Syphilis

Syphilis is a systemic infection caused by the spirochaete Treponema pallidum subspecies pallidum. Transmission occurs through direct contact with mucocutaneous lesions during sex, transplacentally (congenital syphilis), and rarely by blood transfusion. Incidence has risen globally, particularly in MSM and in some heterosexual populations, with a resurgence of congenital syphilis.

Natural history and stages

• Primary syphilis: incubation 10 to 90 days (average 3 weeks). Chancre at the inoculation site.
• Secondary syphilis: 4 to 10 weeks after the chancre (up to 6 months), representing haematogenous dissemination.
• Latent syphilis: serological evidence of infection without symptoms. Early latent (acquired within 1 year, infectious relapses possible) and late latent (over 1 year, or unknown duration, non-infectious sexually).
• Tertiary syphilis: years to decades later in 25 to 40% of untreated people: gummatous disease, cardiovascular syphilis, and late neurosyphilis.
• Neurosyphilis: can occur at any stage (early: meningitis, meningovascular, ocular and otic syphilis; late: general paresis, tabes dorsalis).
• Risk factors: unprotected sex, MSM, multiple partners, HIV infection, sex work, injecting drug use, and previous syphilis. Syphilis and HIV facilitate each other's transmission. HIV co-infection may cause atypical or accelerated disease and, rarely, serological anomalies.

Congenital syphilis

• Vertical transmission after the first trimester, with risk of up to 70 to 100% in primary or secondary maternal disease. Outcomes: stillbirth, neonatal death, prematurity, and congenital syphilis (early: before 2 years; late: after 2 years). Prevention depends on antenatal screening and maternal treatment at least 30 days before delivery.
• The organism cannot be cultured in vitro. Penicillin remains uniformly effective.

Primary syphilis

• Solitary painless, indurated, clean-based ulcer (chancre) with raised edges at the site of inoculation (penis, vulva, cervix, anus, rectum, mouth), with painless regional lymphadenopathy (rubbery, non-tender). Multiple or painful ulcers can occur, especially in HIV. Healing occurs in 3 to 6 weeks without treatment. Extragenital chancres are frequently missed.

Secondary syphilis

• Fever, malaise, sore throat, headache, arthralgia, generalised lymphadenopathy.
• Rash: symmetric, non-itchy, macular or papular, often involving palms and soles, copper-coloured, may be papulosquamous, pustular, or annular. Condylomata lata (flat, moist, grey-white plaques in intertriginous areas, highly infectious), mucous patches in the mouth, patchy alopecia ("moth-eaten"), and "snail-track" oral ulcers.
• Visceral involvement: hepatitis (raised alkaline phosphatase), glomerulonephritis (nephrotic syndrome), periostitis, uveitis, meningitis, and cranial nerve palsies (neurosyphilis early).
• "Lues maligna" (necrotic ulcerative lesions) in advanced HIV.

Latent syphilis: asymptomatic with positive serology.

Tertiary syphilis

• Gummatous syphilis: granulomatous lesions in skin, bone (painful, nocturnal), liver, and other organs.
• Cardiovascular syphilis (10 to 30 years): aortitis with ascending aortic aneurysm, aortic regurgitation, coronary ostial stenosis (angina). Tree-bark appearance of the aorta, eggshell calcification.
• Neurosyphilis:
  • Asymptomatic.
  • Meningeal and meningovascular (stroke in the young, cranial neuropathies, 5 to 12 years).
  • General paresis (dementia, personality change, tremor, dysarthria, 10 to 25 years): Argyll Robertson pupils (accommodate but do not react to light).
  • Tabes dorsalis (15 to 30 years): lightning pains, ataxia, loss of position sense, Charcot joints, bladder dysfunction, Argyll Robertson pupils.
  • Ocular syphilis (uveitis, optic neuritis, retinitis) and otic syphilis (sensorineural hearing loss, tinnitus, vertigo), which can occur at any stage and require urgent management.

