Syphilis: modern diagnosis and the stages of the disease

What is syphilis and why is it still relevant?

Syphilis is a chronic systemic infectious disease caused by the spirochaete Treponema pallidum. Although the organism has been known for more than a century, syphilis remains one of the most treacherous venereal diseases. According to WHO data, more than 7.1 million new cases of syphilis are recorded worldwide each year among adults aged 15–49. In Ukraine there has been a steady upward trend in incidence since 2019 — in 2025 the number of new cases was 34% higher than before the pandemic. The rise among pregnant women and in cases of congenital syphilis is particularly worrying. The disease can affect practically every organ and system — the skin, mucous membranes, bones, the cardiovascular system and the nervous system. Untreated, syphilis passes through distinct stages, each with its own clinical features and diagnostic characteristics. It is precisely this staged course, and the ability to mimic a great many other diseases, that earned syphilis the name "the great imitator" in medical practice.

The stages of syphilis: from chancre to systemic disease

The course of syphilis is divided into four successive stages, each with specific clinical signs and diagnostic markers:

• Primary syphilis: develops 10–90 days (on average 21 days) after infection. The main sign is the chancre: a painless ulcer with firm edges and a clean base at the point where the treponeme entered. The most common site is the genitals, but a chancre can appear on the lips, in the mouth or in the anal area. It is accompanied by regional lymphadenitis (enlarged lymph nodes). The chancre heals on its own within 3–6 weeks, which creates a false sense of recovery. Serological tests become positive 1–4 weeks after the chancre appears.
• Secondary syphilis: occurs 6–12 weeks after infection, when the treponeme has spread through the bloodstream throughout the body. Characteristic features: a polymorphic skin rash (roseolar, papular), notably on the palms and soles — a pathognomonic sign; condylomata lata in the perineum; patches of alopecia ("moth-eaten fur"); involvement of the mucous membranes (erosive papules in the mouth); and general symptoms — fever, fatigue, joint pain, generalised lymphadenopathy. This stage is the most infectious and has the highest serological activity.
• Latent syphilis: a symptomless period in which the diagnosis is made serologically alone. It is divided into early (up to 1 year after infection) and late (more than 1 year). Early latent syphilis can relapse into the secondary stage and is infectious. Late latent syphilis is practically not transmitted by sexual contact, but the risk of vertical transmission (from mother to child) and of progression to tertiary forms remains. Up to 30% of untreated patients remain in the latent stage for the rest of their lives.
• Tertiary (late) syphilis: develops 3–15 years after infection in 15–40% of untreated patients. It comprises three main forms: gummatous syphilis — destructive granulomatous lesions (gummas) in the skin, bones, liver and other organs; cardiovascular syphilis — aortitis, aneurysm of the ascending aorta, aortic valve incompetence; and neurosyphilis — meningovascular (strokes), parenchymatous (general paresis, tabes dorsalis) and asymptomatic. Neurosyphilis can develop at any stage, particularly in HIV-positive patients, so examination of the cerebrospinal fluid is indicated where there are neurological symptoms.

Modern laboratory diagnosis

Diagnosis rests on combining the clinical picture with laboratory methods. Direct detection of the organism: dark-field microscopy of exudate from a chancre or erosion allows living treponemes to be seen — high specificity but limited sensitivity; PCR for Treponema pallidum DNA has a sensitivity of 78–95% in primary syphilis and is ideal for atypical or oral chancres. Non-treponemal (screening) tests: RPR (Rapid Plasma Reagin) and VDRL detect antibodies to lipid antigens released when tissue is destroyed; they are used for screening and for monitoring the response to treatment (the titre falls when therapy succeeds); false positives are possible in pregnancy, in autoimmune disease and in acute infections. Treponemal (confirmatory) tests: TPHA, ELISA, FTA-ABS and rapid immunochromatographic tests detect specific antitreponemal antibodies and remain positive for life after syphilis. The reverse screening algorithm begins with a treponemal test (ELISA/TPHA) confirmed by a non-treponemal one (RPR) — recommended by WHO and CDC as the modern standard.

Treatment: the gold standard

Benzathine benzylpenicillin has been the drug of choice for syphilis for more than 70 years, and not a single case of treponemal resistance to penicillin has yet been recorded. The regimens depend on the stage: early syphilis (primary, secondary, early latent) — a single injection of benzathine benzylpenicillin G 2.4 million units intramuscularly (effectiveness 95–98%); late latent and tertiary syphilis — three injections of benzathine benzylpenicillin 2.4 million units at weekly intervals; neurosyphilis — aqueous crystalline penicillin G 18–24 million units a day intravenously for 10–14 days. Alternatives in penicillin allergy: doxycycline 100 mg twice a day for 14–28 days, or ceftriaxone 1–2 g a day intramuscularly or intravenously. Pregnant women with allergy undergo desensitisation to penicillin, because the alternative drugs do not cross the placental barrier. The Jarisch–Herxheimer reaction — acute fever, muscle aches and headache in the first 24 hours after treatment begins — occurs in 50–75% of patients with early syphilis and reflects the mass destruction of treponemes. Monitoring the response: non-treponemal tests every 3–6 months for 1–2 years; a fourfold fall in RPR titre indicates an adequate response to treatment.

Neurosyphilis: involvement of the nervous system

Neurosyphilis can develop at any stage of the disease and needs separate attention in both diagnosis and treatment. Early neurosyphilis presents with meningitis, cranial nerve involvement (particularly the optic and auditory nerves) and meningovascular disease with strokes at a young age. Late neurosyphilis comprises general paresis (personality change, dementia, psychosis) and tabes dorsalis (impaired coordination, lightning pains, ataxia). Diagnosis requires examination of the cerebrospinal fluid: pleocytosis (more than 5 white cells/µl), a raised protein level, a positive CSF VDRL (specificity close to 100%, but sensitivity only 30–70%) and a positive CSF FTA-ABS (high sensitivity but lower specificity). Treatment of neurosyphilis requires high doses of intravenous penicillin, because benzathine benzylpenicillin does not achieve therapeutic concentrations in the cerebrospinal fluid. After treatment, a follow-up lumbar puncture is performed every 6 months until the fluid normalises. The outlook depends on the stage — early neurosyphilis is usually completely curable, whereas late forms may leave irreversible neurological deficits.

When to see a doctor

See a dermatovenerologist immediately if any painless ulcer appears on the genitals, in the mouth or in the anal area — even if it does not trouble you, it may be the chancre of primary syphilis. An urgent consultation is needed for a rash on the palms and soles that does not itch — a characteristic sign of secondary syphilis. Get tested for syphilis if a sexual partner has been diagnosed with it, if you have had unprotected contact with a new partner, or if you are planning a pregnancy. Screening is mandatory for all pregnant women in the first and third trimesters — congenital syphilis causes severe fetal abnormalities, but is entirely preventable if the mother is treated before the 16th week of pregnancy. If you have been treated for syphilis before, continue follow-up testing on the recommended schedule — re-infection is possible, because having had syphilis does not confer lasting immunity. Remember: syphilis in its early stages is completely curable with a single injection of an antibiotic, but untreated it can lead to serious irreversible complications.