Syphilis

Syphilis is a predominantly sexually transmitted bacterial infection caused by the spirochete Treponema pallidum. The disease presentation consists of four distinct, successive clinical stages if left untreated. Primary syphilis manifests with a painless chancre (primary lesion), typically on the genitals. Secondary syphilis is characterized by a polymorphic, maculopapular rash that appears on the palms and soles. The first two stages are followed by an asymptomatic phase (latent syphilis), which may last indefinitely or progress to tertiary syphilis. During the tertiary stage, characteristic granulomas (gumma) may appear, which can cause irreversible organ damage, particularly in the cardiovascular system (e.g., syphilitic aortic aneurysm). Neurosyphilis, ocular syphilis, and otosyphilis are serious manifestations that can occur at any stage of infection. Treponemal or nontreponemal serological studies are used for screening, and diagnosis is typically made based on clinical assessment and the interpretation of the syphilis serologies. Alternatively, the diagnosis can be made using tests that directly detect T. pallidum (e.g., darkfield microscopy, PCR) if a specimen of infected tissue is obtainable. First-line treatment for syphilis is penicillin G; allergen sensitization should be initiated in patients with a penicillin allergy.

• Sex: ♂ > ♀ (8:1)
• Incidence: 13.5/100,000 per year in the US
• Peak incidence: 25–29 years

References:^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Pathogen: Treponema pallidum: gram-negative, spiral-shaped bacteria belonging to the spirochete family
• Transmission ^[2][3]
  • Sexual contact (via small mucocutaneous lesions)
  • Vertical
  • Blood transfusion or organ donations (rare)

Treponema bacteria (particularly during stages I and II) are highly contagious.

• Spirochetes invade the body → disseminate systemically within hours → bind to endothelial cells → inflammatory reaction → endarteritis and perivascular inflammatory infiltrates ^[2]

See “Subtypes and variants” for details on neurosyphilis, ocular syphilis, and otosyphilis, which can occur at any stage of infection.

Incubation period ^[4]

• 10–90 days
• On average 21 days

Primary syphilis

• Localized disease
  • 90–95%: genital primary syphilis
  • 5–10%: extragenital primary syphilis (most commonly, the oral cavity, finger, and anus or perianal region)
• Primary lesion (chancre)
  • Typically starts out as a solitary, raised papule (usually on the genitals)
  • Evolves into a painless, firm ulcer with indurated borders and smooth base
  • Resolves spontaneously within 3–6 weeks, typically without scarring ^[4]
• Nontender regional lymphadenopathy (e.g., involvement of the inguinal lymph nodes in genital primary syphilis)

Secondary syphilis

• Disseminated disease due to the systemic spread of the spirochetes, inducing an immunologic reaction
• Begins approx. 2–12 weeks after primary infection and typically lasts 2–6 weeks ^[5]
• Constitutional symptoms
  • Generalized nontender lymphadenopathy
  • Fever, fatigue, myalgia, headache
• Polymorphic rash
  • Typically disseminated, nonpruritic macular or papular rash
  • Involves trunk and extremities, also the palms and soles
  • Reddish-brown or copper-colored
  • Heals within 6 months, but may recur
• Condylomata lata
  • Broad-based, wart-like, smooth, white papular erosions
  • Painless
  • Located in the anogenital region, intertriginous folds, and on oral mucosa
• Additional lesions
  • Patchy alopecia (moth-eaten alopecia)
  • Sore throat (acute syphilitic tonsillitis)
• Special variant of secondary syphilis: malignant syphilis
  • Severe clinical course in the setting of underlying immunosuppression (e.g., concurrent HIV infection)
  • Multiple necrotic ulcerations

Remember that Secondary Syphilis causes Systemic Symptoms.

