Syphilis

Organism

Treponema pallidum subsp. pallidum. Thin, tightly coiled spirochete. NOT visible light microscopy (needs dark-field/silver stain). NEVER cultured on artificial media (unique limitation) — why diagnosis leans on serology, not culture.

Transmission

Sexual contact (primary/secondary lesion contact) mainly. Vertical/transplacental = congenital syphilis (separate topic, see Congenital Infections). Rare: transfusion, non-sexual lesion contact.

Clinical Stages (single continuous story)

Primary (incubation ~3wk, 10-90d range): solitary PAINLESS indurated ulcer (CHANCRE) + non-tender regional LAD. Painlessness = KEY distinguisher from chancroid (PAINFUL ulcer, see that topic). Heals spontaneously 3-6wk even untreated → patients often don’t seek care → progression.

Secondary (wk-months after chancre heals, hematogenous spread): systemic illness. Generalized maculopapular rash INVOLVING PALMS+SOLES (distinctive, few other rashes do this), generalized LAD, CONDYLOMATA LATA (broad, moist, HIGHLY infectious plaques — DISTINCT from HPV condylomata acuminata/genital warts), mucous patches, constitutional symptoms. ALSO resolves spontaneously untreated.

Latent: serology+, no clinical manifestations. Early latent (<1yr, still sexually infectious) vs Late latent (>1yr, generally not sexually infectious, but vertical transmission + tertiary progression still possible).

Tertiary (minority, years-decades later) — 3 forms:

Gummatous — destructive granulomatous lesions (gummas), skin/bone/viscera, delayed hypersensitivity to residual organism
Cardiovascular — aortitis, ascending aortic aneurysm + AR, chronic vasa vasorum inflammation
Neurosyphilis — CAN OCCUR AT ANY STAGE (not only tertiary — important exception to staged rule). Asymptomatic CSF abnormality, meningovascular disease, or late tabes dorsalis/general paresis (direct CNS damage)

Laboratory Diagnosis

Direct: dark-field microscopy (chancre/condylomata lata exudate) — motile spirochetes. Primary/secondary only, needs fresh exam + technical skill, limited routine use.

Serology = MAINSTAY (2 categories, need both):

Non-treponemal (VDRL, RPR): anti-cardiolipin Ab (nonspecific, released from damaged cells). Cheap, fast, QUANTITATIVE/TITRATABLE — standard for MONITORING treatment (falling titer=adequate Rx, rising=reinfection/failure). LIMITATION: false+ (pregnancy, autoimmune/SLE, other infections, aging). Never diagnostic alone.

Treponemal (TPHA, FTA-ABS, EIA/CLIA): anti-T. pallidum Ab. MORE SPECIFIC, confirms reactive non-treponemal screen. REMAINS POSITIVE FOR LIFE even after Rx — CANNOT monitor treatment/reinfection.

Modern algorithm: REVERSE SEQUENCE (treponemal EIA/CLIA first screen → confirm with non-treponemal) increasingly used (automation/throughput) vs traditional non-treponemal-first. Logic same either way: one confirms other, only non-treponemal titer tracks Rx.

Neurosyphilis: CSF exam needed (CSF-VDRL — highly specific, INSENSITIVE — + cell count/protein). Serum serology alone insufficient.

Treatment

PENICILLIN = DOC at EVERY STAGE. Like S. pyogenes — T. pallidum NEVER developed significant penicillin resistance (~century use).

Single IM dose Benzathine penicillin G: primary, secondary, early latent. 3-dose weekly regimen: late latent, tertiary (non-neuro). IV aqueous penicillin G: neurosyphilis (needs CSF penetration, benzathine can’t achieve this).

Doxycycline = alternative for penicillin allergy (non-pregnant). PREGNANT + penicillin allergy: DESENSITIZATION + penicillin REGARDLESS (only proven agent to prevent congenital syphilis; doxycycline contraindicated in pregnancy).

Jarisch-Herxheimer reaction (shared with relapsing fever/Lyme — spirochetal disease pattern): acute fever+myalgia+headache within hours of FIRST penicillin dose (antigen release from mass killing). Self-limited, symptomatic Rx. IN PREGNANCY: can precipitate preterm labor — anticipate/monitor, don’t mistake for drug allergy.

The Organism

Treponema pallidum subspecies pallidum is a thin, tightly coiled spirochete, too slender to be seen by ordinary light microscopy (requiring dark-field examination or special stains/silver impregnation to visualize directly) and, notably, never successfully cultured on artificial media despite over a century of attempts — a genuinely unusual limitation for a bacterium of such major clinical importance, and the reason syphilis diagnosis leans so heavily on serology rather than culture-based confirmation (unlike almost any other major bacterial STI).

Transmission

Primarily sexual contact (direct contact with an active primary or secondary lesion), though vertical (transplacental) transmission causing congenital syphilis is a distinct and serious route covered separately (see Congenital and Perinatal Infections), and rare transmission via blood transfusion or direct non-sexual contact with an active lesion can occur.