Congenital syphilis

• Early (under 2 years): snuffles (persistent rhinitis), skin rash with desquamation of palms and soles, hepatosplenomegaly, jaundice, anaemia, thrombocytopenia, bone lesions (osteochondritis, periostitis), pseudoparalysis of Parrot, nephrotic syndrome, and meningitis.
• Late (over 2 years): Hutchinson triad (Hutchinson teeth, interstitial keratitis, eighth nerve deafness), saddle nose, saber shins, Clutton joints, frontal bossing, and mulberry molars.

Differential diagnosis: genital herpes, chancroid, LGV, Behçet disease, pityriasis rosea, drug eruptions, viral exanthems, sarcoidosis, lichen planus, and mono-like illnesses.

Red flags: neurological, ocular or otic symptoms; pregnancy; HIV co-infection; treatment failure; and a newborn of an untreated mother.

No single test is sufficient. Use serology with clinical context.

Direct detection

Darkfield microscopy (live spirochaetes in exudate from chancre or condylomata lata; requires immediate examination), direct fluorescent antibody, and PCR of lesion swabs (sensitivity 70 to 90%, available in some labs).

Serology

• Treponemal tests (T. pallidum particle agglutination TPPA, enzyme immunoassay/chemiluminescence immunoassay for IgG and IgM, FTA-ABS): specific, usually remain positive for life (even after treatment), and are the first-line screen in reverse algorithm.
• Non-treponemal tests (RPR, VDRL): sensitive for activity, used for titres to monitor response. They may be negative in early primary syphilis (up to 25% to 30%) and in late disease, and false-negative in the prozone phenomenon (very high titres, dilute the sample). Biological false positives (pregnancy, autoimmune disease, HIV, infection, drug use, ageing) generally have titres below 1:8.
• Algorithms: traditional (non-treponemal screen then treponemal confirmatory) or reverse (treponemal EIA/CIA, then RPR, then TPPA if discordant).
• Interpretation: after successful therapy, non-treponemal titre falls fourfold (two dilutions) within 6 to 12 months (primary/secondary) or 12 to 24 months (latent), commonly becoming non-reactive in primary syphilis. A serofast state (persistent low titre, usually 1:8 or less) occurs in 15 to 40%.
• Reinfection: a fourfold rise in titre.
• Cerebrospinal fluid examination (lumbar puncture) is indicated for neurological, ocular or otic symptoms; tertiary syphilis (non-cardiovascular, cardiac); treatment failure; and HIV with late latent syphilis or RPR titre of 1:32 or more with low CD4. CSF findings: reactive CSF VDRL (specific, not sensitive), raised white cells (above 5/µL), and raised protein (above 45 mg/dL). CSF FTA-ABS is sensitive but not specific.
• Other tests: HIV test (all patients), hepatitis B and C, gonorrhoea and chlamydia NAAT, pregnancy test, CBC, liver tests, urinalysis (proteinuria), ophthalmic and audiological examination for symptomatic disease. Echocardiography or chest CT for cardiovascular syphilis. Neuroimaging (MRI) for neurosyphilis.
• Congenital syphilis: maternal and infant serology (infant RPR titre compared with the mother's, a fourfold higher infant titre is diagnostic), darkfield of lesions or placental tissue, long bone radiographs, CSF analysis, CBC, liver tests, ophthalmology and hearing testing.

Penicillin G is the treatment of choice at all stages (including pregnancy and HIV).

Primary, secondary and early latent syphilis (under 1 year)

Benzathine penicillin G 2.4 million units IM single dose. Some experts give a second dose after 1 week in pregnancy (third trimester) or HIV with neurological concerns. Penicillin allergy (non-pregnant): doxycycline 100 mg orally twice daily for 14 days (or tetracycline 500 mg four times daily for 14 days). Alternatives with less evidence: ceftriaxone 1 g IM or IV daily for 10 days, and azithromycin 2 g single dose (not recommended due to resistance).

