Syphilis¶

Spirochetal Diseases · Part 5 – Infectious Diseases: Bacterial · Chapter 187

Key Clinical Points¶

Syphilis is a chronic systemic infection caused by Treponema pallidum subspecies pallidum, characterized by active disease episodes interrupted by asymptomatic latency.
Incubation period averages 2–6 weeks (median ~21 days), inversely proportional to the number of organisms transmitted.
Primary chancre: single painless papule that erodes and becomes indurated with a 'cartilaginous consistency' on palpation, typically resolving in 4–6 weeks.
Secondary syphilis: characterized by generalized mucocutaneous/cutaneous lesions, generalized nontender lymphadenopathy (85%), and constitutional signs.
Serology: Non-treponemal tests (RPR, VDRL) measure IgG/IgM against cardiolipin-lecithin-cholesterol; Treponemal tests (EIA/CIA, TPPA) are specific for current/past infection.
Argyll Robertson pupil: Reacts to accommodation but not to light; characteristic of tabes dorsalis and paresis.
Congenital stigmata: Hutchinson's teeth (centrally notched incisors), mulberry molars, saddle nose, and saber shins.
Management: Benzathine Penicillin G (BPG) is the first-line treatment for all stages; Doxycycline is an alternative for nonpregnant patients during BPG shortages.
CSF abnormalities (pleocytosis, increased protein, reactive VDRL) occur in up to 40% of untreated primary/secondary syphilis cases.
Epidemiology: Significant increase in US cases since 2000, with ~45% of cases occurring in men who have sex with men (MSM).

DEFINITION & CLASSIFICATION¶

• Definition (Harrison's 22e): Syphilis, a chronic systemic infection caused by Treponema pallidum subspecies pallidum, is usually sexually transmitted and characterized by episodes of active disease interrupted by asymptomatic periods (latency). • Incubation Period: Average 2–6 weeks; inversely proportional to the number of organisms transmitted (median ~21 days). • Clinical Progression: ◦ Primary stage: Localized infection at site of inoculation. ◦ Secondary stage: Generalized mucocutaneous/cutaneous lesions and lymphadenopathy. ◦ Latent stage: Subclinical infection, detectable only by serology; can last years or decades. ◦ Tertiary stage: Develops in ~1/3 of untreated patients (pre-antibiotic era). • CNS Involvement: Can occur early in infection; may be symptomatic or asymptomatic.

Classification & Subspecies¶

• Treponema pallidum subspecies: ◦ T. pallidum subsp. pallidum (venereal syphilis) ◦ T. pallidum subsp. pertenue (yaws) ◦ T. pallidum subsp. endemicum (bejel) ◦ T. carateum (pinta) • Clinical Continuum: Overlapping 'molecular signatures' and the presence of endemicum genotypes in sexually acquired ulcers suggest a genetic/clinical continuum among these treponemes.

EPIDEMIOLOGY¶

• Transmission Routes: ◦ Primary: Sexual contact with infectious lesions (chancre, mucous patch, skin rash, or condylomata lata). ◦ Other routes: Nonsexual skin contact, in utero infection, blood transfusion, and organ transplantation. • Risk Factors: ◦ Clinical factors: HIV concordance (disinhibition via ART/PrEP), homelessness, incarceration, illicit drug use. ◦ Population trends: Significant increase in US cases since 2000; ~45% of cases are among men who have sex with men (MSM).

Table 187-1: Syphilis Cases in the United States (1990–2022)¶

• Data Summary: ◦ Year 2000: 31,575 total cases; 5,979 were Primary & Secondary (P&S). ◦ Year 2022: 207,255 total cases; 59,061 were P&S; 3,755 were Congenital.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Host: Humans are the only known natural host for T. pallidum subsp. pallidum. • Pathogenesis: ◦ Rapid penetration of mucous membranes or skin abrasions. ◦ Entry into lymphatics and blood occurs within hours, leading to systemic infection before a primary lesion appears. ◦ Clinical progression: Primary lesion (4–6 weeks) → Secondary stage (6–12 weeks post-infection) → Latent stage (serologically detectable) → Tertiary stage (rare in modern era). • Relapse: Up to 25% of untreated patients experience cutaneous relapse of secondary lesions within the first year.

