Syphilis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Syphilis is caused by the spirochaete Treponema pallidum and transmitted mainly through direct contact with infectious lesions during sex or transplacentally. Disease evolves through primary, secondary, latent and tertiary stages, with nervous-system involvement possible at any time.

Clinical diversity makes syphilis a diagnostic mimic. Anogenital ulcer, rash, alopecia, hepatitis, uveitis, meningitis, stroke, cognitive decline and aortic or gummatous disease may occur, while latency is entirely asymptomatic.

Treponemal tests usually remain reactive for life and indicate current or past infection. A quantitative non-treponemal titre reflects activity imperfectly but is the main tool for documenting treatment response and detecting reinfection.

Management requires accurate staging, neurological and pregnancy assessment, penicillin delivery, counselling about the Jarisch–Herxheimer reaction, partner notification and scheduled serology. Previous treatment records prevent both under- and overtreatment.

Key points

Primary syphilis usually causes a painless indurated ulcer with regional lymphadenopathy, but chancres can be painful, multiple or hidden.
Secondary syphilis causes a generalized rash often involving palms and soles, mucous patches, condylomata lata, lymphadenopathy and systemic symptoms.
Latent syphilis has reactive serology without clinical signs; timing determines whether early or late-latent treatment is needed.
Use a treponemal screening and confirmation test plus a quantitative RPR or VDRL titre to assess activity and follow response.
Direct PCR from an early lesion can support diagnosis before serology becomes reactive where locally available.
Treat primary, secondary and early latent syphilis with benzathine benzylpenicillin 2.4 million units intramuscularly once.
Treat late latent or unknown-duration syphilis with benzathine benzylpenicillin 2.4 million units intramuscularly weekly for three doses.
Penicillin is required in pregnancy; allergy needs specialist desensitisation rather than a fetal-risk substitute.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Sexual lesion contact

Spirochaetes enter microscopic mucosal or skin breaks during direct contact with infectious primary or secondary lesions.

Transplacental transmission

Maternal spirochaetaemia crosses the placenta at any stage and can cause fetal loss or congenital multisystem disease.

Blood exposure

Transmission through unscreened blood or shared injecting equipment is now uncommon in the UK but biologically possible.

Reinfection

Successful treatment does not create reliable protective immunity, so future sexual exposure can cause a new infection.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Local replication
T pallidum multiplies at the inoculation site and produces an endarteritis-rich chancre with regional lymph-node spread.
2
Haematogenous dissemination
Early bloodstream spread distributes spirochaetes to skin, mucosa, liver, eyes, ears and nervous system, explaining the varied manifestations of secondary disease.
3
Immune containment
Cell-mediated responses suppress clinical disease into latency without eliminating every organism, so asymptomatic infection remains serologically detectable and can later progress.
4
Chronic endarteritis
Persistent endarteritis narrows small vessels and gradually damages neural, cardiovascular and other organs, sometimes decades after the initial untreated infection.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Primary chancre

A classically painless clean-based indurated ulcer with non-tender nodes appears at the inoculation site, including cervix, rectum or mouth.

Secondary eruption

Diffuse non-itchy maculopapular rash involving palms and soles, patchy alopecia, mucous lesions and generalized nodes suggests secondary disease.

Latent infection

Reactive serology without current manifestations requires history, previous results and exposure dates to determine early or late stage.

Early neurosyphilisRed flag

Meningitis, cranial neuropathy, ocular inflammation, hearing disturbance or meningovascular stroke may occur during early infection.

Late neurological diseaseRed flag

Cognitive and personality change, sensory ataxia, lightning pains, bladder dysfunction and abnormal pupils suggest parenchymal involvement.

Congenital-risk settingRed flag

Any reactive result during pregnancy requires urgent confirmation, staging and treatment because maternal symptoms do not predict fetal risk.