Late latent, latent of unknown duration, and cardiovascular or gummatous (tertiary) syphilis

Benzathine penicillin G 2.4 million units IM once weekly for 3 weeks. Alternative: doxycycline 100 mg twice daily for 28 days. Perform CSF examination before treatment of tertiary syphilis. Cardiovascular syphilis also needs surgery for aneurysm or valve disease.

Neurosyphilis, ocular and otic syphilis

• Aqueous crystalline benzylpenicillin 18 to 24 million units per day, given as 3 to 4 million units IV every 4 hours (or by continuous infusion), for 10 to 14 days. Alternatives: procaine penicillin 2.4 million units IM daily with probenecid 500 mg four times daily, both for 10 to 14 days, or ceftriaxone 2 g IV or IM daily for 10 to 14 days. Some experts follow with benzathine penicillin 2.4 million units IM weekly for 3 doses.
• Corticosteroids (prednisolone 40 to 60 mg daily for 3 days around initiation) may reduce Jarisch-Herxheimer reaction in ocular, otic or cardiovascular disease. Consider hospital admission for ocular and otic syphilis, with ophthalmology or ENT support.

Pregnancy

• Penicillin only. Women with penicillin allergy must be desensitised then treated. Stage-appropriate regimen, with a second dose of benzathine penicillin 2.4 million units a week later in some guidelines for primary, secondary and early latent syphilis. Treat at least 30 days before delivery. Monitor monthly RPR titres, and examine the fetus by ultrasound for hepatomegaly, ascites, placentomegaly, and hydrops (fetal syphilis). Warn about Jarisch-Herxheimer reaction (may cause premature labour or fetal distress).
• HIV co-infection: same treatment. Closer serological follow-up, and a lower threshold for CSF examination. Antiretroviral therapy should be optimised.

Congenital syphilis

• Infants with proven or probable congenital syphilis or born to mothers who were untreated, inadequately treated or treated within 30 days of delivery: aqueous benzylpenicillin 50,000 units/kg IV every 12 hours for the first 7 days of life, then every 8 hours, for a total of 10 days. Alternative: procaine penicillin G 50,000 units/kg IM daily for 10 days. Infants with normal evaluation at risk (adequately treated mother, serological follow-up): benzathine penicillin G 50,000 units/kg IM single dose. Follow-up with serology at 2, 4, 6 and 12 months. Reassess hearing and vision.
• Older children: aqueous benzylpenicillin 200,000 to 300,000 units/kg/day in divided doses every 4 to 6 hours for 10 days.
• Jarisch-Herxheimer reaction: occurs in 10 to 35% within 2 to 24 hours of the first dose (fever, chills, myalgia, headache, tachycardia, hypotension, worsening rash), more in early syphilis and high titres. Management is supportive with antipyretics (paracetamol 1 g), fluids. Reassure patients, and warn pregnant women. Not an allergy.

Follow-up and prevention

• Serological monitoring: RPR/VDRL at 3, 6, 12 and 24 months (also 9 months in HIV and pregnancy; monthly in pregnancy). Treatment failure if titres fail to fall fourfold at 12 months (primary/secondary), or rise fourfold, or clinical signs persist or recur. Evaluate for HIV, reinfection and neurosyphilis (CSF exam), and re-treat with benzathine penicillin weekly for 3 doses.
• Partner management: notify and examine all partners within 90 days of primary syphilis diagnosis, 6 months for secondary, and 1 year for early latent syphilis. Treat presumptively exposed partners within 90 days (benzathine penicillin 2.4 million units IM single dose), even with negative serology.
• Abstain from sexual contact until lesions have healed and 7 days after treatment (all partners treated).
• Screening: antenatal (first visit, repeat at 28 to 32 weeks and at delivery in high prevalence settings), MSM and people with HIV at least annually (3 to 6 monthly if high risk), and those on PrEP. Doxycycline post-exposure prophylaxis (200 mg within 72 hours) reduces syphilis incidence by about 70 to 80% in MSM and transgender women.
• Counselling, HIV testing, vaccination (hepatitis A and B), safer sex, and public health notification.
• Long-term care for complications: neurorehabilitation, valve and aneurysm surgery, and support for hearing and vision loss.