Syphilis (Treponema pallidum)

Overview

Plain-Language Overview

Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum. It primarily affects the skin, mucous membranes, and nervous system. The infection progresses through distinct stages, each with different symptoms, including painless sores, rashes, and potentially serious complications if untreated. It can spread through direct contact with infectious lesions during sexual activity. If left untreated, it can cause damage to the heart, brain, and other organs. Early detection and diagnosis are important to prevent long-term health problems.

Clinical Definition

Syphilis is a chronic systemic infection caused by the spirochete bacterium Treponema pallidum. It is transmitted primarily through sexual contact and progresses through primary, secondary, latent, and tertiary stages. The primary stage is characterized by a painless chancre at the site of inoculation. Secondary syphilis presents with a widespread maculopapular rash and mucocutaneous lesions. Latent syphilis is asymptomatic but serologically positive. Tertiary syphilis can cause gummatous lesions, cardiovascular syphilis, and neurosyphilis, which have significant morbidity. Diagnosis relies on serologic testing and clinical findings.

Inciting Event

Direct contact with infectious lesions during sexual activity initiates infection.
Exposure to infectious mucous membranes or abraded skin allows spirochete entry.
Vertical transmission from mother to fetus during pregnancy or delivery.

Latency Period

Primary syphilis develops within 10-90 days after exposure, typically around 3 weeks.
Secondary syphilis symptoms appear 4-10 weeks after the primary chancre.
Latent syphilis can last months to years without symptoms before tertiary manifestations.
Congenital syphilis symptoms may present at birth or within the first few months of life.

Diagnostic Delay

Painless chancre often goes unnoticed leading to missed primary diagnosis.
Non-specific secondary symptoms such as rash and lymphadenopathy mimic other diseases.
Lack of routine screening in asymptomatic individuals delays detection during latency.
False-negative serologic tests in early primary syphilis can complicate diagnosis.
Misattribution of neurological or cardiovascular symptoms to other causes delays recognition of tertiary syphilis.

Clinical Presentation

Signs & Symptoms

Painless genital ulcer (chancre) is the hallmark of primary syphilis.
Diffuse rash involving palms and soles occurs in secondary syphilis along with systemic symptoms like fever.
Mucous patches and condyloma lata are common mucocutaneous manifestations in secondary syphilis.
Patchy hair loss (moth-eaten alopecia) can be seen in secondary syphilis.
Neurosyphilis symptoms include headache, cranial nerve palsies, and cognitive changes.
Cardiovascular syphilis may present with chest pain or heart failure symptoms in tertiary disease.

History of Present Illness

Painless ulcer (chancre) at the site of inoculation marks primary syphilis onset.
Generalized maculopapular rash including palms and soles develops in secondary syphilis.
Systemic symptoms such as fever, malaise, and lymphadenopathy accompany secondary stage.
Asymptomatic latent phase follows secondary syphilis with no clinical signs.
Late manifestations include gummatous lesions, aortitis, and neurosyphilis presenting months to years later.

Past Medical History

Previous sexually transmitted infections increase risk of syphilis acquisition.
HIV infection alters clinical course and increases risk of neurosyphilis.
History of untreated or inadequately treated syphilis predisposes to tertiary disease.
Prior antibiotic use may partially treat syphilis and mask symptoms.

Family History

Congenital syphilis occurs in infants born to untreated infected mothers.
No known heritable genetic predisposition to syphilis infection or progression.
Family history of sexually transmitted infections may indicate shared risk behaviors.

Physical Exam Findings

A painless chancre with a clean base and indurated border is typical in primary syphilis.
Generalized, non-tender lymphadenopathy often accompanies early infection.
Diffuse maculopapular rash involving the palms and soles is characteristic of secondary syphilis.
Condyloma lata, broad-based, moist, wart-like lesions in intertriginous areas, appear in secondary syphilis.
Gummas, granulomatous lesions, may be found in tertiary syphilis affecting skin, bone, or organs.

Physical Exam Maneuvers

Darkfield microscopy of lesion exudate helps visualize Treponema pallidum in primary or secondary lesions.
Neurological examination including cranial nerves and reflexes assesses for neurosyphilis involvement.
Cardiovascular examination evaluates for aortic regurgitation or aneurysm in tertiary syphilis.
CSF analysis via lumbar puncture is performed to diagnose neurosyphilis in symptomatic patients.
Serologic testing algorithms (nontreponemal followed by treponemal tests) guide diagnosis and staging.