Red flags requiring action

Any visual symptom with reactive syphilis serology is ocular syphilis until urgent ophthalmic assessment proves otherwise.
Sudden hearing loss, tinnitus or vertigo can represent otosyphilis and needs same-day specialist review.
Headache, meningism, cranial neuropathy, cognitive change, tabetic symptoms or young stroke prompts neurosyphilis assessment.
Syphilis in pregnancy can transmit at any stage and requires immediate maternity and sexual-health coordination.
A high-risk chancre with initially negative serology requires lesion testing and repeat serology rather than reassurance.
Failure of the non-treponemal titre to fall appropriately raises reinfection, treatment failure, wrong stage or neurological involvement.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Treponemal screening immunoassayFirst step
Why
Detect antibodies indicating present or previous T pallidum infection.
Interpretation and limitations
Reactive screening requires confirmatory testing and treatment-history review; it generally remains positive after successful therapy.
02
Second treponemal test
Why
Confirm specificity using a different antigen or method such as TPPA.
Interpretation and limitations
Concordant treponemal tests support infection; discordant results need laboratory and sexual-health interpretation rather than automatic treatment.
03
Quantitative RPR or VDRL
Why
Estimate disease activity and provide a baseline titre for follow-up.
Interpretation and limitations
A fourfold titre change equals two dilution steps and is clinically meaningful; low titres can persist after adequate therapy.
04
Lesion PCR or dark-field testing
Why
Detect T pallidum directly during early ulcerative or mucosal disease.
Interpretation and limitations
Availability varies; a positive result confirms infectious syphilis, while a negative test does not replace repeat serology.
05
HIV and wider STI testing
Why
Identify coinfection that changes follow-up and prevention needs.
Interpretation and limitations
Offer HIV, chlamydia, gonorrhoea and hepatitis assessment according to exposure and repeat after window periods where needed.
06
CSF cell count, protein and VDRL
Why
Assess suspected neurological syphilis after clinical neurological evaluation.
Interpretation and limitations
CSF VDRL is specific but insensitive; diagnosis integrates symptoms, CSF inflammation, serology and specialist judgment.
07
Ophthalmic and audiological examination
Why
Identify sight- or hearing-threatening involvement needing neurosyphilis treatment.
Interpretation and limitations
A normal lumbar puncture does not defer treatment of confirmed ocular or otic disease; specialist examination defines the affected structure.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Genital herpes

Painful grouped vesicles and shallow ulcers with HSV PCR distinguish herpes, although syphilitic chancres can occasionally be painful.

Chancroid

Haemophilus ducreyi causes painful ragged ulcers and tender suppurative nodes after exposure in an endemic setting.

Mpox

Firm umbilicated lesions, systemic symptoms and epidemiological exposure may resemble syphilis; lesion PCR and parallel syphilis serology establish the diagnosis.

Drug eruption

Medication-related exanthem can involve palms and soles, but its drug timeline and absent stage-compatible serology distinguish it from secondary syphilis.

Autoimmune or malignant ulcer

Behçet disease, aphthosis and cancer cause persistent or recurrent lesions; negative infection tests, systemic features or induration should prompt biopsy and specialist review.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01TESTConfirm and stage infectionFirst stepScreening serology, a compatible lesion, rash or partner notification raises syphilis probability.

1Take treponemal and quantitative non-treponemal tests and lesion PCR where available before treatment.
2Document previous syphilis results and treatment, symptoms, neurological or sensory features, pregnancy and timing of possible acquisition.
3Examine skin, mouth, anogenital sites, lymph nodes, neurological system and eyes or hearing according to symptoms.
4Classify primary, secondary, early latent, late latent, tertiary or neuro-ocular disease with sexual-health specialists.

02EARLYTreat early syphilisPrimary, secondary or early latent syphilis is confirmed and neuro-ocular disease is absent.

1Give benzathine benzylpenicillin 2.4 million units intramuscularly once using correct divided-site technique and product.
2Use doxycycline 100 mg orally twice daily for 14 days only for a suitable non-pregnant penicillin-allergic adult under guidance.
3Warn about fever, headache and myalgia from a Jarisch–Herxheimer reaction during the first 24 hours and provide symptom advice.
4Arrange partner notification and repeat quantitative RPR or VDRL at stage-appropriate intervals.

03LATETreat late or uncertain durationLate latent syphilis or infection of unknown duration is present without neurosyphilis.

1Give benzathine benzylpenicillin 2.4 million units intramuscularly once weekly for three consecutive doses.
2If a weekly interval is substantially exceeded, seek specialist advice on restarting rather than improvising the course.
3Use doxycycline 100 mg twice daily for 28 days only where penicillin is unsuitable and pregnancy is excluded.
4Assess cardiovascular, neurological and gummatous features and schedule longer serological follow-up.

04NEUROProtect vision, hearing and brainNeurological, ocular or otic syphilis is suspected at any disease stage.

1Arrange urgent specialist examination and CSF assessment when indicated, but do not delay sight- or hearing-saving treatment.
2Give intravenous benzylpenicillin 1.8 to 2.4 g every four hours for 14 days under the neurosyphilis protocol.
3AlternativeUse an exact specialist alternative only when penicillin cannot safely be administered.
4Repeat clinical, serological and selected CSF assessment to document response and investigate recurrence.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Provides prolonged treponemicidal exposure for primary, secondary and early latent infection.