Latent syphilis

• No clinical symptoms, despite seropositivity
• May last months, years, or even for the entire life of the patient
• Disease may resolve, reactivate, or progress to tertiary syphilis
• Early latent: acquired within the last year
• Late latent: acquired > 1 year ago

Tertiary syphilis

Gumma

• Chronic, destructive granulomatous lesions with a necrotic center that tend to ulcerate
• May affect any organ, e.g., skin, internal organs, bones

Cardiovascular syphilis

• Aortitis, ascending aortic aneurysm (thoracic aortic aneurysm), syphilitic mesaortitis, aortic root dilation and insufficiency
• Due to Treponema-induced vasculitis of the vasa vasorum of the large vessels (especially the aorta), resulting in vessel wall atrophy, and thereby, aneurysm formation

Neurosyphilis ^[6][7]

• Definition: Neurosyphilis is an infection with treponemal invasion of the CNS (e.g., meninges, cerebral vasculature and/or parenchyma). The diagnosis is based on characteristic clinical features in conjunction with supportive CSF findings.
• Epidemiology: can occur at any stage of infection
  • ∼ 0.8 % of infected individuals with early syphilis ^[8]
  • More common in states of immunosuppression (e.g., coinfection with HIV)
• Clinical features: highly variable
  • Acute syphilitic meningitis (e.g., neck stiffness, nausea)
  • Subacute stroke, meningitis, and/or cranial nerve disorders
  • Paretic neurosyphilis: chronic, progressive meningoencephalitis, resulting in widespread cerebral atrophy and major neurocognitive disorder
    • Early manifestations include personality changes and deficits of memory and judgment.
    • Can cause neurologic symptoms, including dysarthria, hypotonia, and tremors
  • Argyll Robertson pupil
    • Bilateral miosis
    • Pupils accommodate but do not react to direct or indirect light.
  • Tabes dorsalis (syphilitic myelopathy): demyelination of the dorsal columns and the dorsal root ganglia
    • Impaired proprioception → progressive sensory broad-based ataxia (Romberg test is positive)
    • Absent deep tendon reflexes
    • Dysesthesias
      • Loss of sensation, predominantly in the lower extremities
      • Sharp, shooting pain in the legs and the abdomen
    • Charcot joint
• Diagnostics: CSF studies must be interpreted in the clinical context. Supportive findings are listed.
  • Reactive; Venereal Disease Research Laboratory test (VDRL)
  • Lymphocytic pleocytosis
    • HIV negative: > 5 WBC/mm³
    • HIV positive: > 20 WBC/mm³
  • Elevated protein
  • Positive fluorescent treponemal antibody absorption test
• Treatment: penicillin; See “Treatment of syphilis” for details.

Patients with syphilis but without neurosyphilis can have unexplained CSF abnormalities. In patients with clinical features of neurosyphilis, a reactive CSF-VDRL strongly supports the diagnosis. ^[6]

Other ^[6]

• Otosyphilis: infection affecting the cochleovestibular system
  • Epidemiology: can occur at any stage of infection
  • Clinical features: tinnitus, vertigo, and/or sensorineural hearing loss (unilateral or bilateral)
• Ocular syphilis: infection affecting the eye
  • Epidemiology: can occur at any stage of infection
  • Clinical features: eye pain or redness, floaters, light sensitivity, blurry vision, and/or permanent vision loss
• Syphilis during pregnancy: See “Congenital syphilis.”

Approach

• Perform a focused clinical evaluation that includes exposure history.
• Order both nontreponemal tests and treponemal tests for:
  • Patients with clinical features of syphilis
  • Individuals with risk factors for syphilis infection ^[9]
  • Pregnant individuals at the first prenatal visit ^[10]
• Order direct detection in patients with suitable skin lesions, e.g., exudative chancre, condyloma.
• Consider additional studies (e.g., lumbar puncture) based on the clinical assessment.

