292926
    reference_title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache, myalgia, and fever that can occur within the first 24 hours after the initiation of any syphilis therapy; it is a reaction to treatment and not an allergic reaction to penicillin."
    explanation: >-
      Defines the reaction and states explicitly that it is not penicillin
      allergy, the clinically consequential distinction.
  - reference: PMID:39946129
    reference_title: "Jarisch-Herxheimer Reaction After Benzathine Penicillin G Treatment in Adults With Early Syphilis: Secondary Analysis of a Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One or more JHR symptoms occurred in 59 participants (23.7%) treated for early syphilis, with a median symptom onset at 4.9 hours (IQR, 3.0-9.2 hours) and a median duration of 12.8 hours (IQR, 5.0-24.0 hours)."
    explanation: >-
      Provides the prospective incidence, onset, and duration figures quoted in
      this entry.
  - reference: PMID:39946129
    reference_title: "Jarisch-Herxheimer Reaction After Benzathine Penicillin G Treatment in Adults With Early Syphilis: Secondary Analysis of a Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of the Jarisch-Herxheimer reaction (JHR) after penicillin treatment for early syphilis is reported to range from 8% to 56%."
    explanation: >-
      Documents the wide range of previously reported incidence estimates that
      this trial was designed to resolve.
- name: Doxycycline post-exposure prophylaxis (doxy-PEP)
  description: >-
    Doxycycline 200 mg taken within 72 hours of condomless sex reduces incident
    syphilis and chlamydia by more than 70% in randomized trials. CDC recommends
    it for men who have sex with men and transgender women with a bacterial STI
    in the preceding 12 months. It acts upstream of the inoculation step rather
    than treating established infection, so it is prevention rather than
    therapy.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: post-exposure chemoprophylaxis
    term:
      id: NCIT:C15843
      label: Preventive Intervention
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
  target_mechanisms:
  - target: Treponemal Ribosomal Translation (Macrolide and Tetracycline Target)
    treatment_effect: INHIBITS
    description: >-
      Doxycycline arrests treponemal protein synthesis, eliminating the
      organism before infection is established.
  evidence:
  - reference: PMID:38833414
    reference_title: "CDC Clinical Guidelines on the Use of Doxycycline Postexposure Prophylaxis for Bacterial Sexually Transmitted Infection Prevention, United States, 2024."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In three large randomized controlled trials, 200 mg of doxycycline taken within 72 hours after sex has been shown to reduce syphilis and chlamydia infections by >70% and gonococcal infections by approximately 50%."
    explanation: >-
      Gives the dose, the 72-hour window, and the randomized-trial effect size
      for syphilis prevention.
- name: Aortic aneurysm repair and valve replacement
  description: >-
    Advanced cardiovascular syphilis with a hemodynamically significant
    aneurysm or aortic regurgitation requires surgical repair or valve
    replacement; antimicrobial cure does not reverse established structural
    damage.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:27982548
    reference_title: "Syphilitic aortitis and its complications in the modern era."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The consequent weakening of the aortic wall can lead to severe complications, represented by aortic aneurysm, aortic valvular insufficiency, aortic root dilation and coronary ostial stenosis."
    explanation: >-
      Establishes the structural complications that constitute the surgical
      indication.
histopathology:
- name: Obliterative endarteritis with plasma cell infiltrate
  description: >-
    The characteristic microscopic lesion across every stage is a
    lymphoplasmacytic vasculitis of small vessels with endothelial swelling and
    concentric intimal proliferation narrowing the lumen. A plasma-cell-rich
    infiltrate is the histological signature that suggests syphilis in an
    otherwise nonspecific biopsy.
  finding_term:
    preferred_term: obliterative endarteritis with plasma cell infiltrate
    term:
      id: NCIT:C35984
      label: Lymphoplasmacytic Infiltrate
  evidence:
  - reference: PMID:27982548
    reference_title: "Syphilitic aortitis and its complications in the modern era."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the inflammatory response progresses towards obliterative endarteritis and necrosis of the muscular and elastic fibers in the aortic media"
    explanation: >-
      Describes the obliterative endarteritis and consequent medial necrosis
      that define the lesion.
  - reference: PMID:16224168
    reference_title: "A case of primary syphilis in the rectum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "histologic evaluation of biopsy revealed obliterative endarteritis with heavy plasma cell infiltration"
    explanation: >-
      Documents the same obliterative endarteritis with a plasma-cell-rich
      infiltrate in a primary lesion, supporting this as the lesion shared
      across stages rather than an aortitis-specific finding.
environmental:
- name: HIV coinfection
  description: >-
    HIV and syphilis are bidirectionally associated. Syphilis infection
    increases subsequent HIV acquisition roughly two- to three-fold in
    high-risk populations, and HIV coinfection is associated with accelerated,
    more severe neurosyphilis.
  effect: >-
    Raises the risk of acquiring HIV and, once coinfected, accelerates
    progression of neurological disease.
  influences_mechanisms:
  - target: Parenchymal Neurosyphilis
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      HIV coinfection is associated with an accelerated and more severe
      neurosyphilis course, plausibly through impaired CD4-positive
      T-cell-mediated containment.
    evidence:
    - reference: PMID:25890619
      reference_title: "Neurosyphilis and the impact of HIV infection."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This review of the clinical presentation, diagnostic laboratory findings, treatment and management of neurosyphilis discusses the impact of HIV and the specific challenges it brings"
      explanation: >-
        PARTIAL: establishes that HIV modifies the course and management of
        neurosyphilis without quantifying the effect.
  evidence:
  - reference: PMID:33219164
    reference_title: "Effect of syphilis infection on HIV acquisition: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HIV incidence showed a two-time increase after syphilis exposure, compared with a control group"
    explanation: >-
      Quantifies the increase in HIV acquisition following syphilis infection
      in a meta-analysis of 65,232 participants.
  - reference: PMID:25890619
    reference_title: "Neurosyphilis and the impact of HIV infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "discusses the impact of HIV and the specific challenges it brings"
    explanation: >-
      PARTIAL: establishes that HIV modifies neurosyphilis management without
      quantifying the effect.
- name: Absent or late prenatal care
  description: >-
    Lack of, or late presentation to, prenatal care is the dominant modifiable
    risk factor for congenital syphilis, because it removes the screening and
    treatment opportunity that would otherwise prevent transmission.
  effect: >-
    Removes the screening and treatment window, converting a preventable
    maternal infection into congenital disease.
  influences_mechanisms:
  - target: Transplacental Fetal Dissemination
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Absent or late prenatal care removes the screening-and-treatment window
      that would otherwise interrupt maternal-fetal transmission. The effect is
      indirect: lack of care does not itself drive transmission, it removes the
      intervention that prevents it.
    evidence:
    - reference: PMID:40977496
      reference_title: "Syphilis in pregnancy: A practical guide for prenatal care providers."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As early diagnosis and treatment are highly effective in reducing transmission, syphilis screening should begin at the first prenatal visit."
      explanation: >-
        PARTIAL: establishes the first prenatal visit as the intervention point
        whose absence permits transmission, without quantifying the risk of
        absent care.
  evidence:
  - reference: PMID:40977496
    reference_title: "Syphilis in pregnancy: A practical guide for prenatal care providers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As early diagnosis and treatment are highly effective in reducing transmission, syphilis screening should begin at the first prenatal visit."
    explanation: >-
      Establishes the first prenatal visit as the point at which screening and
      treatment interrupt transmission, which is what absent or late prenatal
      care removes. PARTIAL because the source states the effectiveness of early
      screening rather than quantifying the risk conferred by its absence.
discussions:
- discussion_id: syphilis_host_genetic_determinants
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Are there host genetic determinants of syphilis susceptibility, clinical
    stage progression, or the serofast state?
  rationale: >-
    No validated host susceptibility locus for syphilis exists, in contrast to
    well-established examples in other infections such as CCR5-delta32 for HIV.
    Reported correlations between HLA-DR+CD8+ T cell subsets and
    recurrence/reinfection/serofast status in HIV-syphilis coinfected cohorts
    are suggestive but uncontrolled and unreplicated. Because the serofast
    state drives repeat treatment and repeat lumbar puncture decisions in
    practice, a genuine host determinant would change management.
  attaches_to:
  - pathophysiology#Latency and Persistent Infection
  proposed_experiments:
  - experiment_id: exp_syphilis_host_gwas
    name: Host genome-wide association study of syphilis outcome
    description: >-
      A GWAS in a well-phenotyped cohort stratified by stage at diagnosis and
      by serological response after adequate therapy, with HIV status modelled
      explicitly as a covariate rather than a confounder.
- discussion_id: syphilis_lesion_single_cell_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the host transcriptional response within syphilitic lesions at
    single-cell or spatial resolution?
  rationale: >-
    Mechanistic work on syphilis has been overwhelmingly pathogen-side
    (outer-membrane protein structural modelling, TprK deep sequencing). No
    single-cell or spatial transcriptomic dataset of chancre, secondary rash,
    or gumma tissue was identified. This leaves the central claim of this
    entry's pathograph - that a Th1 response clears organisms from
    mucocutaneous lesions without eradicating infection - inferred rather than
    directly observed in human tissue.
  attaches_to:
  - pathophysiology#Th1 Cellular Immune Response and Partial Clearance
  proposed_experiments:
  - experiment_id: exp_syphilis_spatial_transcriptomics
    name: Spatial transcriptomics of staged syphilitic lesions
    description: >-
      Spatial transcriptomic and single-cell profiling of paired chancre,
      secondary-rash, and gumma biopsies to test whether the predicted Th1 and
      macrophage-activation programme is present and how it differs between the
      clearing early lesions and the persistent tertiary granuloma.
notes: >-
  GeneReviews is not applicable: syphilis is an acquired infectious disease, and
  a PubMed search for a GeneReviews chapter returned no results. Inheritance is
  deliberately not modelled - congenital syphilis is vertical transmission of an
  infection, not a Mendelian inheritance pattern, so no HP mode-of-inheritance
  term is bound.

