2.5.7 Syphilis

World Health Organization (WHO) estimates that in 2020, a total of 7,1 million new cases occurred among adolescents and adults aged 15-49 years worldwide. In Europe, 41,000 syphilis cases (9.9/100,000) were reported in 29 EU/EEA Member States in 2023. Thirteen countries reported altogether 78 congenital syphilis cases. The reported syphilis rates were seven times higher in men than in women and peaked among 25-34 year old men. Two-thirds of the syphilis cases with information on transmission were among men who have sex with men (MSM).

Syphilis is a systemic infection caused by Treponema pallidum spirochete, and has four stages; primary, secondary, latent and tertiary syphilis. Syphilis is mostly considered as a sexually transmitted infection (STI), but a fetus of an untreated mother can get congenital syphilis. The incubation period from infection to the primary stage is 10-90 days. Secondary syphilis develops in 30% of untreated patients 2-3 months after the onset of chancre. Tertiary syphilis is rare and develops in 10% of untreated patients. The European Centre for Disease Prevention and Control (ECDC) defines early or infectious syphilis as an infection acquired ≤1 year earlier and it includes primary, secondary and early latent syphilis stages. Late syphilis, which is divided to late latent and tertiary stages, has been acquired more than a year earlier. Patients are considered infectious during the first year (primary and secondary syphilis). Later transmission vertically and through tissue donation is known.

• The typical symptom of primary syphilis is a single, painless, indurated ulcer (chancre) at the inoculation site, mainly in the anogenital area but can also be detected extragenitally, such as in the oral area. Regional lymphadenopathy is usually observed. The incubation period from infection to the primary stage varies between 10 and 90 days. This stage may be asymptomatic when chancres are not detected (chancres located in the vagina, pharynx or rectal canal).

• The typical feature of secondary syphilis is a non-itching skin rash (roseola) on the trunk and later papular syphilids on the palms and soles. Also, mucocutaneous lesions can be detected. Constitutional symptoms like fever, chills, malaise, generalized lymphadenopathy myalgias and arthritis occur as a consequence of the bacteremia. During the secondary stage of syphilis, symptoms of early neurosyphilis, like uveitis, retinitis, otitis, meningitis, and cranial nerve dysfunction may occur.

• Latent syphilis is clinically asymptomatic.

• The symptoms of tertiary syphilis present as erosive cutaneous or mucosal lesions (gumma), neurological (late neurosyphilis) and cardiovascular (aortic aneurysm) disorders may occur.

Syphilis stages are clinically defined, and they may overlap each other.

• Primary stage: ulcer (ulcus durum) at the inoculation site; regional lymphadenopathy

• Secondary stage: eruptive skin rash (roseola syphilitica); papular syphilids on palms and soles; mucocutaneous lesions; fever with generalized lymphadenopathy. The manifestations of primary and secondary syphilis overlap in ca. 15% of cases.

• Tertiary: plaque-like lesions (gumma), neurological (late neurosyphilis) and cardiovascular (aortic aneurysm) disorders.

The diagnosis of syphilis is commonly done with serological tests for syphilis (STS). The direct verification of the spirochete can be performed with dark-field microscopy in the early chancre but detection of Treponema pallidum by PCR is more specific and sensitive.

Serological tests for syphilis (STS) are obligatory, additionally they are used for screening and follow- up. Both treponemal tests (TT) and non- treponemal tests (NTT) are available.

• NTTs like the Venereal Diseases Research Laboratory test (VDRL) and the Rapid Plasma Reagin test (RPR) become positive 10-15 days after the onset of the primary chancre (i.e. around 6 weeks after infection). It is noteworthy that the STS may remain positive after an adequately treated syphilis infection. A person with a positive STS should be asked about earlier treatments of syphilis and treated as for syphilis if not known.

Titers of NTT correlate with the disease activity, and are used to monitor disease activity and efficacy of treatment.

• The specific TTs include T. pallidum Haemagglutination test (TPHA), T. pallidum Passive Particle Agglutination test (TPPA), Treponemal Enzyme Immunoassay (EIA) or ELISA, Chemiluminescence Immunoassay (CLIA) and IgG immunoblot tests with T. pallidum antigens.

These tests become positive in the first weeks of the chancre and remain positive after the treatment in most patients. If a TT test is positive, a quantitative NTT must be performed on the same serum. To identify reinfection after a previously treated infection, a confirmatory TPHA test (positive 4-8 weeks after infection) is used together with the VDRL test.

Dark-field microscopy of fresh samples obtained from the primary ulcer or erosive cutaneous lesions can identify T. pallidum with a sensitivity of 80%. (Dark-field microscopy cannot be used for oral ulcers, since the mouth harbors normal non-pathogenic treponemes indistinguishable from T. pallidum in microscopy.) This test has been replaced in most settings by amplification tests (PCR T.pallidum).

Notably, none of the STS differentiate venereal syphilis from the non-venereal treponematoses such as yaws, pinta and endemic syphilis (bejel).

The first line therapy for the early syphilis is single dose of benzathine penicillin G (BPG) 2.4 million units intramuscularly (i.m.). The treatment of late latent syphilis is benzathine penicillin G (BPG) 2.4 million units IM weekly on day 1, 8 and 15. In case the patient is allergic to penicillin or refuses the parenteral treatment, oral doxycycline 200 mg daily (2x100) can be used for 14 days (early syphilis) and for 21-28 days (late latent). Benzyl penicillin 18-24 million units intravenously daily (3-4 million units every 4 h) during 10-14 days is the first choice of treatment for neurosyphilis, ocular and auricular syphilis. The Herxheimer reaction often occurs after the first dose of antibiotics.

NTTs are used for monitoring the effectiveness of treatment at 1, 3 and every 6 months thereafter, until it becomes negative or attains a low plateau (1:1-1:4).

All syphilis cases should be reported and contact tracing performed according to the local communicable disease legislation.

Importantly, all patients with syphilis should also be tested for HIV, HCV and HBV if risk factors are evident.