15.1 Syphilis: Pathogenesis, Clinical Stages, Serology & European Management

15.1 Syphilis: Pathogenesis, Clinical Stages, Serology & European Management

Microbiology and Transmission Biology of Treponema pallidum

Treponema pallidum subsp. pallidum is a fastidious, obligate human pathogen belonging to the order Spirochaetales and family Spirochaetaceae. The bacterium exhibits a distinctive helical, corkscrew morphology measuring 6 to 20 µm in length and 0.1 to 0.2 µm in diameter. Its locomotion is driven by endoflagella (periplasmic flagella) located within the periplasmic space between the inner peptidoglycan membrane and the outer lipid bilayer membrane, generating active corkscrew motility that facilitates rapid penetration through intact mucous membranes or microscopic cutaneous abrasions.

Because T. pallidum lacks the metabolic machinery for tricarboxylic acid cycle synthesis and de novo nucleotide synthesis, it cannot be cultured on standard cell-free artificial bacteriological media. Transmission occurs primarily through direct intimate contact with infectious mucocutaneous exudates during vaginal, anal, or oral sexual exposure. Vertical transplacental transmission from an infected mother to the fetus can occur at any stage of pregnancy. Rare modes of transmission include accidental occupational inoculation and direct blood transfusion. The incubation period from initial inoculation to the appearance of clinical disease ranges from 10 to 90 days, with an average of 21 days.

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Clinical Staging Architecture

Syphilis progresses through well-defined clinical and biological stages characterized by periods of florid clinical activity separated by quiescent asymptomatic intervals.

Inoculation (Day 0)
   │
   ▼ (10–90 days, avg 21 days)
Primary Syphilis: Hard Chancre (Ulcus Durum) + Painless Buboes (heals spontaneously in 3–8 weeks)
   │
   ▼ (4–10 weeks after primary lesion)
Secondary Syphilis: Spirochetemia, Roseola, Collarette of Biett, Condylomata Lata, Mucous Patches
   │
   ▼
Latent Syphilis (Asymptomatic seropositivity)
   ├── Early Latent (<1 year duration): Infectious relapses possible
   └── Late Latent (≥1 year or unknown duration): Non-infectious sexually
   │
   ▼ (~30% of untreated patients over 1–30+ years)
Tertiary Syphilis: Gummatous Syphilis, Cardiovascular Aortitis, Neurosyphilis

1. Primary Syphilis

Primary syphilis marks the localized clinical manifestation at the portal of bacterial inoculation:

• The Hard Chancre (Ulcus Durum): Initiates as an erythematous, indurated macule or papule that rapidly erodes into a solitary, rounded, painless ulcer. The classical chancre exhibits an indurated, button-like or cartilaginous base upon digital palpation, sharply defined rolled borders, and a clean, non-purulent granular base containing serous exudate swarming with spirochetes. Multiple chancres can occur, particularly in individuals living with human immunodeficiency virus (HIV).
• Anatomical Distribution: Predominantly localized to anogenital skin (coronal sulcus, prepuce, glans penis, shaft, fourchette, labia majora/minora, cervix, anus, and perianal margin). Extragenital chancres occur in 5% to 10% of cases, commonly involving the vermilion border of the lips, tongue, oral mucosa, and fingers.
• Regional Lymphadenopathy: Develops 1 to 2 weeks after ulcer appearance. Manifests as unilateral or bilateral, firm, discrete, movable, painless, non-suppurative lymph nodes (indolent buboes or "dorsal cords").
• Spontaneous Involution: The primary chancre heals spontaneously without scarring within 3 to 8 weeks, even in the absence of treatment, creating a false impression of cure while spirochetes actively disseminate hematogenously.

2. Secondary Syphilis: The "Great Imitator"

Secondary syphilis develops 4 to 10 weeks after the appearance of the primary chancre, resulting from systemic spirochetal dissemination and vascular endothelial invasion throughout the skin and internal organs:

• Constitutional Symptoms: Low-grade fever, malaise, pharyngitis, anorexia, arthralgias, and generalized non-tender lymphadenopathy. Enlargement of the epitrochlear lymph nodes is highly specific for secondary syphilis.
• Cutaneous Syphilides:
  • Macular Syphilide (Roseola Syphilitica): Early eruption consisting of faint, copper-red, non-pruritic macules on the trunk and proximal extremities, oriented along cutaneous cleavage lines.
  • Papular and Maculopapular Syphilide: Firm, ham-colored or copper-red, infiltrating papules. Prominently involves the palms and soles, characterized pathognomonically by a peripheral ring of fine epidermal scale known as the collarette of Biett.
  • Annular, Follicular, and Pustular Syphilides: Morphological variants common in darker skin types. Crucial clinical rule: True vesicles and bullae DO NOT occur in adult secondary syphilis; bullous luetic lesions are restricted exclusively to early congenital syphilis.
• Condylomata Lata: Hypertrophic, broad-based, flat, moist, whitish or pinkish-gray macerated vegetative plaques occurring in warm, intertriginous friction areas (perianal region, vulva, scrotum, inner thighs, axillae). They are teeming with treponemes and are the most infectious cutaneous lesions of syphilis.
• Mucosal Manifestations:
  • Mucous Patches: Painless, superficial, oval, grayish-white macerated plaques surrounded by an erythematous halo located on the oral mucosa, lips, and tongue.
  • Snail-Track Ulcers: Confluent, serpiginous, superficial mucosal erosions resembling snail tracks on the soft palate and tonsils.
• Syphilitic Alopecia: Non-scarring, non-inflammatory hair loss presenting in a patchy, irregular "moth-eaten" pattern predominantly involving the temporo-occipital scalp. Loss of the lateral third of the eyebrows may accompany this.
• Systemic Involvement: Luetic hepatitis (marked elevation of alkaline phosphatase out of proportion to transaminases), glomerulonephritis, periostitis, uveitis, and splenomegaly.

3. Latent Syphilis

Latent syphilis is defined as serological reactivity for syphilis in the absence of clinical signs or symptoms of active mucocutaneous or visceral disease:

• Early Latent Syphilis: Documented acquisition within the preceding 12 months (European IUSTI definition based on seroconversion, 4-fold non-treponemal titer elevation, or unequivocal primary/secondary symptoms in past year). Up to 25% of untreated patients experience mucocutaneous infectious relapses during this period.
• Late Latent Syphilis: Infection acquired ≥1 year prior, or where the duration of acquisition cannot be verified. Patients are non-infectious to sexual contacts (spirochetes sequestered), but vertical mother-to-child transmission remains possible.

4. Tertiary Syphilis

Tertiary syphilis develops in approximately 30% of untreated individuals after an asymptomatic latent latency period lasting 1 to 30 or more years:

• Gummatous Syphilis (Late Benign Syphilis): Chronic granulomatous destructive lesions occurring in skin, subcutaneous tissues, and skeletal bones. Characterized histologically by central coagulative necrosis surrounded by epithelioid histiocytes, Langhans-type multinucleated giant cells, fibroblasts, and an intense plasma cell infiltration with endarteritis obliterans. Lesions present as noduloulcerative plaques that heal with punch-out atrophic tissue destruction and "tissue-paper" scarring.
• Cardiovascular Syphilis (10–30 years): Endarteritis obliterans of the vasa vasorum in the ascending thoracic aorta. Results in destruction of elastic fibers in the aortic tunica media, producing thoracic aortic aneurysm (with characteristic tree-bark appearance of the aortic intima), aortic valve regurgitation, and coronary ostial stenosis.
• Neurosyphilis: Can develop at any stage of infection:
  • Early Neurosyphilis (months to early years): Acute syphilitic meningitis (cranial nerve palsies, specifically CN VII, VIII, and II) and meningovascular syphilis (endarteritis of cerebral vessels leading to stroke syndromes in young adults).
  • Late Neurosyphilis (10–25+ years): Parenchymatous neurosyphilis:
    • Tabes Dorsalis: Demyelination and degeneration of the posterior (dorsal) columns and dorsal nerve roots of the spinal cord. Presents with lightning shooting pains, sensory ataxia, loss of vibration/proprioception, positive Romberg sign, Charcot neuropathic joints, and Argyll Robertson pupils (bilateral small, irregular pupils that constrict upon accommodation for near vision but fail to react to direct light: "accommodates but does not react").
    • General Paresis (Dementia Paralytica): Chronic frontotemporal meningoencephalitis resulting in progressive dementia, delusions of grandeur, personality dissolution, dysarthria, and tremors.