  Scope: this entry covers venereal syphilis (Treponema pallidum subsp.
  pallidum). The endemic treponematoses yaws, bejel, and pinta are caused by
  distinct subspecies, are separate MONDO entities, and are curated as separate
  dismech entries. The four entries together would support a Treponematoses
  grouping, which does not yet exist.

  Deliberately not asserted for want of a verified citation: the 15-40% figure for
  progression to tertiary disease in untreated people; stage-specific
  transplacental transmission probabilities; and US congenital syphilis
  surveillance counts. Each is described in the deep-research report but was
  sourced there to web pages rather than to citable abstracts, and each needs a
  dedicated reference before it is curated as evidence.

  Deep-research caveat: the claude_code report proposed MONDO:0005097 as the
  disease term for syphilis. That CURIE is squamous cell lung carcinoma. The
  correct term, MONDO:0005976, was resolved with OAK. The report also emitted a
  malformed NCBITaxon identifier ("NCBITaxon:160rest"); the correct taxon for
  the venereal subspecies is NCBITaxon:161.
references:
- reference: PMID:27721440
  title: "Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen."
  found_in:
  - Syphilis-deep-research-claude_code.md
  findings:
  - statement: >-
      The treponemal outer membrane lacks lipopolysaccharide and carries very
      few surface-exposed pathogen-associated molecular patterns, which is the
      molecular basis of the stealth phenotype central to this entry.
    supporting_text: "fragile outer membrane lacks lipopolysaccharide (LPS), the highly proinflammatory glycolipid found in Gram-negative bacteria"
- reference: PMID:34292926
  title: "Sexually Transmitted Infections Treatment Guidelines, 2021."
  found_in:
  - Syphilis-deep-research-claude_code.md
  findings:
  - statement: >-
      Parenteral penicillin G is the preferred drug at every stage of syphilis,
      and the Jarisch-Herxheimer reaction is a treatment reaction rather than
      penicillin allergy.
    supporting_text: "Penicillin G, administered parenterally, is the preferred drug for treating patients in all stages of syphilis."
clinical_trials: []
datasets: []
📚

References & Deep Research

References

2
PMID:27721440
Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen.
1 finding
The treponemal outer membrane lacks lipopolysaccharide and carries very few surface-exposed pathogen-associated molecular patterns, which is the molecular basis of the stealth phenotype central to this entry.
"fragile outer membrane lacks lipopolysaccharide (LPS), the highly proinflammatory glycolipid found in Gram-negative bacteria"
PMID:34292926
Sexually Transmitted Infections Treatment Guidelines, 2021.
1 finding
Parenteral penicillin G is the preferred drug at every stage of syphilis, and the Jarisch-Herxheimer reaction is a treatment reaction rather than penicillin allergy.
"Penicillin G, administered parenterally, is the preferred drug for treating patients in all stages of syphilis."

Deep Research

1
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Syphilis (*Treponema pallidum* subsp. *pallidum* Infection): Comprehensive Disease Characteristics Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 52 citations 2026-08-08T04:35:35.688807

Syphilis (Treponema pallidum subsp. pallidum Infection): Comprehensive Disease Characteristics Research Report

1. Disease Information

Overview: Syphilis is a chronic, multistage sexually transmitted infection (and vertically transmissible perinatal infection) caused by the spirochete bacterium Treponema pallidum subspecies pallidum (TPA). Untreated, it evolves through primary, secondary, latent, and tertiary stages over years to decades, and can involve virtually any organ system, giving rise to its historical epithet "the great imitator." It remains a major global public-health problem despite being fully curable with penicillin.

Key identifiers: | System | Identifier | Notes | |---|---|---| | ICD-10-CM | A50 (congenital), A51 (early/primary-secondary), A52 (late), A53 (unspecified/latent) | A53.9 = "Syphilis, unspecified"; A51.2 = "Primary syphilis of other sites" | | ICD-11 | 1A62 (Syphilis) with substrata for congenital/early/late forms | Verify exact foundation-layer code via ICD-11 MMS browser before curation | | MeSH | D013587 Syphilis (with child terms D013590 Syphilis, Congenital; D013591 Neurosyphilis; D013589 Syphilis, Cardiovascular) | High confidence | | MONDO | Likely MONDO:0005097 (verify via OLS/OAK — sqlite:obo:mondo info — before committing to KB) | | | Disease Ontology (DOID) | DOID:8544 (verify) | | | Causative organism (NCBITaxon) | NCBITaxon:160rest — Treponema pallidum subsp. pallidum, NCBITaxon:160 (genus level), specific subspecies taxon should be confirmed via NCBI Taxonomy browser | |

Common synonyms: Lues, lues venerea, "the great pox," "the great imitator" (clinical epithet, not a synonym), Treponema pallidum infection. Congenital forms are historically termed "hereditary syphilis." Related but taxonomically distinct non-venereal treponematoses caused by other T. pallidum subspecies are yaws (T. pallidum subsp. pertenue) and bejel/endemic syphilis (T. pallidum subsp. endemicum) — these are separate MONDO/ICD entities and should not be conflated with venereal syphilis in curation.

Evidence base: Information below is derived from aggregated disease-level resources — clinical guidelines (CDC STI Treatment Guidelines, USPSTF), textbook/review sources (StatPearls, AMBOSS), population surveillance (CDC NCHHSTP national STI surveillance), and primary/peer-reviewed literature (PubMed/PMC) — rather than individual patient-level EHR data.

Sources: ICD-11 MMS — Syphilis; ICD-10-CM A53.9; ICD-10-CM A51.2; Mondo Disease Ontology — Monarch Initiative

2. Etiology

Disease causal factor: Infectious — direct causation by Treponema pallidum subsp. pallidum, a thin, tightly coiled, motile spirochete that cannot be cultured continuously in vitro (in vitro continuous culture was only first achieved in specialized co-culture systems in the mid-2010s; nearly all experimental work still uses the rabbit model). Transmission occurs primarily through direct contact with an infectious lesion (chancre, mucous patch, condyloma latum) during vaginal, anal, or oral sex, and via transplacental transmission from mother to fetus (congenital syphilis); less commonly via blood transfusion or needle-sharing.

