Treponema pallidum - Syphilis

Diagnosis

Indications for Testing

• Suspicion of syphilis (classic lesions, known exposure, high-risk behaviors)
  • Concurrent STI testing

Laboratory Testing

• Cannot be cultured in vitro
• Darkfield exam only if chancre (primary) or condylomata lata (secondary) present
• Nontreponemal tests – inexpensive and rapid; require treponemal-based confirmation due to modest specificity
  • Rapid plasma reagin (RPR) – if reactive, order titers
  • Venereal disease research laboratory (VDRL) test may be used first but has higher false-positive rate
• Treponemal tests used for confirmation of positive nontreponemal test
  • Microhemagglutination or indirect hemagglutination assay for antibodies to T. pallidum (MHA-TP, TP-PA)
  • Fluorescent treponemal antibody absorption assay (FTA-Abs) – higher rates of false positives than TP-PA
  • IgM antibody detection by enzyme-linked immunosorbent assay (ELISA)
  • IgG antibodies by immunoblot
• Neurosyphilis
  • In suspected cases, order VDRL on cerebrospinal fluid (CSF) with concurrent RPR serum
  • If RPR is negative and a high index of suspicion for neurosyphilis remains, perform FTA-Abs on serum
    • Some patients have non-reactive nontreponemal tests in late neurosyphilis
  • CNS is usually the affected site in an HIV patient
• For further testing recommendations, see the Syphilis Testing Algorithm

Differential Diagnosis

• Genital chancre/ulcer – primary syphilis
  • Herpes simplex virus 
  • Chancroid
  • Lymphogranuloma venereum
  • Behçet disease
• Macular rash – secondary syphilis
  • Contact dermatosis
  • Lichen planus
  • Squamous cell carcinoma
  • Eczema
  • Psoriasis
• Vasculitic syphilis – secondary syphilis
  • Connective tissue disease
  • Vasculitis
  • Chronic hepatitis
    • Hepatitis B
    • Hepatitis C
  • Multiple sclerosis
  • Brucella spp
• Gummatous syphilis – tertiary syphilis
  • Malignancy
  • Sarcoidosis
  • Fungal disease
• Congenital syphilis
  • TORCH-like illness
    • Toxoplasma gondii
    • Rubella virus
    • Cytomegalovirus
    • Herpes simplex virus
    • Parvovirus
  • Inherited syndromes
• CNS syphilis
  • Infectious meningitis
    • Viral
    • Bacterial
    • Fungal – eg, yeasts
    • Parasitic
  • Vasculitis
  • Connective tissue disease
  • Stroke
  • Vitamin deficiency (B₁₂)
  • Dementia
  • Psychiatric disease
  • Antiphospholipid syndrome
  • Diabetic neuropathy

Screening

Monitoring

Clinical Background

Treponema pallidum subspecies pallidum is the causative agent of syphilis, a sexually transmitted infection (STI).

Epidemiology

• Incidence
  • 2-5/100,000
  • Varies by region
  • Incidence has increased in last 5-10 years
• Age – peaks in teens to late 20s
• Transmission    
  • Sexual contact
  • Maternal vertical transmission

Organism

• T. pallidum subspecies pallidum is a member of the Spirochaetales family that causes syphilis and is distinct from the subspecies causing yaws (T. pallidum subspecies pertenue), pinta (T. pallidum subspecies carateum) and endemic syphilis (T. pallidum subspecies endemicum)
• The Spirochaetales family also includes the following
  • Leptospira species
  • Borrelia species, including B. burgdorferi

Risk Factors for Syphilis

• Early age at onset of sexual activity
• HIV infection
• Gonorrhea infection
• Multiple sex partners
• Non-Caucasian race
• Non-use of barrier methods of birth control
• Previous history of STI

Clinical Presentation

• Primary syphilis

  Incubation – 2-3 weeks Painless chancre at site of inoculation – may persist 4-6 weeks Local nontender adenopathy is frequent