5. Congenital Syphilis

Occurs via transplacental transmission of T. pallidum. Risk of transmission is highest in primary and secondary maternal syphilis (up to 70–100%) and declines in late latent syphilis (~10%):

• Early Congenital Syphilis (Manifesting < 2 years of age):
  • Syphilitic Rhinitis ("Snuffles"): Persistent, highly infectious, bloody, purulent nasal discharge causing nasal mucosal ulceration and cartilage destruction.
  • Pemphigus Syphiliticus: Vesiculobullous and pustular eruption on the palms and soles with desquamation. Diagnostic pearl: Bullae occur exclusively in neonatal/congenital syphilis and are never seen in adult secondary syphilis.
  • Hepatosplenomegaly, Jaundice, and Lymphadenopathy.
  • Skeletal Lesions: Osteochondritis, periostitis (Wimberger sign on long-bone radiography), and Parrot pseudoparalysis (painful limb immobility secondary to syphilitic periostitis mimicking motor palsy).
  • Rhagades: Radiating linear fissures around the mouth, nares, and anus that heal leaving persistent radial scars.
• Late Congenital Syphilis (Manifesting ≥ 2 years of age / Developmental Stigmata):
  • The Hutchinson Triad: 1) Hutchinson teeth (widely spaced, barrel-shaped, notched upper permanent central incisors); 2) Interstitial keratitis (bilateral chronic corneal inflammation leading to opacification and blindness); 3) Sensorineural Eighth nerve deafness.
  • Mulberry (Moon) Molars: First lower permanent molars with hypoplastic, multiple dwarfed cusps.
  • Saddle Nose: Depressed nasal bridge secondary to destructive gummatous necrosis of nasal cartilage.
  • Saber Shins: Marked anterior convexity and periosteal thickening of the tibia.
  • Higouménakis Sign: Unilateral thickening of the sternal third of the clavicle.
  • Clutton Joints: Painless, symmetrical hydrarthrosis, classically affecting the knees.

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Master Syphilis Staging Reference Table

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Diagnostic Serology Algorithm (European IUSTI Guidelines)

Laboratory confirmation relies on two broad categories of serological assays: Treponemal tests and Non-treponemal tests.

1. Test Characteristics

• Treponemal Tests: Detect antibodies directed against specific T. pallidum protein antigens. Methodologies include Enzyme Immunoassays (EIA), Chemiluminescence Immunoassays (CLIA), T. pallidum Particle Agglutination (TPPA), T. pallidum Hemagglutination Assay (TPHA), and Fluorescent Treponemal Antibody Absorbed (FTA-ABS). Treponemal tests are qualitative (reported as positive/negative) and remain positive for life in over 85% to 90% of individuals regardless of successful treatment (the serological scar).
• Non-Treponemal Tests: Detect non-specific antibodies (reagin) directed against cardiolipin-lecithin-cholesterol antigen complexes released from host cells damaged by treponemal infection. Standard assays include the Venereal Disease Research Laboratory (VDRL) and Rapid Plasma Reagin (RPR) tests. Non-treponemal tests are quantitative and reported as serial dilution titers (e.g., 1:1, 1:2, 1:4, 1:8, 1:16, 1:32, 1:64). The titer reflects biological disease activity and serves as the clinical standard for monitoring response to therapy.

2. Screening Algorithms in the 2020 IUSTI European Guideline

The 2020 IUSTI guideline accepts three screening approaches: treponemal-test (TT) first, non-treponemal-test (NTT) first, or both together. TT-first screening, preferably with an automated EIA/ELISA/CLIA, is used in many large European laboratories because it suits high-throughput testing and is more sensitive for very early syphilis than NTT-first screening:

1. Screening Assay: An automated treponemal test (EIA/ELISA/CLIA, or TPHA/TPPA).
   • If Negative: Syphilis is unlikely. If a very early chancre is suspected, use darkfield microscopy or PCR on the lesion and repeat serology later; combined TT + NTT screening helps when suspicion of very early syphilis is high.
   • If Positive: Proceed to Step 2.
2. Reflex Quantitative Non-Treponemal Assay: A quantitative RPR or VDRL should be performed on the same serum in all TT-positive cases (titrated to at least 1:8 to 1:16).
   • If RPR/VDRL is Positive: Consistent with active infection (or recent treatment); stage clinically and use the titre as the baseline for monitoring.
   • If RPR/VDRL is Negative: With no chancre and no suspicion of very early syphilis, repeat both tests after 1 month.
3. Confirmatory Treponemal Assay: Because CLIA and EIA have suboptimal specificity in low-prevalence populations, a reflex confirmatory TPHA or TPPA should be performed when these assays are used for screening.
   • If the Confirmatory Test is Positive with a Negative NTT: Possible explanations are a) previously treated syphilis with persistent treponemal antibodies; b) very early primary syphilis before non-treponemal antibodies emerge; or c) late latent syphilis in which non-treponemal titres have waned. Review treatment history and examine the patient.
   • If the Confirmatory Test is Negative: The screening result was probably a false positive.