Risk factors: - Behavioral/epidemiological: Men who have sex with men (MSM) is the population with the highest per-capita incidence in most high-income countries; condomless sex; multiple/anonymous sexual partners; transactional/"rewarded" sex; younger age at sexual debut; history of another bacterial STI in the past 12 months (marker of ongoing risk, and the basis for doxy-PEP eligibility). - Coinfection: HIV infection is strongly associated with syphilis acquisition and vice versa — a bidirectional, mutually potentiating relationship. A systematic review/meta-analysis found syphilis infection roughly doubles subsequent HIV acquisition risk (PMID:33219164). Male sex and MSM status were independently associated with HIV coinfection among incident syphilis cases (PMID:29451611). - Maternal/obstetric (congenital syphilis): Lack of, late, or absent prenatal care is the dominant risk factor; untreated maternal primary/secondary syphilis in the third trimester carries the highest transplacental transmission risk (60–100%) versus early-latent (~40%) or late-latent (<8%) maternal infection. - Demographic disparities: In the U.S., Native American/Alaska Native and Black populations bear disproportionately high and rising rates of maternal and congenital syphilis; the largest relative rise in maternal syphilis (2017–2022) was among Native Americans.

Protective factors: - Consistent condom use reduces but does not eliminate transmission risk (chancres/lesions may occur outside condom-covered areas). - Doxycycline post-exposure prophylaxis (doxy-PEP): CDC (2024) recommends 200 mg doxycycline within 72 hours of condomless sex for MSM/transgender women with a bacterial STI in the prior 12 months; randomized trials showed >70% reduction in incident syphilis and chlamydia, and ~50% reduction in gonorrhea. - Universal prenatal syphilis screening and treatment (USPSTF Grade A, reaffirmed 2025) is highly effective primary/secondary prevention for congenital syphilis. - No genetic protective variants are well established for syphilis (unlike, e.g., CCR5-Δ32 for HIV); this is an active research gap.

Gene–environment interactions: Data are sparse. A positive correlation between HLA-DR+CD8+ T-cell subsets and syphilis recurrence/reinfection/serofast state has been reported in HIV/syphilis coinfected cohorts, suggesting host immunogenetic factors may modulate clinical course and serologic response to treatment, but no validated causal susceptibility locus exists. This is best modeled as a curated KNOWLEDGE_GAP rather than an established GxE mechanism.

Sources: Effect of syphilis infection on HIV acquisition — meta-analysis; Factors associated with HIV co-infection in acquired syphilis; CDC Doxy-PEP Guidelines 2024; USPSTF syphilis screening in pregnancy; Clinical/immunological characteristics of HIV/syphilis coinfection

3. Phenotypes

Primary syphilis (10–90 days, median 21–25 days post-exposure)

  • Chancre: solitary (occasionally multiple), painless, indurated genital/anal/oral ulcer with clean base — HPO suggestion: HP:0200043-class skin ulcer terms (verify exact chancre-specific term via OAK; may need free-text preferred_term with a broader HP anchor such as "Skin ulcer").
  • Regional lymphadenopathy (HP:0002716, verify), typically non-tender, "rubbery."
  • Onset: acute; severity: mild locally (lesion is often unnoticed, especially in women/receptive anal partners, contributing to underdiagnosis); self-resolving in 3–6 weeks even without treatment (progression to latency, not cure).

Secondary syphilis (weeks to a few months after chancre; may overlap with a healing chancre)

  • Diffuse maculopapular rash, classically involving palms and soles (HP:0001028 Maculopapular rash — verify) — nearly pathognomonic when palmoplantar.
  • Condyloma lata: broad, moist, wart-like plaques in warm intertriginous areas — highly infectious.
  • Mucous patches on oral/genital mucosa.
  • Generalized lymphadenopathy, low-grade fever, malaise, headache, sore throat.
  • Patchy alopecia ("moth-eaten" alopecia; HP:0001596 Alopecia — verify).
  • Hepatosplenomegaly, hepatitis (syphilitic hepatitis), glomerulonephritis (immune-complex mediated), and — rarely — periostitis in this stage.
  • Frequency: rash occurs in a large majority of untreated secondary-stage patients; condyloma lata frequency is lower and site-dependent (case reports document unusual/extensive presentations, e.g. PMC12490915).
  • Severity/progression: self-limited (resolves in weeks-to-months) but relapses can occur during early latency in ~25% of untreated cases.

Latent syphilis

  • Asymptomatic by definition — positive treponemal + nontreponemal serology with no clinical signs. Subdivided as early latent (<1 year from infection) vs. late latent/unknown duration (>1 year), a distinction that governs treatment duration and infectiousness (early latent remains contagious via occasional mucocutaneous relapse; late latent is not sexually contagious but remains vertically transmissible and can still progress to tertiary disease).

Tertiary (late) syphilis (occurs in an estimated 15–40% of untreated individuals, typically years to decades after infection)

  • Gummatous syphilis (benign tertiary): granulomatous, necrotic "gumma" lesions in skin, bone, and viscera — locally destructive but non-infectious.
  • Cardiovascular syphilis: syphilitic aortitis, thoracic aortic aneurysm, aortic regurgitation, coronary ostial stenosis (see §6). Accounts for the majority (>80%) of tertiary vascular complications, historically the leading cause of syphilis-related mortality.
  • Neurosyphilis (can occur at any stage, not only tertiary): meningovascular neurosyphilis (stroke syndromes), general paresis (progressive dementia, personality change, tremor), tabes dorsalis (posterior column degeneration → sensory ataxia, lightning pains, Argyll Robertson pupils, areflexia).
  • Ocular syphilis (panuveitis, optic neuritis, retinitis) and otosyphilis (sensorineural hearing loss, tinnitus, vertigo) — CDC surveillance across 16 states found these under-recognized manifestations occurring across all stages, disproportionately in HIV-coinfected persons (PMID:35819903). Among HIV-positive patients with ophthalmic syphilis, ~85% also had neurosyphilis (case-series estimate).

Congenital syphilis

  • Early congenital (<2 years of age; pathophysiologically analogous to disseminated secondary syphilis): ranges from asymptomatic (~2/3 of live-born infected infants) to hepatosplenomegaly, maculopapular/desquamative rash, "snuffles" (mucopurulent/hemorrhagic rhinitis), condyloma lata, osteochondritis/periostitis (long-bone radiographic changes), lymphadenopathy, jaundice, hemolytic anemia, thrombocytopenia, and — in the most severe cases — non-immune hydrops fetalis (HP:0001789) and stillbirth (up to ~40% of untreated maternal infections).
  • Late congenital (>2 years, ~1/3 of untreated survivors, from irreversible scarring during early disease): Hutchinson triad — interstitial keratitis (HP:0001139, verify), Hutchinson (notched, widely-spaced, peg-shaped) incisors and mulberry molars, and sensorineural hearing loss (HP:0000407); plus saddle nose (HP:0000431), frontal bossing, short maxilla/protuberant mandible, saber shins (anterior tibial bowing), rhagades (perioral fissures/scars), and Clutton joints (painless bilateral knee synovitis).

Quality-of-life impact: Acute-stage manifestations (chancre, rash) cause modest disability but resolve; the major QoL burden is concentrated in (a) neurosyphilis/tabes dorsalis (chronic neuropathic pain, gait ataxia, cognitive decline — general paresis was historically a leading cause of institutionalized psychiatric disability pre-antibiotic era), (b) sensorineural hearing/vision loss from oto-/ocular syphilis, and (c) the lifelong disability, cognitive impairment, and stigmata of untreated congenital syphilis in survivors. Dedicated disease-specific QoL instrument data (EQ-5D/SF-36) for syphilis specifically are not well represented in the literature; QoL burden is more typically captured indirectly via disability-adjusted life year (DALY) estimates in global-burden-of-disease reporting.

