Infectious Disease and Microbiology – Syphilis

Syphilis is a sexually transmitted infection caused by Treponema pallidum. The disease progresses through overlapping stages known as primary, secondary, latent, and tertiary syphilis, while neurosyphilis can occur at any stage.

Epidemiology

Syphilis occurs worldwide and remains an important sexually transmitted infection. Rates are particularly high in populations with increased sexual exposure risk, including people with multiple or anonymous partners.

Coinfection with HIV is relatively common because syphilis and HIV can facilitate the acquisition and transmission of one another.

Risk factors

Important risk factors include unprotected sexual activity, multiple sexual partners, anonymous sexual encounters, injection-drug use, and exchanging sex for money or drugs.

Prevention

Prevention is based on safer sexual practices, including appropriate use of barrier protection during vaginal, anal, and oral sexual contact.

Testing and treatment of infected individuals and their sexual partners are also essential for interrupting transmission.

Pathophysiology

Syphilis is transmitted primarily through direct contact with infectious mucocutaneous lesions, which are most commonly present during primary and secondary disease.

Transmission may occur through sexual contact, kissing, or direct contact with an infectious lesion.

After penetrating the skin or mucous membranes, T. pallidum enters the lymphatic system and bloodstream, allowing widespread dissemination throughout the body.

Vertical transmission across the placenta can cause congenital syphilis.

Transmission through blood products is possible but is now extremely uncommon.

Primary syphilis

Primary syphilis usually appears after an incubation period of approximately 2–4 weeks.

The characteristic lesion is a chancre, which begins as a small papule at the inoculation site and subsequently erodes into a firm, well-defined ulcer.

The classic chancre is painless, indurated, and nonpurulent.

It may occur on the external genitalia, anus, lips, oral cavity, breasts, fingers, or other sites exposed during transmission.

Regional lymphadenopathy may accompany the lesion.

Secondary syphilis

Secondary syphilis develops after systemic dissemination of the organism, usually several weeks after the primary lesion appears or resolves.

Patients may develop fever, malaise, headache, sore throat, weight loss, myalgias, and arthralgias.

A generalized rash occurs in most patients.

The eruption often begins as faint pink macules on the trunk and proximal extremities and later becomes more prominent and papular.

A particularly important clue is involvement of the palms and soles.

The rash is generally nonpruritic and may be macular, papular, maculopapular, or occasionally pustular.

Generalized painless lymphadenopathy is common.

Mucous patches may develop in the mouth and other mucosal surfaces.

Condylomata lata are broad, moist, flat or exophytic lesions occurring particularly in warm intertriginous or perianal regions. These lesions contain large numbers of organisms and are highly infectious.

Other manifestations may include patchy alopecia, loss of eyebrows or beard hair, hepatitis, arthritis, osteitis, periosteitis, gastrointestinal involvement, and immune-complex glomerulonephritis.

Latent syphilis

After secondary manifestations resolve, patients enter the latent stage, during which they have no clinical signs or symptoms but remain serologically positive.

Early latent disease refers to infection acquired relatively recently and carries a greater chance of relapse or transmission than late latent infection.

Late latent syphilis refers to infection of longer duration, during which sexual transmission becomes much less likely.

When the timing of infection cannot be established, the condition is classified as latent syphilis of unknown duration.

Tertiary syphilis

Tertiary disease may develop years or decades after untreated infection.

Cardiovascular manifestations include syphilitic aortitis, particularly involving the ascending aorta, which can lead to aortic aneurysm or aortic valve regurgitation.

Gummas are granulomatous destructive lesions that may involve the skin, bone, or internal organs.

Neurosyphilis

Neurosyphilis can occur during any stage of infection.

Early neurosyphilis commonly manifests as aseptic meningitis or meningovascular disease.

Patients may develop cranial nerve abnormalities, stroke-like syndromes, or spinal cord involvement.

Ocular syphilis can cause uveitis, interstitial keratitis, optic neuritis, retinal disease, or other visual abnormalities.

Otosyphilis can produce sensorineural hearing loss, tinnitus, vertigo, or disequilibrium.

Late neurologic manifestations include general paresis, characterized by progressive cognitive and behavioral deterioration, and tabes dorsalis, characterized by sensory ataxia, lightning-like pains, and impaired proprioception.

The classic Argyll Robertson pupil is small and fails to constrict normally to light but retains accommodation.

Diagnosis

Diagnosis generally requires a combination of clinical assessment and serologic testing.

Direct detection methods include dark-field microscopy, immunofluorescence, and molecular techniques such as PCR, where available.

Dark-field examination can identify T. pallidum from primary or secondary lesions but is generally unsuitable for oral lesions because nonpathogenic oral spirochetes can complicate interpretation.

Serologic testing

Serologic diagnosis usually combines a nontreponemal test with a treponemal test.