Clinical evaluation ^[6]

• All patients
  • Exposure history and any prior syphilis diagnoses
  • Examination of skin and mucosal surfaces (e.g., oral cavity, rectum, vagina, cervix)
• Patients with visual or hearing symptoms
  • Focused sensory assessment (e.g., visual acuity, focused hearing exam)
  • Cranial nerve exam
• Patients with neurological deficits : complete neurologic examination

A detailed assessment of exposure history is essential for distinguishing early latent syphilis (infected ≤ 1 year) versus late latent syphilis (infected > 1 year) in asymptomatic seropositive patients. ^[6]

Serological studies ^[7]

Nontreponemal tests (NTT) ^[6][11]

• Indications
  • Initial screening
  • Monitoring response to treatment, i.e., with titer level
  • Assessing for syphilis reinfection ^[6]
• Mechanism: quantitative detection of antibodies against lipoidal antigens, e.g., cardiolipin
• Types: both have comparable performance, are widely available, and cost-efficient
  • Rapid plasma reagin (RPR): most commonly used test
  • Venereal Disease Research Laboratory test (VDRL): often used in the evaluation of cerebrospinal fluid for neurosyphilis ^[12]
• Accuracy: highly sensitive but nonspecific; positive in ∼ 62–78% of patients with primary syphilis ^[12]
  • False-negative NTT:
    • Early primary syphilis
    • Prozone phenomenon
    • Longstanding untreated syphilis with seroreversion
  • False-positive NTT: due to cross-reacting antibodies ^[12][13]
    • Autoimmune (e.g., systemic lupus erythematosus, rheumatoid arthritis)
    • Infections (e.g., malaria, leprosy, Epstein-Barr virus, viral hepatitis)
    • Rheumatic fever ^[14]
    • Pregnancy
    • Prescription drugs (e.g., chlorpromazine, procainamide) ^[15]
    • Intravenous drug use
• Important considerations: : After infection, NTT titers can undergo seroreversion and convert to negative even if syphilis is not treated.

False-Positive results on VDRL with Pregnancy, Viral infection (e.g., EBV, hepatitis), Drugs (e.g., chlorpromazine, procainamide), Rheumatic fever (rare), Lupus, and Leprosy

Treponemal tests (TT) ^[11][13]

• Indications
  • Initial screening
  • Confirmatory test in the standard testing algorithm
• Mechanism: : qualitative detection of antibodies to treponemal antigens
• Types: Many TTs exist; examples of common types are listed here.
  • Fluorescent treponemal antibody absorption test (FTA-ABS)
  • Treponema pallidum particle agglutination (TPPA)
  • IgG/IgM immunoassay (enzyme or chemiluminescence)
• Accuracy
  • New infection: high sensitivity and specificity
    • False-negative TT: early primary syphilis
    • False-positive TT: inflammatory diseases (e.g., SLE); infections (e.g., Lyme disease) ^[16]
  • Reinfection: limited sensitivity and specificity ^[17]
• Important considerations: After infection, TT titer typically stays positive indefinitely.

Testing algorithms ^[13]

Standard and reverse testing algorithms involve both NTT and TT to reduce the chance of false-positive and false-negative results. ^[6]

• Standard algorithm
  • Nontreponemal test (NTT) first
  • If positive, perform a treponemal test (TT)
• Reverse algorithm ^[13]
  • TT first
  • If positive, perform an NTT
  • If NTT is negative, perform a second TT.

Interpretation

• Interpret serology results based on the clinical context (i.e., clinical features, risk factors, treatment history).
• Consider consulting an infectious disease specialist for assistance with interpreting serology results.

Serologic tests may be negative in early syphilis. If there is high clinical suspicion, repeat serologic testing after 2–4 weeks. Alternatively, if a suitable lesion exists, order a direct pathogen test (e.g., darkfield microscopy, PCR) to establish the diagnosis. ^[7][18]

Direct detection ^[11]

• Indication: the presence of a rash or lesions consistent with syphilis, e.g., exudative chancre, condyloma ^[6]
• Methods: Detection requires specialized laboratory equipment since T. pallidum cannot be cultivated in vitro or visualized with light microscopy. ^[19]
  • Darkfield microscopy: visualization of motile spirochetes on wet mount under a dark-field microscope ^[11]
  • Direct fluorescent antibody for T. pallidum: visualization of immunofluorescent antibodies on the specimen
  • Nucleic acid amplification (e.g., PCR)
  • Immunohistopathology
• Accuracy: gold standard to detect primary and secondary syphilis; high specificity but nonsensitive

Additional studies ^[6]

After confirming syphilis infection, order the following studies based on the clinical scenario.