Benzathine benzylpenicillin for early syphilis

Give 2.4 million units intramuscularly once, usually divided between two gluteal sites according to product and local administration protocol.

Confirm the long-acting benzathine product, never give intravenously, clarify anaphylaxis history and counsel about Jarisch–Herxheimer symptoms.

Provides sustained exposure across the longer organism replication interval in late asymptomatic disease.

Benzathine benzylpenicillin for late latent syphilis

Give 2.4 million units intramuscularly once weekly for three doses for late latent or unknown-duration infection.

Record every date, seek advice after a missed interval, and use specialist pregnancy management because complete penicillin treatment is essential.

Provides an oral alternative for selected non-pregnant adults who cannot receive penicillin.

Doxycycline penicillin-allergy alternative

Give 100 mg orally twice daily for 14 days in early syphilis or 28 days in late latent disease when current guidance permits.

Not adequate for pregnancy or neurosyphilis; check adherence, photosensitivity, oesophageal injury, interactions and ensure close serological follow-up.

Achieves treponemicidal CSF exposure for neurological, ocular and otic disease.

Intravenous benzylpenicillin for neurosyphilis

Give 1.8 to 2.4 g intravenously every four hours for 14 days under specialist neuro-ocular syphilis guidance.

Adjust for severe renal dysfunction, monitor electrolytes and neurotoxicity, and manage allergy with expert input rather than substituting an unproven short course.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Neurosyphilis

Meningeal, vascular or parenchymal infection causes cranial neuropathy, stroke, sensory ataxia, pain and cognitive decline, with deficits potentially becoming irreversible.

Ocular and otic loss

Uveitis, retinitis, optic neuropathy or inner-ear inflammation can cause permanent visual or hearing impairment if specialist assessment and penicillin treatment are delayed.

Cardiovascular syphilis

Chronic aortitis weakens the ascending aorta and may produce aneurysm, aortic regurgitation or coronary ostial disease.

Gummatous disease

Granulomatous destructive lesions form in skin, bone or internal organs and mimic inflammatory or malignant masses.

Congenital syphilis

Untreated maternal infection causes miscarriage, stillbirth, neonatal disease and delayed skeletal, dental, auditory and neurological injury.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Record baseline quantitative RPR or VDRL in the same laboratory method for meaningful comparison.
Repeat titres at stage- and HIV-appropriate intervals and assess for a fourfold fall from the baseline.
Review early after treatment for Jarisch–Herxheimer reaction, allergy and persistent lesion or neurological symptoms.
Investigate a fourfold titre rise for reinfection or treatment failure and repeat sexual history and HIV testing.
Follow ocular, otic and neurological function with the relevant specialty rather than relying on serology alone.
In pregnancy monitor fetal and maternal care through a specialist pathway and ensure neonatal assessment at birth.
Document partner-notification outcomes and reinforce risk reduction, condoms and PrEP discussion where appropriate.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Treponemal tests stay positive

A reactive treponemal assay usually records lifetime exposure and cannot by itself distinguish active from successfully treated infection.

RPR change needs fourfold movement

A shift from 1:32 to 1:8 is a clinically meaningful two-dilution fall; 1:32 to 1:16 may reflect assay variation.

Neurosyphilis has no stage boundary

Nervous-system, eye and ear involvement can occur during primary, secondary, latent or late disease.

Early serology can be negative

Antibody may not yet be detectable at chancre onset, so direct lesion testing and repeat serology preserve diagnosis.

Jarisch–Herxheimer is not allergy

Transient inflammatory fever after effective therapy differs from urticaria, bronchospasm or hypotension caused by immediate hypersensitivity.

Pregnancy requires penicillin

Alternative agents do not have equivalent evidence for fetal treatment, making desensitisation and penicillin delivery the safe specialist route.

11Common pitfallsFrequent interpretation and management errors.

01
Do not exclude primary syphilis after one negative early serology result.
02
Do not interpret a lifelong treponemal positive result without treatment history and RPR titre.
03
Do not treat ocular or otic syphilis with a single benzathine injection.
04
Do not use doxycycline as pregnancy treatment.
05
Do not confuse the Jarisch–Herxheimer reaction with penicillin anaphylaxis.
06
Do not discharge without scheduled quantitative serology and partner notification.