3. Critical Serological Diagnostic Traps

• The Prozone Phenomenon: In patients with high concentrations of antibodies (most frequently encountered in florid secondary syphilis and in pregnant or HIV-coinfected individuals), an extreme excess of antibodies prevents optimal antigen-antibody lattice cross-linking. This results in a false-negative or spuriously low non-treponemal test (RPR/VDRL). When high clinical suspicion exists for secondary syphilis despite a negative RPR, the clinician must explicitly instruct the laboratory to dilute the serum specimen (e.g., 1:16, 1:64) to unmask the true high titer.
• Biological False-Positive (BFP) Non-Treponemal Tests: Occur when non-treponemal antibodies are stimulated by conditions other than syphilis. Acute BFP (<6 months duration) is associated with acute viral infections (EBV, hepatitis, varicella), malaria, immunization, and pregnancy. Chronic BFP (≥6 months duration) is seen in antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE), chronic liver disease, advanced age, and intravenous drug use. In BFPs, the non-treponemal test is reactive (usually titer ≤ 1:4), but all confirmatory treponemal tests are strictly negative.

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The Jarisch-Herxheimer Reaction (JHR)

The Jarisch-Herxheimer reaction is an acute, self-limiting systemic inflammatory response triggered within 2 to 24 hours (peak 6–8 hours) following the initiation of effective antimicrobial therapy for spirochetal infections, predominantly syphilis:

• Pathophysiology: Caused by the rapid, massive lysis of treponemes upon exposure to bactericidal agents (principally penicillin). This sudden degradation releases endotoxin-like pyrogenic bacterial lipoproteins into the circulation, precipitating an intense systemic inflammatory cascade with massive surges of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8).
• Clinical Presentation: Characterized by abrupt high fever, shaking rigors, tachycardia, mild hypotension, flushing, diaphoresis, headache, arthralgias, and transient exacerbation of existing cutaneous syphilides.
• Epidemiology: Common after treatment of early syphilis (10% to 25% in the 2020 IUSTI guideline) and more frequent with penicillin than with doxycycline. It is uncommon in late syphilis but can be dangerous when strategic sites are involved (coronary ostia, larynx, nervous system).
• Clinical Management: The JHR is self-limited, resolving spontaneously within 12 to 24 hours. Management is supportive with oral antipyretics and analgesics (paracetamol, ibuprofen). Crucial examination pearl: The Jarisch-Herxheimer reaction is NOT an allergic reaction to penicillin! Penicillin therapy must NEVER be discontinued or withheld because of a JHR.
• High-Risk Considerations:
  • Pregnancy: In pregnant patients treated in the second or third trimester, the JHR can induce uterine contractions, premature labor, and transient fetal distress. Pregnant women must be counseled and monitored in an obstetric setting equipped for fetal cardiotocography (CTG), but antimicrobial treatment must not be delayed.
  • Cardiovascular, Neurological & Ocular Syphilis: Inpatient management is advisable. To reduce the risk of focal inflammatory complications (e.g., coronary ostial swelling or worsening optic neuritis), IUSTI suggests prednisolone 20–60 mg daily for 3 days, starting syphilis treatment 24 hours after the first prednisolone dose (low-grade evidence).

European IUSTI Treatment Guidelines

Penicillin G remains the gold standard treatment for syphilis; Treponema pallidum has never developed biological resistance to penicillin.

1. Primary, Secondary, and Early Latent Syphilis (< 1 Year Duration)

• First-Line Regimen: Benzathine Penicillin G 2.4 million units IM as a single dose (administered either as a single 2.4 MU injection or divided into two 1.2 MU injections into each buttock at the same visit).
• Second-Line (if BPG is unavailable): Procaine penicillin 600,000 units IM daily for 10–14 days.
• Bleeding Disorders (intramuscular injection unsuitable): Ceftriaxone 1 g IV daily for 10 days, or doxycycline 200 mg daily for 14 days.
• Penicillin Allergy or Parenteral Treatment Refused (Non-Pregnant): Doxycycline 200 mg daily (100 mg twice daily or 200 mg once) orally for 14 days.
• Azithromycin: Excluded as an alternative at any stage because of widespread macrolide resistance.