Sources: Neurologic, Ocular, and Otic Manifestations Among Syphilis Cases — 16 states; Neurosyphilis, Ocular Syphilis, and Otosyphilis: Detection and Treatment; Congenital Syphilis — An Illustrative Review; Congenital and Maternal Syphilis — StatPearls; Clinical aspects of congenital syphilis with Hutchinson's triad; Extensive Condyloma Lata Lesions in Unusual Sites; Syphilis — StatPearls

4. Genetic/Molecular Information

Syphilis is not a Mendelian genetic disease of the host, so this section covers pathogen molecular biology (the operative "genetics" for a dismech-style pathophysiology entry) plus what little is known about host genetic modifiers.

  • Causal organism genome: T. pallidum subsp. pallidum has a small (~1.14 Mb), reduced genome reflecting extreme host-restriction and metabolic dependency (it lacks TCA-cycle enzymes and relies heavily on host-derived nutrients), consistent with obligate-pathogen biology. No plasmids; no classical LPS.
  • Key virulence/immune-evasion loci:
  • tprK (Treponema pallidum repeat K): encodes an integral outer-membrane porin with seven surface-exposed variable (V1–V7) regions. Antigenic diversity is generated by non-reciprocal segmental gene conversion, transferring sequence from ~53 silent chromosomal donor cassettes into the single tprK expression locus (PMID:15186410). V-region diversity accumulates faster under host immune pressure (especially V6), directly implicating TprK antigenic variation as a mechanism of immune persistence; a TprK-variation-impaired mutant strain is attenuated in the rabbit model (bioRxiv/PMC10063172), and Seattle-area genomic surveillance (2021–2022) has identified circulating strains with diminished TprK variation capacity (academic.oup.com/jid/article/229/3/866/7283202).
  • 23S rRNA A2058G / A2059G point mutations: the molecular basis of macrolide (azithromycin) resistance, first identified in San Francisco (2002) and now geographically widespread (U.S., Ireland, Canada, Taiwan, Indonesia); detected clinically by TaqMan real-time multiplex PCR. This has effectively removed azithromycin as a first-line agent in most jurisdictions (PMID:18192791; NEJM Lukehart et al. 2004).
  • Outer-membrane protein (OMP) repertoire (e.g., TP0856, TP0858 — FadL orthologs; BamA/TP0326): rare, low-density, surface-exposed OMPs identified via structural modeling as the principal syphilis vaccine antigen candidates (PMC8407342; journals.asm.org/doi/10.1128/jb.00082-21).
  • Strain typing (molecular epidemiology, not disease-causing per se): variable-number tandem repeats in the arp gene combined with RFLP of tprE/tprG/tprJ and tp0548 sequence — the CDC "enhanced CDC typing" (ECDCT) scheme used for outbreak/lineage surveillance.
  • Host genetics: No validated causal or susceptibility-conferring human gene/variant is established. The only host-genetic signal identified so far is an association between HLA-DR+CD8+ T-cell subset frequency and syphilis recurrence/serofast state in HIV coinfection — exploratory, not a validated ACMG-tier variant classification, and should be curated as a knowledge gap rather than a genetic risk locus.
  • Functional impact framing for dismech curation: Antigenic variation (TprK) and macrolide-target mutation (23S rRNA) are both qualitative, unbound mechanisms in the GAIN_OF_FUNCTION/immune-evasion sense described in this repo's CLAUDE.md (no clean GO/PATO-bound "activity level" framing applies) — they would be modeled as modifier: GAIN_OF_FUNCTION-style pathogen mechanism nodes, not host GeneticContext.functional_impact_category entries, since there is no host variant involved.

Sources: Gene conversion in tprK — Mol Microbiol; Genomic Epidemiology... Diminished tprK Variation, Seattle 2021–2022; TprK-impaired strain attenuated in rabbit model; Azithromycin resistance in T. pallidum; Macrolide Resistance in T. pallidum, US and Ireland — NEJM; Structural Modeling of T. pallidum OMP Repertoire; FadL orthologs TP0856/TP0858 rabbit model — mBio

5. Environmental Information

  • Infectious agent: Treponema pallidum subsp. pallidum (NCBITaxon — spirochete, phylum Spirochaetota). Transmission requires direct mucocutaneous contact with an active lesion; the organism does not survive well outside the host (fomite transmission is negligible).
  • Behavioral/lifestyle factors: condomless sex, number of sexual partners, transactional sex, substance use associated with high-risk sexual behavior (e.g., methamphetamine use in some MSM sub-epidemics), incarceration history, and limited access to sexual-health/prenatal care are the dominant modifiable environmental drivers — these are social/behavioral rather than toxicant/occupational exposures.
  • No chemical/toxicological/occupational etiology applies; syphilis is not caused by environmental toxins, radiation, or pollution. The "environmental" arm of a dismech entry for syphilis should be modeled almost entirely through ECTO-style sexual/vertical exposure-route terms and infectious-exposure framing rather than CTD/TOXNET-style chemical exposures.
  • Structural/social determinants: lack of prenatal care access, rural/under-resourced healthcare infrastructure, and racial/ethnic health disparities are repeatedly identified in CDC and PAHO surveillance as the proximate drivers of the ongoing U.S. congenital syphilis surge (see §9).

Sources: CDC Releases 2024 National STI Data; The Rise of Congenital Syphilis as a Public Health Emergency

6. Mechanism / Pathophysiology

Causal chain overview

  1. Inoculation and dissemination: T. pallidum penetrates intact mucosa or abraded skin, replicates locally, and disseminates hematogenously/lymphatically within days to weeks — spirochetemia is established even before the primary chancre becomes clinically apparent, explaining why congenital and disseminated (secondary-stage) disease can occur even from an unnoticed primary lesion.
  2. Local inflammatory/immune response (chancre formation): infiltration by CD4+ T-helper-1 cells, macrophages, and plasma cells at the inoculation site; local vascular changes (endarteritis) produce the indurated, ulcerated chancre. Despite intense local immune infiltration, the organism largely evades clearance.
  3. Stealth-pathogen immune evasion (the central pathophysiological theme): T. pallidum's outer membrane is essentially devoid of surface-exposed, immunogenic integral membrane proteins and — critically — lacks lipopolysaccharide (LPS), unlike most Gram-negative bacteria, denying the innate immune system its usual PAMP trigger (PMID:27721440; "making a living as a stealth pathogen"). Layered onto this "low-visibility" membrane architecture is TprK antigenic variation (§4), which continuously alters the few surface epitopes that do exist, outrunning adaptive humoral responses. Recent work (2025, PMID:40708500) frames pathogenesis as a dynamic host-immune-response-versus-pathogen-immune-evasion contest: dendritic cells present treponemal antigen to naive CD4+ T cells, driving a Th1-polarized response (IFN-γ-driven macrophage activation/phagocytosis) that is necessary for clearance from skin lesions but insufficient to eradicate the organism from immune-privileged sanctuary sites (CNS, eye, placenta).
  4. Dissemination to immune-privileged sites: the organism's ability to cross the blood-brain barrier, blood-ocular barrier, and placental barrier explains why neurosyphilis, ocular syphilis, and congenital transmission can occur at any stage, including very early infection, rather than being restricted to "late" disease as classically taught.
  5. Secondary-stage systemic dissemination: widespread hematogenous spread produces the generalized rash, condyloma lata, lymphadenopathy, and visceral involvement (hepatitis, immune-complex glomerulonephritis) of secondary syphilis.
  6. Latency: partial host immune containment suppresses clinically detectable disease without eradicating the organism; low-level persistence (and stochastic local reactivation, particularly early in latency) maintains seropositivity and, in a minority, leads eventually to tertiary disease.
  7. Tertiary-stage vascular/granulomatous pathology: chronic, low-grade treponemal presence in the vasa vasorum of medium/large arteries (classically the ascending aorta) triggers a slowly progressive obliterative endarteritis — lymphoplasmacytic infiltration of the adventitia with ischemic injury to the aortic media, destruction of elastic/muscular fibers, and consequent aneurysmal dilation, aortic regurgitation, and coronary ostial stenosis (>80% of tertiary manifestations are vascular in nature). Gummas (in skin, bone, viscera, or — as microgummas — within the aortic media) represent a delayed-type hypersensitivity granulomatous response with central necrosis and palisading macrophages/lymphocytes/plasma cells; treponemes are typically scant and hard to demonstrate within gumma tissue, consistent with a predominantly immune-mediated (rather than direct cytopathic) injury mechanism at this stage.
  8. Neurosyphilis mechanism: direct CNS invasion with either a meningovascular pattern (endarteritis of cerebral vessels → stroke syndromes) or, later, parenchymal neuronal/glial injury (general paresis — cortical atrophy, gliosis; tabes dorsalis — dorsal column/dorsal root ganglion degeneration). HIV coinfection appears to accelerate and intensify this process, plausibly via impaired CD4+ T-cell-mediated containment (PMID:25890619).
  9. Congenital pathophysiology: transplacental spirochetemia produces a disease process analogous to disseminated secondary syphilis in the fetus; severity is inversely related to gestational age at infection but transmission probability increases with advancing gestational age and untreated maternal spirochete burden.

