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 (primary, secondary, latent, and tertiary) 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 the diagnosis is typically made based on clinical assessment and the interpretation of syphilis serologies. Alternatively, the diagnosis can be made using studies 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. Prevention of syphilis includes providing counseling on safe sex practices to all individuals and offering syphilis screening to individuals with indications.

• 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.
• If lesions are present, order direct detection.
• Order both nontreponemal tests and treponemal tests for:
  • Patients with clinical features of syphilis
  • Patients who meet the criteria for screening for syphilis.
• 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 neurological 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]

Direct detection ^[9]

• 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. ^[10]
  • Darkfield microscopy: visualization of motile spirochetes on wet mount under a dark-field microscope ^[9]
  • 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

Serological studies ^[6][7][11]

• Serological studies for syphilis can miss early primary syphilis, as antibodies do not develop until 1–4 weeks after lesions appear. ^[11]
• Syphilis testing algorithms, which combine nontreponemal and treponemal tests, are used to confirm a diagnosis.
• When interpreting results:
  • Consider clinical context (i.e., clinical features, risk factors, treatment history)
  • Be aware that serologic testing may remain positive in patients previously treated for syphilis.
  • Consider consulting an infectious disease specialist for assistance.

Nontreponemal tests (NTT) ^[6][9]

• 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 ^[11][12]
    • Autoimmune (e.g., systemic lupus erythematosus, rheumatoid arthritis)
    • Infections (e.g., malaria, leprosy, Epstein-Barr virus, viral hepatitis)
    • Rheumatic fever ^[13]
    • Pregnancy
    • Prescription drugs (e.g., chlorpromazine, procainamide) ^[14]
    • Intravenous drug use
• Important considerations
  • After infection, NTT titers can undergo seroreversion and convert to negative even if syphilis is not treated.
  • After treatment, NTT titers can remain elevated despite successful treatment (serofast state).

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) ^[9][11]

• 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) ^[15]
  • Reinfection: limited sensitivity and specificity ^[16]
• Important considerations: After infection, TT titer typically stays positive indefinitely.

Syphilis testing algorithms ^[6][11]

Overview of syphilis testing algorithms ^[6][11]

• Either the standard algorithm or reverse algorithm can be used to diagnose syphilis.
• If the initial test is positive, both algorithms require an additional test to confirm the diagnosis.
  • Both tests positive: A current or past infection is likely.
    • Previously treated: Consider possible reinfection, treatment failure, or a serofast state; see “Posttreatment assessment for syphilis.”
    • No previous treatment: active syphilis infection highly likely
  • Second test negative: Next steps vary based on the testing algorithm used.
• If the initial test in either algorithm is negative
  • Low-risk patients: Syphilis is unlikely; no further testing is necessary.
  • High-risk patients
    • Early primary syphilis cannot be excluded.
    • Offer presumptive treatment; if declined, repeat testing.

Standard algorithm ^[6][11]

• Initial test: NTT
  • Positive NTT: Perform a TT.
  • Negative NTT: Further management depends on risk status; see “Overview of syphilis testing algorithms.”
• Second test: TT
  • Positive TT: Current or past syphilis infection is likely; see “Overview of syphilis testing algorithms.”
  • Negative TT
    • False-positive NTT likely
    • If risk factors are present, repeat after 2–4 weeks or, if follow-up is unlikely, consider treating.

Reverse algorithm ^[6][11]

• Initial test: TT
  • Positive TT: Perform an NTT.
  • Negative TT: Further management depends on risk status; see “Overview of syphilis testing algorithms.”
• Second test: NTT
  • Positive NTT: current syphilis infection or serofast state; see “Overview of syphilis testing algorithms”
  • Negative NTT: Perform a different TT.
    • Positive second TT: Current or past infection is likely; see “Overview of syphilis testing algorithms.”
    • Negative second TT
      • False-positive TT likely
      • If risk factors are present, repeat after 2–4 weeks or, if follow-up is unlikely, consider treating.

Serologic tests may be negative in early syphilis. If there is high clinical suspicion, offer presumptive treatment. Alternatively, if a suitable lesion exists, order a direct pathogen test (e.g., darkfield microscopy, PCR) to establish the diagnosis. ^[7][11][17]

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 ^[18]

• 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 ^[19]
  • 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. ^[20]

Approach ^[6]

• Initiate antibiotic treatment in patients with:
  • Confirmed syphilis infection
  • Suspected early infection (prior to seroconversion, history of sexual contact with a person with syphilis)
• Inform patients about the possibility of a Jarisch-Herxheimer reaction to treatment.
• Screen for and treat any coinfections with other STIs. (see “Diagnostics of syphilis”).
• Evaluate and treat sexual partners.
  • Initiate presumptive treatment for:
    • All sexual partners from the 90 days before diagnosis
    • Sexual partners from > 90 days before diagnosis if there is concern for loss to follow-up
  • The trace-back period for testing depends on the stage of syphilis.
    • Primary syphilis: 3 months before symptoms started
    • Secondary syphilis: 6 months before symptoms started
    • Early latent syphilis: 12 months before diagnosis
• Advise patients to:
  • Abstain from all sexual contact until all of the following criteria are met: ^[11]
    • Symptoms have resolved
    • 7 days have passed since the treatment course was completed
    • Sexual partners have been treated and meet the above criteria
  • Use barrier contraception until treatment response has been confirmed with NTT titers.
• Offer counseling on STI prevention, including HIV PrEP if appropriate. ^[6]
• Consult infectious diseases for complex cases and specialists for affected organs (e.g., ophthalmology for ocular syphilis).
• For further information on management in pregnancy, see “Syphilis in pregnancy.”