2. Late Latent, Latent of Unknown Duration, Gummatous & Cardiovascular Syphilis

• First-Line Regimen: Benzathine Penicillin G 2.4 million units IM once weekly for 3 consecutive weeks (administered on Days 1, 8, and 15; cumulative dose: 7.2 million units).
• Second-Line (if BPG is unavailable): Procaine penicillin 600,000 units IM daily for 17–21 days.
• Timing and Missed Doses: The IUSTI guideline does not give a missed-dose rule. Commonly used US (CDC) guidance accepts an interval of up to 14 days between doses in non-pregnant patients before the course is restarted; in pregnancy, 7–9 days is optimal and a missed dose means repeating the full course.
• Penicillin Allergy or Parenteral Treatment Refused (Non-Pregnant): Doxycycline 200 mg daily orally for 21 to 28 days. Some specialists prefer penicillin desensitisation because the evidence for non-penicillin regimens is weak.

3. Neurosyphilis, Ocular Syphilis, and Otosyphilis

Benzathine penicillin fails to achieve treponemicidal levels in the cerebrospinal fluid (CSF) and is strictly contraindicated for active neurological, ocular, or otic involvement.

• First-Line Regimen: Benzylpenicillin 18 to 24 million units IV daily, given as 3 to 4 million units every 4 hours, for 10 to 14 days.
• Second-Line (if hospitalisation and IV benzylpenicillin are impossible): Ceftriaxone 1–2 g IV daily for 10 to 14 days, OR procaine penicillin 1.2 to 2.4 million units IM daily PLUS oral probenecid 500 mg four times daily, both for 10 to 14 days.
• Penicillin Allergy: Desensitisation to penicillin followed by the first-line regimen.

4. Syphilis in Pregnancy

• Penicillin is the treatment of choice. IUSTI recommends benzathine penicillin G 2.4 million units IM (single dose for early syphilis), with procaine penicillin 600,000 units daily for 10–14 days if BPG is unavailable. Penicillin is the agent with proven efficacy for preventing congenital syphilis.
• Contraindicated Alternatives:
  • Doxycycline and Tetracyclines: Strictly contraindicated due to embryotoxicity, permanent fetal tooth discoloration, and inhibition of fetal bone growth.
  • Macrolides (Azithromycin, Erythromycin): Strictly contraindicated due to rampant T. pallidum 23S rRNA gene mutations causing clinical treatment failure, combined with extremely poor transplacental drug penetration (leaving the infected fetus untreated despite maternal clearance).
• Management of Penicillin Allergy in Pregnancy: IUSTI recommends penicillin desensitisation followed by the first-line penicillin regimen, carried out in a hospital setting with resuscitation facilities.

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Serological Monitoring and Definition of Cure

Therapeutic success is established exclusively through quantitative non-treponemal titers (RPR or VDRL):

• Follow-up Protocol (IUSTI 2020): After early syphilis, minimum clinical and serological (RPR/VDRL) follow-up at 1, 3, 6, and 12 months. In late latent syphilis the NTT response is often absent, and in HIV-negative patients with a stable low-titre NTT, follow-up after treatment is generally not needed.
• Adequate Response: A four-fold (two-dilution) or greater decline in the non-treponemal titre within 6 months of treating early syphilis. About 15% of HIV-negative patients do not reach this by 6 months; they should be retested at 12 months.
  • Example: A pre-treatment titer of 1:32 declining to 1:8 or lower (a drop from 1:32 → 1:16 → 1:8 represents two dilution steps, or a 4-fold decline).
• The "Serofast" State: Some treated patients keep a persistent low non-treponemal titre (≤4). IUSTI advises strict follow-up, but in the absence of ongoing risk these patients are considered successfully treated. With persistent titres of 8 or more, CSF examination may be considered.
• Serological Failure: No four-fold decline after 6–12 months. Some experts give an additional course of BPG 2.4 million units weekly for 3 weeks, although robust evidence is lacking.
• Reinfection or Relapse: A four-fold (two-dilution) rise in titre (e.g., from 1:4 to 1:16) suggests reinfection or relapse; retreat according to stage and rescreen sexual partners.