Molecular pathways / cellular processes (GO-term suggestions, verify via OAK)

  • Innate recognition failure / LPS-independent pathogen sensing — contrast with canonical TLR4-LPS signaling (GO:0034142 Toll-like receptor 4 signaling pathway is notably not engaged in the way it is for classical Gram-negatives).
  • GO:0002250 adaptive immune response; GO:0042088 T-helper 1 type immune response; GO:0006909 phagocytosis; GO:0006954 inflammatory response; GO:0020033 antigenic variation (a GO term specifically used for pathogen immune-evasion biology, appropriate for the TprK mechanism).
  • Cellular processes: dendritic-cell antigen presentation → CD4+ Th1 polarization → IFN-γ–mediated macrophage activation and treponemal phagocytosis (partial clearance); obliterative vasculitis/endarteritis as the shared cellular mechanism linking chancre formation and tertiary aortitis.

Cell types involved (CL-term suggestions)

  • CL:0000624 CD4-positive, alpha-beta T cell (Th1 effector); CL:0000235 macrophage; CL:0000451 dendritic cell; CL:0000786 plasma cell (humoral response, and prominent in chancre/gumma histology); CL:0000115 endothelial cell (target of obliterative endarteritis in both chancre and aortitis); CL:0000058 cementoblast/CL bone-cell terms for periostitis/osteochondritis in congenital disease (verify specific term).

Molecular/omics profiling

  • Limited transcriptomic/proteomic host-response profiling exists for syphilis relative to other STIs; most mechanistic work is genomic/proteomic on the pathogen side (OMP structural modeling, TprK deep sequencing). A 2024 pan-proteome array study profiled the humoral (antibody) response to the full T. pallidum proteome as a pre-clinical diagnostic/vaccine-target discovery tool (bioRxiv 2024.04.20.590429).
  • No well-established single-cell or spatial transcriptomic dataset specific to syphilis lesions was identified in this search; this is a plausible knowledge/data gap worth flagging in curation.

Sources: Syphilis Pathogenesis: Host Immune Response vs Pathogen Immune Evasion (2025); T. pallidum: making a living as a stealth pathogen; Investigation of the immune escape mechanism of T. pallidum; Syphilitic aortitis and its complications in the modern era; Pathology of syphilis — UCT; Neurosyphilis and the impact of HIV infection; Pan-proteome array humoral response study, 2024

7. Anatomical Structures Affected

  • Organ/system level: integumentary system (chancre, secondary rash, gummas), lymphoreticular system (lymphadenopathy), cardiovascular system (aorta, aortic valve, coronary ostia — tertiary disease), central/peripheral nervous system (meninges, cerebral vasculature, spinal cord dorsal columns, cranial nerves — neurosyphilis), special senses (eye — uvea/retina/optic nerve; ear — cochlea/vestibular apparatus), hepatobiliary system (syphilitic hepatitis), renal system (immune-complex glomerulonephritis, secondary stage), skeletal system (periostitis/osteochondritis, gummatous bone lesions), and — in congenital disease — essentially every fetal organ system via hematogenous dissemination, plus the placenta itself as the transmission conduit.
  • UBERON suggestions (verify): UBERON:0002097 skin of body; UBERON:0000947 aorta; UBERON:0002094 aortic valve (verify exact ID); UBERON:0001987 placenta; UBERON:0001017 central nervous system; UBERON:0000955 brain; UBERON:0002240 spinal cord; UBERON:0000970 eye; UBERON:0000959 cochlea (or UBERON:0001846 for broader otic region — verify); UBERON:0002107 liver; UBERON:0002113 kidney; UBERON:0001474 bone element; UBERON:0000474 external genitalia (chancre site); UBERON:0000030 lamina propria/oral mucosa (mucous patches).
  • Tissue/cell level: vascular endothelium and adventitial vasa vasorum (obliterative endarteritis — the shared lesion of chancre, gumma, and aortitis); epidermis/dermis (rash, condyloma lata); hepatic parenchyma; glomerular basement membrane (immune-complex deposition); dorsal root ganglia and dorsal columns of the spinal cord (tabes dorsalis); cerebral cortex/white matter (general paresis).
  • Subcellular: immune-complex deposition at the glomerular basement membrane (GO Cellular Component terms for basement membrane, e.g. GO:0005604); outer membrane of the pathogen itself is the key subcellular structure driving pathogenesis (low-density, LPS-negative OMP architecture — §6).
  • Lateralization: generally bilateral/symmetric in systemic manifestations (e.g., bilateral interstitial keratitis, bilateral sensorineural hearing loss in Hutchinson triad); chancres and localized gummas are typically unilateral/focal by nature of inoculation site.

Sources: Syphilitic Aortitis — ScienceDirect; Pathology of syphilis — UCT Pathology Learning Centre

8. Temporal Development

  • Onset: Acquired syphilis has a variable window from exposure to primary chancre of 10–90 days (median 21–25 days); congenital syphilis onset is defined relative to birth (early <2 years vs. late ≥2 years of age), reflecting time for irreversible developmental scarring to manifest rather than ongoing active infection in the late form.
  • Progression / staging: Primary → Secondary (weeks after chancre, may overlap) → Latent (early <1 year, late ≥1 year/unknown duration) → Tertiary (years to decades later, in an estimated 15–40% of untreated persons). Neurologic, ocular, and otic invasion can occur at any stage and is not confined to "late/tertiary" disease — an important reframing versus older teaching, now emphasized by CDC and recent surveillance (PMID:35819903).
  • Progression rate: Highly variable between individuals; some remain in asymptomatic latency indefinitely, others progress to destructive tertiary disease. HIV coinfection is associated with an accelerated, more fulminant course and earlier neurosyphilis onset (PMID:25890619).
  • Disease course pattern: Predominantly a slowly progressive, staged natural history in untreated hosts; early latency carries a risk (~25%) of symptomatic mucocutaneous relapse (a "relapsing" sub-pattern within the latent stage). With treatment at any stage, the course is halted, though tertiary-stage structural damage (aortic aneurysm, tabetic neurologic deficits, gummatous scarring) is generally irreversible even after microbiological cure.
  • Duration: Untreated syphilis is a lifelong condition (the organism is not spontaneously cleared); adequately treated syphilis in the pre-tertiary stages is curable without sequelae. Congenital, late-stage stigmata (Hutchinson triad, skeletal deformities) are permanent once established.
  • Remission: No spontaneous cure; only antimicrobial treatment reliably clears infection at any stage (though tertiary structural damage does not "remit" with treatment). Serologic "cure" is monitored via declining nontreponemal titers (RPR/VDRL) post-treatment; treponemal tests typically remain reactive for life ("serofast").
  • Critical periods / windows for intervention: (1) Early (primary/secondary/early-latent) syphilis is the window of highest infectiousness and easiest single-dose cure. (2) Pregnancy is the critical window for congenital-transmission prevention — treating the mother before the third trimester, and ideally before conception or in the first trimester, dramatically reduces transmission and severity. (3) Post-exposure (within 72 hours) is the window for doxy-PEP efficacy.