Common nontreponemal tests include RPR and VDRL.

Nontreponemal titers correlate approximately with disease activity and are therefore useful for monitoring treatment response.

False-positive nontreponemal tests can occur with pregnancy, autoimmune disease, intravenous drug use, older age, and certain infections.

Treponemal tests include assays such as FTA-ABS, TPPA, TPHA, and treponemal enzyme immunoassays.

Treponemal tests are more specific but usually remain positive for a prolonged period or for life, so their titers are not useful for assessing treatment response.

Many laboratories now use a reverse screening algorithm, beginning with a treponemal immunoassay followed by a quantitative nontreponemal test.

When the treponemal screening assay is reactive but the nontreponemal test is negative, an additional treponemal assay can help clarify whether the result represents previous treated infection, early infection, or a false-positive screening test.

Cerebrospinal fluid evaluation

Lumbar puncture may be indicated when patients have neurologic, ophthalmic, or otologic manifestations suggestive of neurosyphilis, or in selected cases of treatment failure or tertiary disease.

CSF findings may include lymphocytic pleocytosis, increased protein concentration, and a reactive CSF-VDRL.

A reactive CSF-VDRL is highly supportive of neurosyphilis, although a negative result does not completely exclude the diagnosis.

Differential diagnosis

Primary genital lesions may resemble genital herpes, chancroid, lymphogranuloma venereum, granuloma inguinale, traumatic ulcers, malignancy, or fixed drug eruptions.

Secondary syphilis can mimic many conditions, including acute HIV infection, viral exanthems, drug eruptions, erythema multiforme, scabies, fungal disease, and other systemic infections.

Because its clinical manifestations are extremely diverse, syphilis is often described as a “great imitator.”

Treatment of primary, secondary, and early latent syphilis

The traditional first-line treatment is benzathine penicillin G administered intramuscularly.

Patients with early disease generally require a single appropriately dosed injection, provided there is no evidence of neurosyphilis.

Late latent and tertiary syphilis

Late latent syphilis, syphilis of unknown duration, and tertiary syphilis without neurologic involvement generally require multiple weekly doses of benzathine penicillin G.

Neurosyphilis

Neurosyphilis requires high-dose intravenous aqueous crystalline penicillin G for an extended treatment course because adequate concentrations must be achieved in the cerebrospinal fluid.

An alternative regimen involving procaine penicillin plus probenecid may be used in selected circumstances.

Penicillin allergy

For certain nonpregnant patients with early syphilis who cannot receive penicillin, doxycycline may be used as an alternative.

Alternative regimens for late latent disease generally require a longer course than those used for early syphilis.

Macrolide therapy is unreliable because T. pallidum resistance and treatment failures have been documented.

Pregnancy

Penicillin is the only established effective treatment for syphilis during pregnancy and is essential for prevention and treatment of fetal infection.

Pregnant patients who report a penicillin allergy should generally undergo penicillin desensitization so that appropriate penicillin treatment can be administered.

Jarisch–Herxheimer reaction

A Jarisch–Herxheimer reaction may occur within the first 24 hours after starting treatment.

It is characterized by an acute onset of fever, chills, headache, myalgia, and transient worsening of symptoms caused by the inflammatory response to rapid destruction of spirochetes.

It occurs particularly often in early syphilis and should not be mistaken for penicillin allergy.

Follow-up

Sexual partners should be clinically evaluated and tested, and treated when indicated according to the timing and stage of exposure.

Partners with recent exposure to someone diagnosed with primary, secondary, or early latent syphilis may require presumptive treatment even when initial serologic testing is negative.

Treatment response is monitored using quantitative nontreponemal titers, such as RPR or VDRL.

An appropriate decline in nontreponemal titers over time supports successful therapy, whereas persistently high or increasing titers may indicate reinfection, inadequate treatment, or treatment failure.

Patients with late disease require longer-term serologic monitoring than patients with early syphilis.

Patients treated for neurosyphilis may require additional neurologic, ophthalmologic, or audiologic follow-up depending on their presenting manifestations.

Prognosis

Early diagnosis and appropriate treatment generally produce an excellent prognosis and prevent progression to late destructive disease.

Neurologic or cardiovascular damage that has already occurred in advanced syphilis may not completely reverse after antimicrobial treatment.

High-Yield Pattern

Painless indurated genital ulcer → primary syphilis

Diffuse nonpruritic rash involving palms and soles → secondary syphilis

Positive serology without symptoms → latent syphilis

Aortic disease, gummas, or late neurologic manifestations → tertiary syphilis

Neurologic, ocular, or auditory manifestations can occur at any stage → consider neurosyphilis

Diagnosis → treponemal + nontreponemal testing

Treatment → penicillin remains the cornerstone of therapy