Clinical Stages

Untreated syphilis progresses through a genuinely distinctive, well-defined natural history — a fact worth understanding as a single continuous story, since each stage’s clinical picture only makes sense in relation to the others:

Primary syphilis (average incubation 3 weeks, range 10–90 days): a solitary, classically painless, indurated ulcer (the chancre) at the inoculation site, with non-tender regional lymphadenopathy — the painlessness is a genuinely important distinguishing clinical feature from most other genital ulcer diseases (contrast chancroid, covered under Chancroid and Donovanosis, whose ulcer is characteristically painful). The chancre heals spontaneously within 3–6 weeks even without treatment, which is exactly why patients often don’t seek care at this stage, allowing progression.

Secondary syphilis (occurring weeks to a few months after the chancre heals, reflecting haematogenous dissemination of the organism): a systemic illness with a characteristic generalized maculopapular rash notably involving the palms and soles (a genuinely distinctive feature, since few other rashes classically involve these sites), generalized lymphadenopathy, condylomata lata (broad, moist, highly infectious wart-like plaques in warm, moist body areas — genuinely distinct from the viral genital warts of HPV, condylomata acuminata), mucous patches, and constitutional symptoms (fever, malaise, sore throat). This stage, like primary syphilis, also resolves spontaneously without treatment.

Latent syphilis: a period of serological positivity without any clinical manifestations, split into early latent (infection within the preceding year, still potentially infectious via sexual contact) and late latent (beyond one year, generally not sexually infectious, though still capable of vertical transmission and of progressing to tertiary disease).

Tertiary syphilis (developing in a minority of untreated patients, typically years to decades after initial infection) takes three forms, worth naming individually since each reflects a genuinely different pathological process: gummatous syphilis (destructive, granulomatous lesions — gummas — in skin, bone, or viscera, from a delayed hypersensitivity-type response to residual organism); cardiovascular syphilis (aortitis, classically causing ascending aortic aneurysm and aortic regurgitation, from chronic vasa vasorum inflammation damaging the aortic wall); and neurosyphilis (which can actually occur at any stage of infection, not only tertiary disease — a genuinely important exception to the staged-progression rule — presenting as asymptomatic CSF abnormality, meningovascular disease, or the late, classic tabes dorsalis/general paresis picture from direct CNS parenchymal damage).

Laboratory Diagnosis

Direct detection: dark-field microscopy of chancre or condylomata lata exudate directly visualizes motile spirochetes — useful specifically in primary/secondary disease when a moist, exudative lesion is available, but requires immediate fresh examination and real technical skill, limiting its practical routine use.

Serology is the diagnostic mainstay, and understanding the two test categories together is essential, since neither alone tells the full story:

Non-treponemal tests (VDRL, RPR) detect antibody against cardiolipin, a non-specific lipid antigen released from damaged host cells during infection — cheap, fast, and, critically, quantitative/titratable, making them the standard tool for monitoring treatment response (a properly falling titre confirms adequate treatment; a rising titre signals reinfection or treatment failure). Their key limitation is a real false-positive rate from unrelated conditions (pregnancy, autoimmune disease — notably SLE, other acute infections, ageing) — a positive non-treponemal test is never diagnostic alone and always needs confirmation.
Treponemal tests (TPHA, FTA-ABS, and newer treponemal-specific EIA/CLIA formats) detect antibody against T. pallidum itself — more specific, used to confirm a reactive non-treponemal screen, but remain positive for life even after adequate treatment, meaning they cannot be used to monitor treatment response or diagnose reinfection the way non-treponemal titres can.

Modern laboratory algorithms increasingly use the reverse sequence (treponemal EIA/CLIA first, as the initial screen, with a reactive result confirmed by a non-treponemal test) rather than the traditional non-treponemal-first approach, reflecting improved automation and throughput of newer treponemal assays — though the underlying logic (one test type confirms the other, and only the non-treponemal titre tracks treatment) stays the same regardless of which order is used.

Neurosyphilis specifically requires CSF examination (CSF-VDRL, which is highly specific but insensitive, alongside CSF cell count/protein) when clinically suspected, since serum serology alone cannot confirm or exclude CNS involvement.

Treatment

Penicillin remains the drug of choice at every stage — genuinely notable, since, like S. pyogenes, T. pallidum has never developed clinically significant penicillin resistance despite nearly a century of use. A single intramuscular dose of benzathine penicillin G treats primary, secondary, and early latent syphilis; late latent and tertiary (non-neurological) disease need a longer three-dose weekly regimen; neurosyphilis requires IV aqueous penicillin G given the need for adequate CSF penetration, which the long-acting benzathine formulation cannot reliably achieve. Doxycycline serves as the alternative for genuine penicillin allergy in non-pregnant patients — but pregnant women with penicillin allergy require desensitization and penicillin treatment regardless, since penicillin is the only agent proven to reliably prevent congenital syphilis, and doxycycline is itself contraindicated in pregnancy.

A genuinely important treatment-related phenomenon, shared with the spirochetal relapsing fevers (see Relapsing Fever and Lyme Disease), is the Jarisch-Herxheimer reaction — an acute febrile reaction with myalgia and headache within hours of the first penicillin dose, from the sudden release of treponemal antigen as large numbers of organisms are killed; it is generally self-limited and managed symptomatically, but in pregnancy it can precipitate preterm labour, which is why it needs to be anticipated and monitored for rather than mistaken for a drug allergy.