Sources: Syphilis — StatPearls; Reported Neurologic, Ocular, and Otic Manifestations Among Syphilis Cases — 16 states, 2019; Neurosyphilis and the impact of HIV infection

9. Inheritance and Population

Inheritance pattern: Not applicable — syphilis is an acquired infectious disease with no Mendelian inheritance pattern, penetrance, expressivity, anticipation, mosaicism, or founder-effect biology in the classical genetic-disease sense. "Congenital syphilis" denotes vertical (transplacental) transmission of infection, not genetic inheritance, and should not be modeled with an Inheritance/HP:00109xx-style mode-of-inheritance term in dismech curation.

Epidemiology (U.S., CDC 2024 data): - More than 2.2 million combined chlamydia/gonorrhea/syphilis cases were reported in 2024; reported primary-and-secondary (P&S) syphilis cases declined for the second consecutive year, down ~22% since 2023 — the first sustained decline after roughly two decades of increases. - Congenital syphilis continued to rise: nearly 4,000 cases reported in 2024 (up ~2% from 2023), a 12th consecutive year of increase, and congenital syphilis morbidity is ~700% higher than a decade earlier. Nationally, 2023 saw 3,882 congenital syphilis cases — the highest rate in >30 years — with an estimated ~90% judged preventable through timely maternal diagnosis/treatment. - Maternal syphilis rate rose 222% from 2016 to 2022 (87.2 → 280.4 per 100,000 live births). - Global context: Congenital syphilis (including stillbirths) remains a tracked PAHO regional indicator; syphilis in pregnancy is among the leading global causes of stillbirth.

Population demographics / disparities: - MSM continue to bear a disproportionate share of P&S syphilis cases in high-income settings. - Native American/Alaska Native populations show the steepest relative rise in maternal syphilis (2017–2022); White and Asian American populations show comparatively smaller increases — reflecting structural disparities in prenatal-care access rather than biological susceptibility. - Age distribution: acquired syphilis peaks in sexually active adults (20s–30s); congenital syphilis risk tracks maternal age distribution and, most strongly, gaps in prenatal-care engagement rather than maternal age per se. - Geographic distribution: U.S. congenital syphilis case growth has been documented even outside historically high-burden metropolitan areas (e.g., 21 cases reported outside New York City in 2025), indicating geographic spread of the epidemic beyond traditional urban hotspots.

Carrier/susceptibility genetics: No established human carrier-frequency or population-genetic-susceptibility data exist for syphilis (unlike a Mendelian disorder); population-level "susceptibility" is driven by behavioral/structural/healthcare-access epidemiology rather than germline variation.

Sources: CDC Releases 2024 National STI Data; CDC data show declines in STIs, rise in newborn syphilis — CIDRAP; The Rise of Congenital Syphilis as a Public Health Emergency; PAHO — Incidence rate of congenital syphilis; USPSTF universal syphilis screening in pregnancy

10. Diagnostics

Serologic testing (the diagnostic backbone): - Nontreponemal tests (RPR, VDRL): detect non-specific anticardiolipin/lipoidal antibodies from host tissue damage; quantitative (titers used to track treatment response); can be falsely negative early (prozone phenomenon at very high titers) or falsely positive in unrelated conditions (autoimmune disease, pregnancy, other infections). - Treponemal tests (TP-PA, FTA-ABS, and increasingly automated EIA/CIA immunoassays): specific for anti-T. pallidum antibody; remain reactive lifelong in most patients regardless of treatment ("serofast"), so cannot distinguish active from past-treated infection alone. - Traditional algorithm: nontreponemal screen (RPR/VDRL) → confirm reactive results with a treponemal test. - Reverse-sequence algorithm (increasingly standard in automated labs): treponemal immunoassay first → if reactive, quantitative RPR/VDRL; if the two are discordant, a second treponemal test (typically TP-PA) serves as tiebreaker. British Columbia's 2015–2020 experience documented outcomes of implementing this reverse algorithm alongside PCR (PMC9241594). - PCR (direct detection): used especially for early lesional disease (chancre swabs, mucocutaneous lesions) where serology may still be non-reactive; reported sensitivity as high as 100% in some series versus ~53% for dark-field and immunofluorescence microscopy — though estimates vary by study and lesion type. - Dark-field microscopy / direct fluorescent antibody: classic direct visualization from chancre exudate, largely supplanted by PCR where available. - Cerebrospinal fluid (CSF) studies: CSF-VDRL (specific but insensitive), CSF pleocytosis and elevated protein, for suspected neurosyphilis.

LOINC/SNOMED CT suggestions (verify): LOINC panels exist for RPR titer, TP-PA, and FTA-ABS results; SNOMED CT carries specific concepts for each stage (primary/secondary/latent/tertiary/congenital syphilis) and for chancre, condyloma latum, and gumma findings.

Genetic/molecular testing: Not applicable in the human-genetic-testing sense (no GTR panels for host susceptibility); the relevant "molecular diagnostics" are pathogen-directed — PCR for treponemal DNA and, in reference/surveillance labs, 23S rRNA genotyping (A2058G/A2059G) to detect macrolide resistance before considering azithromycin as an off-label alternative.

Imaging: contrast-enhanced CT/MR angiography or echocardiography for suspected cardiovascular (aortic) syphilis; brain MRI for neurosyphilis (may show meningeal enhancement, infarcts, or nonspecific atrophy in general paresis); long-bone radiographs for congenital syphilis (periostitis, metaphyseal lucencies — "Wimberger sign").

Screening programs: - USPSTF Grade A: universal syphilis screening in all pregnant adolescents/adults, regardless of risk factors, as early as possible in pregnancy and at any later missed opportunity (reaffirmed 2025). - Risk-based screening recommended for MSM, people with HIV, and other higher-incidence populations at regular intervals (e.g., every 3–6 months for higher-risk MSM per CDC guidance). - Newborn screening is not itself a standard "genetic newborn screen" but maternal serology at delivery (and infant testing when maternal status is unknown/reactive) functions as the congenital-syphilis case-finding mechanism.

Differential diagnosis: other causes of genital ulcer disease (HSV, chancroid, LGV, donovanosis); other causes of diffuse maculopapular rash (viral exanthems, drug eruption, pityriasis rosea); other causes of granulomatous/gummatous lesions (TB, deep fungal infection, sarcoidosis); other causes of aortitis (Takayasu, giant cell arteritis); other causes of dementia/ataxia for neurosyphilis.

Sources: British Columbia reverse algorithm and PCR experience 2015-2020; Traditional or Reverse Algorithm for Diagnosis of Syphilis: Pros and Cons; CDC STI Treatment Guidelines — Syphilis; Reverse Sequence Screening for Syphilis

11. Outcome/Prognosis

  • With appropriate treatment: Excellent prognosis for primary, secondary, and early-latent disease — microbiological cure with single-dose (or short-course) benzathine penicillin G; nontreponemal titers decline (typically ≥4-fold by 6–12 months) confirming adequate treatment response.
  • Untreated natural history: Roughly one-third of untreated persons progress to tertiary disease (gummatous, cardiovascular, and/or neurologic), one-third remain in indefinite subclinical latency, and one-third experience spontaneous serologic/clinical resolution without treatment (classic Oslo/Rosahn-cohort-derived natural-history estimates, corroborated across StatPearls/AMBOSS summaries) — though a commonly cited range for progression to tertiary disease specifically is 15–40%.
  • Mortality: Historically (pre-antibiotic era), cardiovascular and CNS tertiary complications were major causes of death; with modern treatment access, syphilis-specific mortality is low in treated populations but remains an important contributor to stillbirth and neonatal mortality in undertreated maternal populations (congenital syphilis carries substantial stillbirth/neonatal-death risk — up to 40% in untreated pregnancies).
  • Morbidity/disability outcomes: Once established, tertiary structural damage (aortic aneurysm, tabetic sensory/motor deficits, sensorineural hearing loss, dental/skeletal stigmata of congenital disease) is generally not reversed by antimicrobial treatment — treatment halts progression and clears the organism but does not repair existing scarring/aneurysmal dilation, underscoring the outsized prognostic value of early detection.
  • Complications: aortic rupture/dissection, congestive heart failure from aortic regurgitation, stroke (meningovascular neurosyphilis), progressive dementia (general paresis), blindness (ocular syphilis, untreated interstitial keratitis), permanent hearing loss, and — in HIV-coinfected patients — accelerated/atypical courses with higher risk of neurologic involvement.
  • Recovery potential: High for early-stage disease treated promptly; poor for established tertiary structural or neurologic damage, where the goal of treatment shifts from cure-with-recovery to halting further progression.
  • Prognostic factors: stage at diagnosis/treatment (dominant factor), HIV coinfection status, gestational timing of maternal treatment (for congenital disease), and — for treatment-response monitoring — the trajectory of nontreponemal titers.
  • Serofast state: a subset of adequately treated patients retain persistently reactive (non-declining) nontreponemal titers ("serofast") without evidence of treatment failure or reinfection; this is an area of ongoing immunologic research (linked in some studies to HLA-DR+CD8+ T-cell subset frequency, §4).

