Syphilis

Etiology: Caused by Treponema pallidum subspecies pallidum, a spirochete bacterium. Transmitted primarily via sexual contact (direct mucosal/skin contact with active lesions), vertically (congenital syphilis), or rarely via blood transfusion.

Stages & Clinical Presentation

Primary Syphilis

Incubation: 10–90 days (average ~3 weeks)
Hallmark: Painless indurated chancre at the inoculation site (genitals, anus, oropharynx, lips)
Regional lymphadenopathy (painless, firm)
Heals spontaneously in 3–6 weeks even without treatment

Secondary Syphilis

Develops 2–12 weeks after chancre appearance
Diffuse maculopapular rash — classically involves palms and soles; non-pruritic
Condylomata lata (moist, flat, warty lesions in moist areas)
Mucous patches, alopecia, fever, malaise, lymphadenopathy, hepatosplenomegaly
Resolves spontaneously → enters latent phase

Panel A/B: Symmetric maculopapular rash of secondary syphilis. Panel C: Solitary indurated chancre on penile shaft (primary syphilis).

Latent Syphilis

Early latent: Infection < 1 year, no symptoms
Late latent: Infection ≥ 1 year (or unknown duration), no symptoms
Still seroreactive; patient can transmit vertically

Tertiary Syphilis

Occurs years to decades after untreated infection (~30% of untreated cases)
Gummatous syphilis: Granulomatous lesions in skin, bone, liver
Cardiovascular syphilis: Aortitis, aortic aneurysm (ascending), aortic regurgitation
Neurosyphilis: Can occur at any stage; manifestations include meningitis (early), tabes dorsalis, general paresis, Argyll Robertson pupil (accommodates but does not react to light)

Diagnosis

Serological Testing (Two-Step Algorithm)

Test Type	Tests	Role
Non-treponemal (lipoidal antigen)	RPR, VDRL	Screening; titers reflect disease activity and treatment response
Treponemal	FTA-ABS, TPPA, EIA/CIA	Confirmatory; remain positive for life even after treatment

Traditional algorithm: Non-treponemal screen → if reactive, confirm with treponemal test
Reverse algorithm (now common): Treponemal EIA/CIA screen first → if reactive, confirm/stage with RPR

Key testing notes (Laboratory Recommendations for Syphilis Testing, p. 17):

RPR and VDRL have similar sensitivity/specificity but titers are NOT interchangeable — use the same test type serially to monitor treatment response
FTA-ABS sensitivity ~78% and TPPA sensitivity ~94.5% in primary syphilis — TPPA is preferred for primary-stage confirmation
False positives with non-treponemal tests: pregnancy, autoimmune disease (SLE), viral infections, IV drug use

CSF Examination (Neurosyphilis)

Indicated when neurological/ocular/otologic symptoms present, treatment failure, or HIV with CD4 < 350 and RPR ≥ 1:32. CSF findings: lymphocytic pleocytosis, elevated protein, reactive CSF-VDRL (specific but insensitive).

Dark-field Microscopy / Direct Detection

Direct visualization of spirochetes from chancre exudate or condylomata lata — useful in primary syphilis before seroreactivity develops. PCR-based assays also available.

Treatment

Per CDC STI Treatment Guidelines 2021 (Laboratory Recommendations for Syphilis Testing, p. 7):

Stage	First-Line	Alternative (PCN allergy)
Primary, Secondary, Early Latent	Benzathine penicillin G 2.4 million units IM × 1 dose	Doxycycline 100 mg PO BID × 14 days
Late Latent / Latent Unknown Duration	Benzathine penicillin G 2.4 MU IM weekly × 3 doses	Doxycycline 100 mg PO BID × 28 days
Tertiary (gumma/cardiovascular)	Benzathine penicillin G 2.4 MU IM weekly × 3 doses	Consult ID specialist
Neurosyphilis	Aqueous crystalline penicillin G 18–24 MU IV/day × 10–14 days	Procaine PCN G + probenecid; or ceftriaxone 2g IV/IM × 10–14 days

Penicillin allergy: Desensitization is recommended in pregnancy — no proven alternatives exist for congenital syphilis prevention.

Jarisch-Herxheimer Reaction

Febrile reaction occurring within 24 hours of first treatment dose (fever, rigors, hypotension, worsening rash). Managed with antipyretics; does NOT indicate treatment failure. Caution in pregnancy (can precipitate preterm labor).

Follow-up

Non-treponemal titers should decline ≥4-fold (two dilutions) by 6–12 months in primary/secondary syphilis — treatment success
Persistent titers or rising titers → re-infection or treatment failure → re-treat and consider CSF examination

Special Populations

Congenital Syphilis

Transmitted transplacentally, any trimester (risk highest in secondary syphilis)
Manifestations: stillbirth, hydrops fetalis, snuffles (bloody rhinorrhea), saddle-nose deformity, Hutchinson teeth, interstitial keratitis, saber shins, periostitis
All pregnant women screened at first prenatal visit; repeat at 28 weeks and delivery in high-prevalence areas
Treatment: Aqueous penicillin G IV × 10 days

HIV Co-infection

Atypical presentations more common; may have higher rates of neurosyphilis
Serological testing generally reliable; some false negatives possible at very low CD4 counts
Standard regimens used, but close follow-up essential; lower threshold for LP

Complications Summary

System	Complication
Neurological	Meningitis, stroke, general paresis, tabes dorsalis
Cardiovascular	Ascending aortitis, aortic aneurysm, aortic regurgitation
Ocular	Uveitis, optic neuritis, retinitis
Obstetric	Spontaneous abortion, stillbirth, congenital infection

Key Takeaway: Syphilis is a multi-stage systemic infection with highly variable presentations ("the great imitator"). Diagnosis relies on a two-step serological algorithm, and benzathine penicillin G remains the cornerstone of treatment at all stages.

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