Common Comorbidities

HIV infection frequently co-occurs and alters syphilis presentation and progression.
Other sexually transmitted infections such as gonorrhea and chlamydia are common in affected populations.
Hepatitis B and C infections may coexist due to shared transmission routes.
Pelvic inflammatory disease can be a comorbidity in women with genital ulcers.
Secondary bacterial infections of syphilitic lesions may complicate the clinical picture.

Diagnostic Workup

Diagnostic Criteria

Diagnosis of syphilis is established by a combination of clinical findings and serologic tests. Initial screening is typically done with a nontreponemal test such as the Rapid Plasma Reagin (RPR) or Venereal Disease Research Laboratory (VDRL) test. Positive results are confirmed with a treponemal-specific test like the Fluorescent Treponemal Antibody Absorption (FTA-ABS) or Treponema pallidum particle agglutination assay (TP-PA). Direct visualization of Treponema pallidum by darkfield microscopy from lesion exudate can also confirm early infection. Diagnosis requires correlation of test results with clinical presentation.

Pathophysiology

Key Mechanisms

Spirochete invasion of mucous membranes or skin leading to local infection and systemic dissemination.
Immune-mediated inflammation causing characteristic lesions such as chancres and gummas.
Endarteritis obliterans resulting in ischemic tissue damage in tertiary syphilis.
Neurosyphilis due to direct invasion of the central nervous system by Treponema pallidum.
Placental transmission causing congenital syphilis with multisystem involvement.

Involvement	Details
Organs	Heart can be affected in tertiary syphilis causing syphilitic aortitis and aneurysm formation.
	Central nervous system involvement in neurosyphilis leads to meningitis, stroke, and cognitive decline.
	Liver may show periportal inflammation and granulomas in secondary syphilis.
Tissues	Skin is the primary site of chancre formation in primary syphilis and rash in secondary syphilis.
	Mucous membranes of the genitalia and oral cavity are commonly involved in syphilitic lesions and transmission.
	Blood vessels can develop endarteritis obliterans in tertiary syphilis, leading to ischemic tissue damage.
Cells	Plasma cells produce antibodies against Treponema pallidum during the immune response in syphilis.
	Macrophages phagocytose spirochetes and present antigens to activate adaptive immunity in syphilitic lesions.
	T helper cells coordinate the immune response by releasing cytokines that recruit other immune cells to infected tissues.
Chemical Mediators	Tumor necrosis factor-alpha (TNF-α) is elevated in syphilitic inflammation and contributes to tissue damage and granuloma formation.
	Interferon-gamma (IFN-γ) activates macrophages to enhance killing of Treponema pallidum in infected tissues.
	C-reactive protein (CRP) levels may be elevated as a nonspecific marker of systemic inflammation in secondary syphilis.

Treatments

Pharmacological Treatments

Benzathine penicillin G
- Mechanism:
  - Inhibits bacterial cell wall synthesis by binding penicillin-binding proteins, leading to lysis of Treponema pallidum.
- Side effects:
  - Jarisch-Herxheimer reaction
  - Allergic reactions
  - Injection site pain
- Clinical role:
  - First-line
Doxycycline
- Mechanism:
  - Inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit, effective against Treponema pallidum in penicillin-allergic patients.
- Side effects:
  - Photosensitivity
  - Gastrointestinal upset
  - Tooth discoloration in children
- Clinical role:
  - Second-line
Ceftriaxone
- Mechanism:
  - Third-generation cephalosporin that inhibits bacterial cell wall synthesis, used as an alternative in penicillin allergy.
- Side effects:
  - Allergic reactions
  - Biliary sludge
  - Injection site reactions
- Clinical role:
  - Second-line

Non-pharmacological Treatments

Counseling on safe sexual practices to prevent transmission of syphilis.
Regular follow-up with serologic testing to monitor treatment response and detect reinfection.
Screening and treatment of sexual partners to control spread of Treponema pallidum.

Prevention

Pharmacological Prevention

Benzathine penicillin G administered to exposed individuals prevents progression to active disease.
Post-exposure prophylaxis with penicillin is recommended for sexual contacts of infectious cases.
Routine screening and early treatment in high-risk populations reduce transmission rates.
HIV pre-exposure prophylaxis (PrEP) indirectly reduces syphilis risk by decreasing risky sexual behaviors.
Treatment of co-infections with appropriate antibiotics helps prevent syphilis complications.

Non-pharmacological Prevention

Consistent condom use significantly reduces transmission of Treponema pallidum during sexual activity.
Regular screening of high-risk populations enables early detection and treatment.
Partner notification and treatment prevent reinfection and further spread.
Abstinence or mutual monogamy with an uninfected partner effectively prevents syphilis.
Education on safe sexual practices is critical for reducing incidence in vulnerable groups.