All sexual contacts of patients 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 for syphilis ^[6]

• Perform a clinical evaluation and measure NTT titers at:
  • Nonpregnant patients: 6 and 12 months after treatment ^[6]
  • Pregnant patients: depends on gestation, see “Syphilis in pregnancy.”
• Compare NTT titers to pretreatment results.
  • NTT titer decreased by ≥ fourfold: successful treatment response
  • NTT titer increased by ≥ fourfold: treatment failure or reinfection
  • NTT titer unchanged or changed by < fourfold within 12 months: serofast state or treatment failure
• If NTT titers have not decreased by ≥ fourfold, determine whether this is due to a serofast state, reinfection, or treatment failure.
  • Factors suggestive of a serofast state
    • Neurosyphilis
    • Older age
    • Later stage syphilis
    • Low titers (< 1:8)
    • Recurrent treated infections
  • Factors suggestive of reinfection or treatment failure
    • A fourfold increase in titers for > 2 weeks
    • Persistent or recurrent symptoms
  • Consult a specialist if the diagnosis is uncertain.
• If a serofast state is suspected:
  • Assess for HIV.
  • Perform additional neurological examinations.
  • Reassess clinically every year and perform serology.
  • If there is concern for loss to follow-up, re-treat.
• If reinfection or treatment failure is suspected: Re-treat patients with weekly IM penicillin G for 3 weeks (see “Antibiotic therapy for syphilis infection”).

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 ; ^[21][22][23]
  • 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 ^[24]

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

Primary prevention

• Provide counseling on prevention of STIs (e.g., condom use) to all individuals. ^[6]
• Encourage patients to:
  • Undergo STI screening ^[25][26]
  • Request new partners to undergo STI screening
• Offer doxycycline postexposure prophylaxis to MSM and transgender women with ≥ 1 bacterial STI in the past 12 months (see “Postexposure prophylaxis for STIs”). ^[27]

Screening for syphilis ^[6][28][29]

Screening is performed on a blood sample using the standard or reverse syphilis testing algorithm.

Further management

• Positive screen
  • Initiate treatment of syphilis.
  • Report to the local or state health department, as syphilis is a nationally notifiable disease. ^[32]
  • For management of pregnant patients, see “Syphilis in pregnancy.”
• Negative screen: Repeat screening as determined by the individual's ongoing risk factors (see “Overview of syphilis screening”).

Syphilis in pregnancy

• Infants born to mothers with syphilis are at risk of congenital syphilis. ^[6][33]
• If maternal syphilis is not treated, up to 40% of pregnancies end in miscarriage, stillbirth, or perinatal death. ^[33]
• All pregnant individuals should undergo prenatal screening for syphilis. ^[6][31]

Diagnostics for syphilis in pregnancy ^[6]

• Initial test: TT or NTT
• Follow the syphilis testing algorithm to confirm the diagnosis.

Screen patients with syphilis for coinfection with other STIs, including HIV. ^[6]

Treatment of syphilis in pregnancy ^[6]

Antibiotic therapy

• Penicillin G is the only treatment recommended for the prevention of congenital syphilis. ^[6][34]
• Patients with a severe penicillin reaction should undergo allergen desensitization prior to treatment.
• See “Antibiotic therapy for syphilis infection by stage” for dosages.
• For patients with primary, secondary, or early latent syphilis: Consider a second dose after 1 week.
• For patients with late latent syphilis and > 9 days between doses: Repeat the full course of therapy.

Obstetric management

For patients diagnosed at ≥ 20 weeks' gestation:

• Perform an obstetric ultrasound to assess for signs of congenital syphilis.
• If there is evidence of congenital syphilis, manage patients in consultation with an obstetric specialist.
• Advise patients to seek immediate medical attention if, after treatment, they develop:
  • Fever or other signs of the Jarisch-Herxheimer reaction
  • Contractions
  • Decreased fetal movements

Follow-up

• Repeat NTT titers.
  • Diagnosis at ≤ 24 weeks' gestation: Repeat after 8 weeks and at delivery.
  • Diagnosis at > 24 weeks' gestation: Repeat at delivery.
• If there is a fourfold or greater increase in titers for > 2 weeks: Repeat treatment.
• For management of neonates, see “Congenital syphilis.”

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