• All patients: screening for sexually transmitted infections (e.g., HIV, gonorrhea, chlamydia)
• Patients of childbearing age: pregnancy test
• Suspected neurosyphilis
  • Lumbar puncture prior to initiating treatment
  • See “Subtypes and variants” for details on interpreting CSF studies. ^[6][7]
• Suspected ocular syphilis or otosyphilis: functional sensory testing (e.g., audiogram, slit lamp examination)

No single finding can establish a diagnosis of neurosyphilis, ocular syphilis, or otosyphilis. These diagnoses can occur at any stage of infection and, if suspected, require prompt evaluation by a specialist. ^[6]

Imaging ^[20]

• Indication: concern for cardiovascular syphilis (e.g., reports of chest pain, dyspnea)
• Modalities
  • Initial study: CT or MRI chest with contrast
  • If inconclusive: angiography
• Findings ^[21]
  • Aneurysms of the thoracic aorta or aortic arch
  • Heavy aortic calcification: may include the aortic root, ascending aorta, aortic arch, and thoracic aorta

Intimal calcifications of the aorta may have a tree bark appearance on CT or MRI. ^[22]

General principles ^[6]

• Initiate antibiotic treatment in patients with:
  • Confirmed syphilis infection
  • Suspected early infection (prior to seroconversion, history of sexual contact with an infected person)
• Inform patients about the possibility of a Jarisch-Herxheimer reaction to treatment.
• Assess for treatment response with NTT titer.
• Consult infectious disease for assistance with complex cases , and specialists for affected organs (e.g., ophthalmology for ocular syphilis).

All sexual contacts of a patient with syphilis should be identified, evaluated, and treated.

Antibiotic therapy ^[6]

• Penicillin G is the first-line therapy for all patients.
• Patients with confirmed penicillin allergy
  • For patients with neurosyphilis; , ocular syphilis, otosyphilis, and/or during pregnancy, initiate allergen desensitization and treat with penicillin.
  • For all other patients, consider, e.g., doxycycline or ceftriaxone.

If neurosyphilis is suspected, perform a lumbar puncture and CSF analysis before starting treatment.

Posttreatment assessment ^[6]

• Perform a clinical evaluation and measure NTT titers at 6 and 12 months after treatment. ^[6]
• Compare NTT titers to pretreatment results.
  • NTT titer decreased by ≥ fourfold: successful treatment response
  • Unchanged NTT titers within 12 months: treatment failure or serofast state
  • NTT titer increased by ≥ fourfold after successful treatment: reinfection

Either type of NTT (i.e., RPR or VDRL) may be used to assess treatment response, but do not compare across types when assessing the trend in titers. For example, a titer for RPR can only be compared to prior titers of RPR.

• Jarisch-Herxheimer reaction: acute, transient, systemic reaction to bacterial endotoxin-like substances and pyrogens that are released after initiation of antibiotic therapy ; ^[23][24][25]
  • Epidemiology
    • Commonly seen during treatment of infections with spirochetes (Borrelia, Leptospira)
    • In syphilis, the Jarisch-Herxheimer reaction is most often seen if treatment begins in the early phases of the secondary stage.
  • Clinical features
    • Flu-like symptoms: fever, chills, headache, myalgia
    • Accompanied by tachypnea, hypotension, and tachycardia
    • Syphilitic exanthema may flare up
    • Usually self-limiting within 12–24 hours
  • Treatment
    • NSAIDs for symptomatic treatment
    • May consider meptazinol
• Chorioretinitis ^[26]

We list the most important complications. The selection is not exhaustive.

• Condoms prevent the transmission of syphilis and other STIs.
• Syphilis is a nationally notifiable disease. ^[27]
• Screen at least once in every pregnancy ^[10]

• One-Minute Telegram 65-2022-1/3: 2022 U.S. Preventive Services Task Force: summary of recommendations

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