Outcome & Complications

Complications

Neurosyphilis causing meningitis, tabes dorsalis, or general paresis is a serious complication.
Cardiovascular syphilis can lead to aortitis, aortic aneurysm, or aortic valve insufficiency.
Congenital syphilis results from vertical transmission causing severe fetal and neonatal morbidity.
Gummatous lesions cause tissue destruction in skin, bone, and other organs.
Jarisch-Herxheimer reaction is an acute febrile response to antibiotic treatment.

Short-term Sequelae	Long-term Sequelae
Resolution of chancre with or without treatment typically occurs within weeks. Secondary syphilis rash and systemic symptoms may resolve spontaneously or with therapy. Jarisch-Herxheimer reaction occurs within hours of initiating treatment causing fever and malaise. Transient lymphadenopathy often persists during early infection phases. Mucous patches and condyloma lata may heal or persist depending on treatment.	Neurosyphilis can cause irreversible neurological deficits if untreated. Aortic aneurysm and valvular heart disease develop in tertiary syphilis over years. Gummatous destruction leads to chronic tissue damage and deformities. Blindness from optic nerve involvement or interstitial keratitis may occur in late disease. Congenital syphilis sequelae include bone deformities, deafness, and developmental delays.

Short-term Sequelae

Long-term Sequelae

Resolution of chancre with or without treatment typically occurs within weeks.
Secondary syphilis rash and systemic symptoms may resolve spontaneously or with therapy.
Jarisch-Herxheimer reaction occurs within hours of initiating treatment causing fever and malaise.
Transient lymphadenopathy often persists during early infection phases.
Mucous patches and condyloma lata may heal or persist depending on treatment.

Neurosyphilis can cause irreversible neurological deficits if untreated.
Aortic aneurysm and valvular heart disease develop in tertiary syphilis over years.
Gummatous destruction leads to chronic tissue damage and deformities.
Blindness from optic nerve involvement or interstitial keratitis may occur in late disease.
Congenital syphilis sequelae include bone deformities, deafness, and developmental delays.

Differential Diagnoses

Syphilis (Treponema pallidum) versus Herpes Simplex Virus (HSV) Infection

Syphilis (Treponema pallidum)	Herpes Simplex Virus (HSV) Infection
Painless, indurated chancre	Painful vesicular lesions that ulcerate
Single primary lesion with progression through stages	Recurrent episodes of lesions
Positive darkfield microscopy or treponemal antibody test	Positive PCR or viral culture for HSV

Syphilis (Treponema pallidum) versus Chancroid (Haemophilus ducreyi Infection)

Syphilis (Treponema pallidum)	Chancroid (Haemophilus ducreyi Infection)
Painless, hard chancre with clean base	Painful, soft ulcer with ragged edges
Non-tender, rubbery lymphadenopathy	Tender, suppurative inguinal lymphadenopathy
Spirochete visualized by darkfield microscopy	Gram-negative coccobacillus on culture

Syphilis (Treponema pallidum) versus Lymphogranuloma Venereum (Chlamydia trachomatis L1-L3)

Syphilis (Treponema pallidum)	Lymphogranuloma Venereum (Chlamydia trachomatis L1-L3)
Non-tender, rubbery lymphadenopathy	Painful, unilateral inguinal lymphadenopathy with suppuration
Painless, persistent chancre	Small, transient genital ulcer often unnoticed
Positive treponemal antibody test	Positive nucleic acid amplification test for Chlamydia trachomatis L1-L3

Syphilis (Treponema pallidum) versus Granuloma Inguinale (Klebsiella granulomatis Infection)

Syphilis (Treponema pallidum)	Granuloma Inguinale (Klebsiella granulomatis Infection)
Painless, indurated chancre with clean base	Painless, beefy-red granulomatous ulcer that bleeds easily
Presence of spirochetes on darkfield microscopy	Presence of Donovan bodies in macrophages
Primary lesion followed by systemic dissemination if untreated	Chronic progressive ulcer without regional lymphadenopathy

Syphilis (Treponema pallidum) versus Fixed Drug Eruption

Syphilis (Treponema pallidum)	Fixed Drug Eruption
Single painless chancre progressing through syphilis stages	Recurrent, well-demarcated erythematous patches or plaques at same site
History of sexual exposure to infected partner	Recent exposure to offending medication
Progressive disease without treatment	Lesions resolve with drug withdrawal and recur on re-exposure