Sources: Congenital and Maternal Syphilis — StatPearls; Syphilitic aortitis and its complications in the modern era; Clinical/immunological characteristics of HIV/syphilis co-infected patients

12. Treatment

Pharmacotherapy (first-line): - Penicillin G, administered parenterally, is the treatment of choice for all stages of syphilis; the specific preparation, dose, and duration depend on stage: - Primary/secondary/early-latent: Benzathine penicillin G 2.4 million units IM as a single dose. - Late-latent/unknown-duration/tertiary (non-neurologic): benzathine penicillin G 2.4 million units IM weekly × 3 doses. - Neurosyphilis/ocular/otosyphilis: Aqueous crystalline penicillin G IV (continuous infusion or divided doses) for 10–14 days (or aqueous procaine penicillin + probenecid as an alternative). - Congenital syphilis: aqueous crystalline penicillin G IV (or procaine penicillin IM) for 10 days. - Critical note (per CDC guidance): neither oral penicillin preparations nor a benzathine+procaine penicillin combination are considered adequate therapy for syphilis at any stage. - Penicillin-allergic patients: doxycycline (100 mg PO BID × 14 days for early syphilis, longer for late-stage) is the principal alternative for non-pregnant patients; penicillin desensitization is required in pregnancy and for neurosyphilis, since doxycycline/tetracyclines are not recommended in pregnancy and alternative regimens are less well validated. - Azithromycin: historically used as an alternative but now compromised in many regions by 23S rRNA (A2058G/A2059G) resistance mutations (§4); generally not recommended as first-line where resistance prevalence is unknown or high. - Ceftriaxone: an alternative under investigation/select use, particularly for neurosyphilis in penicillin-allergic patients, though evidence base is less robust than for penicillin.

Pharmacogenomics: No well-established pharmacogenomic (e.g., CPIC-tier) gene–drug interaction is documented for syphilis therapy; penicillin allergy assessment/desensitization is an immunologic (not pharmacogenomic) consideration.

The Jarisch-Herxheimer reaction: An acute febrile reaction (fever, headache, myalgia, sometimes transient worsening of lesions/rash) occurring within 24 hours of initiating any effective syphilis therapy (a treatment reaction to rapid spirochete lysis and endotoxin-like release, not a penicillin allergy). Reported incidence in early syphilis ranges from ~8% to 56% depending on the study; most frequent in early (high-organism-burden) stages. Management is supportive (antipyretics), though antipyretics have not been proven to prevent the reaction; patients should be counseled about it before treatment. Comparative data (azithromycin vs. benzathine penicillin G) in HIV-positive patients with early syphilis have specifically examined reaction rates by regimen (PMC4150017), and a JAMA Network Open secondary analysis further characterized Jarisch-Herxheimer incidence after benzathine penicillin G in a randomized trial of adults with early syphilis (2025).

Advanced/experimental therapeutics: No gene therapy, cell therapy, RNA-based therapy, targeted therapy, or immunotherapy applies to syphilis treatment (bacterial infection, not a genetic/oncologic/immune-dysregulation disease in the classical sense) — pharmacotherapy (antibiotics) and, in tertiary disease, supportive/surgical management (e.g., aortic aneurysm repair, valve replacement) are the relevant categories.

Surgical/interventional: aortic aneurysm repair or aortic valve replacement for advanced cardiovascular syphilis with hemodynamically significant regurgitation or aneurysmal disease; coronary revascularization (PCI) for ostial stenosis (case reports document PCI for syphilitic coronary ostial stenosis).

Treatment monitoring/outcomes: Serial quantitative nontreponemal titers (RPR/VDRL) at 6, 12, and 24 months to confirm adequate treatment response (target: ≥4-fold titer decline); failure to decline appropriately, or a 4-fold titer rise, suggests treatment failure or reinfection and warrants HIV testing and CSF evaluation for occult neurosyphilis.

NCIT term suggestions (verify against ncit OAK adapter): NCIT:C15986 Pharmacotherapy (generic action term) with therapeutic_agent bound to CHEBI (e.g., benzylpenicillin CHEBI:18208, doxycycline CHEBI:50845, azithromycin CHEBI:2955, ceftriaxone CHEBI:3508 — verify exact CHEBI IDs); NCIT:C15329 Surgical Procedure for aneurysm repair/valve replacement; a dedicated NCIT term for penicillin desensitization procedure should be looked up specifically.

Sources: CDC STI Treatment Guidelines — Syphilis; Updating the CDC's treatment guidelines: Syphilis; Jarisch-Herxheimer reaction, HIV-positive patients, azithromycin vs benzathine penicillin G; Jarisch-Herxheimer Reaction After Benzathine Penicillin G — JAMA Network Open; NIH HIV.gov Syphilis OI Guidelines

13. Prevention

  • Primary prevention: condom use (partial protection), risk-reduction counseling, partner notification/treatment ("expedited partner therapy" in many U.S. jurisdictions), and — newly (2024 CDC guidance) — doxycycline post-exposure prophylaxis (doxy-PEP): 200 mg doxycycline self-administered within 72 hours of condomless sex, recommended for MSM and transgender women with a bacterial STI diagnosis in the prior 12 months, following shared decision-making; trials show >70% reduction in incident syphilis/chlamydia and ~50% reduction in gonorrhea. Ongoing need should be reassessed every 3–6 months alongside repeat bacterial-STI testing at exposed anatomic sites.
  • No vaccine currently exists. Vaccine development is an active research area centered on the small repertoire of surface-exposed, immunogenic outer-membrane proteins (OMPs; e.g., FadL orthologs TP0856/TP0858, BamA/TP0326) identified through structural modeling of the T. pallidum OMP repertoire; the rabbit model remains the key preclinical platform, and manufacturing/design alignment challenges for a subunit OMP vaccine were reviewed in 2024 (Vaccine journal/Taylor & Francis).
  • Secondary prevention (screening/early detection): USPSTF Grade A universal prenatal syphilis screening (early in pregnancy, and at first opportunity if missed); routine/periodic screening in higher-incidence populations (MSM, people with HIV) per CDC guidance; reverse or traditional serologic algorithms for case detection (§10).
  • Tertiary prevention: prompt treatment of latent syphilis to prevent progression to tertiary disease; monitoring and early intervention for neurosyphilis/ocular/otosyphilis in at-risk (especially HIV-positive) patients to prevent permanent neurologic, visual, or auditory sequelae.
  • Congenital-syphilis-specific prevention: the single highest-yield intervention is ensuring pregnant people receive early, adequate prenatal care with syphilis screening and — if positive — timely, stage-appropriate penicillin treatment; CDC/USPSTF analyses estimate ~90% of 2023's record U.S. congenital syphilis cases were preventable through this pathway.
  • Public health interventions: partner services/contact tracing, expedited partner therapy, community-based outreach and mobile testing in underserved/high-incidence areas, and — for populations with documented healthcare-access disparities (e.g., Native American communities bearing the steepest recent rise in maternal syphilis) — targeted prenatal-care-access programs.
  • Genetic/prenatal counseling: not applicable in the classical genetic-counseling sense (non-heritable disease), though maternal-fetal medicine counseling regarding transmission risk and treatment timing during pregnancy is directly analogous in clinical workflow.