CLINICAL FEATURES¶

• Primary Syphilis: ◦ Presentation: Single painless papule → erosion → induration (cartilaginous consistency). ◦ Location: Penis (heterosexual men); anal canal, rectum, or mouth (MSM); cervix, vaginal wall, or labia (women). ◦ Lymphadenopathy: Regional (usually inguinal) nodes; firm, nonsuppurative, painless; appears within 1 week of lesion. • Secondary Syphilis: ◦ Cutaneous: Maculopapular, papular, papulosquamous, or pustular syphilides. ◦ Lymphadenopathy: Generalized, nontender (85%). ◦ Constitutional Symptoms: ◦ Sore throat (15–30%) ◦ Fever (5–8%) ◦ Weight loss (2–20%) ◦ Malaise (25%) ◦ Anorexia (10–20%) ◦ Headache (10%) ◦ Meningismus (5%) • Latent Syphilis: ◦ Early: ≤ 1 year since infection. ◦ Late: ≥ 1 year or unknown duration. • Congenital Syphilis: ◦ Stigmata: Hutchinson's teeth (centrally notched incisors), mulberry molars, saddle nose, and saber shins. ◦ Maternal Infection: Untreated infection can lead to up to 40% fetal loss (second-trimester abortion, stillbirth, prematurity, or neonatal death).

DIFFERENTIAL DIAGNOSIS¶

• Primary Lesion: ◦ Herpes simplex virus infection ◦ Chancroid ◦ Traumatic injury ◦ Donovanosis • Congenital Infection: ◦ Other congenital infections (e.g., toxoplasmosis, rubella) ◦ Congenital syphilis with specific stigmata.

DIAGNOSTIC APPROACH¶

Serologic Testing: • Non-treponemal tests (RPR, VDRL): Measure IgG/IgM against cardiolipin-lecithin-cholesterol antigen. • Treponemal tests (EIA/CIA, TPPA): Specific for current or past infection.
CSF Evaluation: • Indicated if neurosyphilis is suspected. • Findings: Pleocytosis, increased protein, and reactive VDRL are found in up to 40% of untreated primary/secondary cases.

MANAGEMENT & TREATMENT¶

Primary, Secondary, or Early Latent (No Penicillin Allergy): • CSF normal or not examined → Benzathine Penicillin G (BPG) 2.4 mU IM single dose. • CSF abnormal → Treat as neurosyphilis.
Primary, Secondary, or Early Latent (Confirmed Penicillin Allergy): • CSF normal or not examined → Doxycycline 100 mg PO bid OR Tetracycline HCl 500 mg PO qid for 2 weeks. • CSF abnormal → Treat as neurosyphilis.
Neurosyphilis, Ocular Syphilis, or Otic Syphilis: • Option A: Aqueous crystalline penicillin G (18–24 mU/d IV, given as 3–4 mU q4h or continuous infusion) for 10–14 days. • Option B: Aqueous procaine penicillin G (2.4 mU/d IM) plus oral probenecid (500 mg qid) for 10–14 days. • Note: Desensitize and treat with penicillin if allergic.
Monitoring: • Follow-up serologic testing at 3, 6, and 12 months post-treatment.

COMPLICATIONS & PROGNOSIS¶

• Historical vs. Modern: ◦ Pre-antibiotic: 1/3 of untreated patients developed tertiary syphilis. ◦ Modern: Tertiary syphilis nearly eliminated in Western countries. • CNS Involvement: Asymptomatic CNS involvement remains detectable in up to 40% of persons with early syphilis.

SPECIAL POPULATIONS¶

• Pregnancy: ◦ Treatment before the 16th week of pregnancy prevents fetal damage. • HIV Co-infection: ◦ Increases risk of neurosyphilis and reinfection. • MSM Population: ◦ 32% of MSM in longitudinal studies had multiple syphilis episodes; reinfections are often asymptomatic but serologically detectable.

KEY PEARLS & HIGH-YIELD POINTS¶

• Argyll Robertson Pupil: Reacts to accommodation, not light → hallmark of tabes dorsalis/paresis. • Congenital Stigmata: Hutchinson's teeth, mulberry molars, saddle nose, saber shins. • Treatment Choice: BPG is first-line; Doxycycline used for nonpregnant patients during BPG shortage. • Clinical Clue: Cartilaginous consistency of the primary chancre.

Reference Tables¶

TABLE 187-1 Recommendations for the Treatment of Syphilis a¶

Harrison's 22e, p.1434

STAGE OF SYPHILIS	PATIENTS WITHOUT PENICILLIN ALLERGY	PATIENTS WITH CONFIRMED PENICILLIN ALLERGY
Primary, secondary, or early latent	CSF normal or not examined: Penicillin G benzathine (single dose of 2.4 mU IM) CSF abnormal: Treat as neurosyphilis	CSF normal or not examined: Doxycycline (100 mg PO bid) or tetracycline HCl (500 mg PO qid) for 2 weeks CSF abnormal: Treat as neurosyphilis
	CSF normal or not examined: Penicillin G benzathine (2.4 mU IM weekly for 3 weeks) CSF abnormal: Treat as neurosyphilis
Neurosyphilis, ocular syphilis, or otic syphilis	Aqueous crystalline penicillin G (18–24 mU/d IV, given as 3–4 mU q4h or continuous infusion) for 10–14 days or Aqueous procaine penicillin G (2.4 mU/d IM) plus oral probenecid (500 mg qid), both for 10–14 days	Desensitize and treat with penicillin
	According to stage