  Secondary syphilis

  Incubation – 6-12 weeks Two types Latent and early latent <1 year infection Late latent ≥1 year infection Diffuse lymphadenopathy Mucocutaneous lesions (condyloma lata) – coalescence in genital regions Macular skin rash (frequently involves palms and soles) Widespread syphilitic vasculitis (~10% of cases) Meningitis (rare) Hepatitis Nephritis Iritis Cranial nerve involvement (most commonly, eighth nerve deafness)

  Tertiary (late) syphilis

  Incubation – 5-15 years 15-40% of untreated patients develop disease Cardiovascular – aortitis, aneurysm, aortic valvular incompetence Gummatous syphilis – granulomatous, nodular lesions in organs (most commonly skin and bones) Neurologic – general paresis, tabes dorsalis

  Congenital syphilis

  Can occur during all stages of maternal syphilis – usually in first 2 years of infection One-third of babies born without infection One-third born with congenital syphilis One-third result in miscarriage or stillbirth Typed according to age at diagnosis Early (<2 years, untreated) Snuffles Rash Condyloma lata Bone changes Hepatosplenomegaly Jaundice Anemia Late (>2 years, untreated) Eighth-nerve deafness Arthropathy (Clutton joints) Neurosyphilis Keratitis Residual stigmata Hutchinson teeth Mulberry molars Saddle nose Saber shin Rhagades scars

  Central nervous system (CNS) manifestations

  May occur at any stage Symptomatic forms Meningeal syphilis (usually <1 year after infection) Involves the brain or spinal cord Symptoms include headache, stiff neck Meningovascular syphilis (usually 5-10 years after infection) Inflammation of pia and arachnoid, with focal arteritis Stroke syndrome involving middle cerebral artery is common in young adults Parenchymatous (late syphilis) General PARESIS (acronym for Personality, Affect; Reflexes, Eye [Argyll Robertson pupil], Sensorium, Intellect, Speech) Tabes dorsalis – demyelination of posterior columns, dorsal roots and dorsal root ganglia Results in weakness, paresthesias, ataxia, dementia, personality changes, decreased reflexes Characterized by wide-based gait and bladder symptoms Optic atrophy (Argyll Robertson pupil) frequently associated with tabes dorsalis Charcot joints – trophic joint degeneration May also be asymptomatic

  Coinfection with HIV

  Primary syphilis – multiple, large, painful ulcers Secondary syphilis – genital ulcers more common Tertiary syphilis – possibly more rapid progression to neurosyphilis

Treatment

• All stages of neurosyphilis require treatment to prevent disease progression and sequelae
• Jarisch-Herxheimer reaction sometimes follows initial syphilis treatment
  • Fever/chills
  • Headache
  • Tachypnea
  • Tachycardia
  • Usually lasts <24 hours
  • Supportive care only
• Intrauterine treatment <16 weeks into pregnancy prevents fetal damage

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Treponema pallidum (VDRL), Cerebrospinal Fluid with Reflex to Titer 0050206 Method: Semi-Quantitative Flocculation
Treponema pallidum (Rapid Plasma Reagin) with Reflex to Titer, FTA-ABS and TP-PA 0050011 Method: Semi-Quantitative Charcoal Agglutination/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Particle Agglutination	Follow treatment response Satisfactory first-line test but higher rate of false positives Panel is for clients in states requiring automatic confirmation via treponemal test for all reactive RPR tests
Treponema pallidum (Rapid Plasma Reagin) with Reflex to Titer and TP-PA Confirmation 0050478 Method: Semi-Quantitative Charcoal Agglutination/Semi-Quantitative Particle Agglutination
Treponema pallidum Antibody, IgG by ELISA 0050920 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Treponema pallidum Antibody, IgG by IFA (CSF) 0055273 Method: Semi-Quantitative Indirect Fluorescent Antibody
Treponema pallidum Antibody Panel (FTA-ABS) IgG & IgM 0093067 Method: Qualitative Immunofluorescence Assay (Indirect Fluorescent Antibody)

Diagnostic Algorithm

  Syphilis Testing Algorithm