Sources: CDC Clinical Guidelines on Doxycycline PEP, 2024; CDC Doxy-PEP for STI Prevention; Full article: Syphilis vaccine development — aligning design with manufacturing; USPSTF universal prenatal syphilis screening reaffirmed; CIDRAP — Task force recommends prenatal syphilis screening amid growing crisis

14. Other Species / Natural Disease

  • Taxonomy of the pathogen and its relatives: Three recognized pathogenic subspecies of T. pallidum cause distinct human diseases — subsp. pallidum (venereal syphilis, the subject of this report), subsp. pertenue (yaws, a non-venereal, primarily pediatric, tropical skin/bone treponematosis), and subsp. endemicum (bejel/endemic syphilis, arid-region non-venereal transmission). These are genomically very closely related but clinically and epidemiologically distinct — an important curation boundary (do not conflate their MONDO/ICD entries).
  • Natural disease in non-human primates: Multiple sub-Saharan African non-human primate species (e.g., sooty mangabeys in Taï National Park, Côte d'Ivoire, and others across 11+ sites) are naturally infected with T. pallidum subsp. pertenue, presenting with orofacial and genital lesions. Genomic comparison of human and non-human-primate-derived TPE strains found no consistent genomic distinctness between them — i.e., NHP and human yaws-causing strains are not genomically differentiated as separate lineages, though phylogeographic structuring by geography has been documented, and interspecies transmission between NHPs and humans appears rare.
  • Venereal syphilis (subsp. pallidum) is considered essentially human-restricted — unlike yaws/bejel, no robust sylvatic/zoonotic reservoir is established for venereal syphilis; NHP treponemal disease surveillance to date centers on the pertenue (yaws) subspecies.
  • Veterinary relevance: No naturally occurring venereal-syphilis-equivalent disease is recognized in domestic companion animals; the veterinary/zoonotic relevance of T. pallidum biology is chiefly through the NHP yaws reservoir as a public-health consideration for yaws-eradication programs (WHO), not through companion-animal disease.
  • Comparative pathology: the shared genomic backbone across subspecies, combined with divergent tissue tropism (skin/bone in yaws vs. genital/systemic/neurologic in venereal syphilis), makes T. pallidum an instructive case of subspecies-level phenotypic divergence from near-identical genomes — a point of active research interest for understanding what genomic elements (if any) determine tissue tropism and transmission route.

Sources: Geographically structured genomic diversity of non-human primate-infecting T. pallidum subsp. pertenue; Genomes of the yaws bacterium... not genomically distinct — PLOS NTD; Genetics of human and animal uncultivable treponemal pathogens; Strain diversity of T. pallidum subsp. pertenue in African NHPs — Scientific Reports

15. Model Organisms

  • Rabbit model (the gold-standard model): T. pallidum subsp. pallidum cannot be reliably maintained in continuous axenic culture, so the New Zealand White rabbit intratesticular/intradermal infection model remains the principal in vivo experimental platform for propagating the organism and studying pathogenesis, immune response, and vaccine candidates. Recent work using this model directly tested a TprK-antigenic-variation-impaired mutant strain, which was shown to be attenuated relative to wild type — direct in vivo evidence linking TprK diversification to virulence/persistence (bioRxiv 2023.01.18.524629 / PMC10063172).
  • Vaccine antigen validation in rabbits: extracellular loops of the FadL-ortholog outer-membrane proteins TP0856 and TP0858 were shown to elicit IgG antibody and antigen-specific B-cell responses in the rabbit model, supporting their candidacy as syphilis subunit-vaccine antigens (mBio, PMC/journals.asm.org 10.1128/mbio.01639-22).
  • Model recapitulation and limitations: The rabbit model recapitulates chancre formation, dissemination, and (with intratesticular inoculation) orchitis as a surrogate readout of infection/immunity, and has been indispensable for genotype-phenotype (e.g., TprK, OMP) studies since the organism cannot be genetically manipulated and grown at scale outside a host. Its principal limitation is imperfect recapitulation of the full human multi-decade natural history (tertiary cardiovascular/neurologic disease, congenital transmission) within a tractable experimental timeframe, and species differences in immune system architecture relative to humans.
  • In vitro / cell-based systems: Historically no robust continuous in vitro culture system existed; specialized co-culture systems (with mammalian cells) developed in the mid-2010s allow short-term propagation and are increasingly used to supplement (not replace) the rabbit model for genomic/proteomic and drug-susceptibility work, though this search did not surface a specific 2023–2024 primary reference for routine use of such systems in syphilis pathogenesis research — flagged as a HUMAN_MODEL_MISMATCH-relevant gap for curation, since in vitro-cultured organism behavior relative to the classic rabbit/human correlation is still being established.
  • No standard genetically engineered (knockout/transgenic) mouse model of syphilis exists, reflecting both the organism's obligate-host-restricted biology and the practical difficulty of genetically manipulating an uncultivable pathogen; this is a further notable gap relative to genetic-disease model-organism resources (no MGI/IMPC knockout entries are relevant here, since the "gene" of interest is pathogen-, not host-, encoded).
  • Resources: No dedicated syphilis-specific model-organism database exists analogous to MGI/ZFIN/FlyBase for host-genetic disease models; primary sourcing for rabbit-model syphilis research is the peer-reviewed literature (PubMed/PMC) and specialized STI-research consortia rather than a curated model-organism repository.

Sources: TprK-impaired T. pallidum attenuated in rabbit model of syphilis; Extracellular Loops of FadL Orthologs TP0856/TP0858 elicit IgG in rabbit model — mBio; Structural Modeling of T. pallidum OMP Repertoire — road map for vaccine development

Curation Notes for dismech Integration

  • Ontology terms flagged "(verify)" above must be confirmed via runoak/OAK against HP, GO, CL, UBERON, CHEBI, NCIT, and MONDO before being written into any term: block — several IDs in this report reflect strong-but-not-100%-certain recall and are exactly the class of claim the dismech anti-hallucination validation stack (just validate-terms) is designed to catch. Treat every ID above as a lead, not ground truth, per the repo's own DR-output guidance.
  • PMIDs actually surfaced with confidence during this research (safe starting points for just fetch-reference): 40708500, 27721440 (older PMID, review still current), 25890619, 36776779, 35819903, 35977144, 33125317, 29578082, 27982548, 18192791, 15186410, 33219164, 29451611, 22670010. Several other claims above are sourced to non-PMID URLs (CDC/USPSTF/PMC full-text pages without a captured PMID) — these should be re-resolved to a PMID/DOI where a quotable snippet is needed for dismech evidence items.
  • Structural sources applicable: given the disease's clinical-guideline-heavy evidence base, ORPHA: and NCIT: structured-source citation (per this repo's framework) may be more efficient than literature PMIDs for several treatment/epidemiology claims; an Orphanet entry for congenital syphilis specifically should be checked.
  • Mechanism-module fit: syphilis' pathophysiology (obliterative endarteritis as a shared lesion across chancre, gumma, and tertiary aortitis; granulomatous gumma formation) is a strong candidate for conforms_to: granuloma_formation (gummas) and shows thematic overlap with atherogenesis/thrombogenesis-adjacent vascular-injury logic, though syphilitic aortitis is mechanistically an infectious obliterative endarteritis rather than atherosclerotic — worth an explicit differentiating note if conformance is declared.
  • NEC risk: "syphilis" as a search term is not itself eponym-ambiguous, but curators should take care to keep venereal syphilis (subsp. pallidum) cleanly separated from yaws/bejel (subsp. pertenue/endemicum) literature when sourcing PMIDs — a Named-Entity-Confusion risk specific to this pathogen's close subspecies relatives.