Also called chancre, it appears at the inoculation site after an incubation period of 10-90 days.4 Although traditionally described as a single, painless, indurated, reddish ulcer of 0.5cm to 3cm in diameter (fig. 1),4,5 a study confirmed that it can sometimes be painful (49.2%) or multiple ulcers.6 It is usually associated with a loco-regional adenopathy7 and resolves within 3-6 weeks without scarring if left untreated.8

Figure 1.

Firm consistency ulcer, syphilitic chancre.

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Although it is generally located in the anogenital region, it can appear in any exposed areas, including mouth, fingers, nipples, etc.9.

Syphilitic balanitis of Follmann is a less common, possibly underdiagnosed presentation (fig. 2), presenting as erosive and painful balanitis.6,10

Figure 2.

Painful erosive lesions in Follmann balanitis.

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The hematogenous and lymphatic dissemination of spirochetes occurs 3 to 12 weeks after the resolution of the chancre (although both stages may overlap) and results in a wide array of clinical signs.

Mucocutaneous signs are the most common ones—in up to 97% of patients4—and are usually accompanied by systemic signs and symptoms, such as generalized lymphadenopathy, malaise, sore throat, myalgia, headache, and low-grade fever4.

We call syphilides11 to all those mucocutaneous signs of early syphilis other than chancre, which can be localized or generalized and are generally mildly symptomatic.

The most common presentation is a diffuse maculopapular rash on the trunk and extremities with fine scaling called “roseola” (fig. 3). Numerous atypical forms of cutaneous presentation have been reported, such as nodular, pustular, lichenoid, psoriasiform, annular, follicular, ulceronodular (also called malignant syphilis, etc.)12,13. Malignant syphilis is a rare and aggressive presentation consisting of necrotic ulcers and nodules. It is associated with HIV infection, low CD4 count, malnutrition, MSM, previous syphilis, diabetes mellitus, and alcohol abuse14.

Figure 3.

Maculopapular rash on trunk with fine scaling called syphilitic roseola.

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Syphilides may appear on palms and soles in up to 40%-80%4 of cases, often exhibiting reddish-brown macules with or without a slight collarette of scaling called clavos (fig. 4).

Figure 4.

Plantar papules with scaling collar known as «clavos».

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Lesions in the anogenital region are a common finding, appearing as patches or geographic lesions (fig. 5). In areas prone to maceration, exophytic, moist, and friable lesions called condylomata lata may appear (fig. 6).4 They can be confused with condylomata acuminata and tumor lesions7, and are highly contagious.

Figure 5.

Lesions in the anogenital region in the form of patches of secondary syphilis.

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Figure 6.

Exophytic, moist, and friable lesions called flat condylomas.

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Oral mucosal involvement occurs in up to 30%-40%15 of patients, and these lesions are also highly infectious. Small, rounded patches on the dorsal tongue, larger depapillated plaques, and erosions on the tongue or lips are common findings (fig. 7).15 Other oral presentations include “rhagades,” enanthema, and whitish plaques on the palate, uvula, and tonsils (fig. 8).16

Figure 7.

Small rounded patches on the back of the tongue with larger depapillated plaques typical of secondary syphilis.

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Figure 8.

Whitish plaques on the uvula and tonsils that are sometimes a presentation of secondary syphilis.

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Alopecia is a less common sign, and is usually of moth-eaten appearance (fig. 9)15.

Figure 9

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If left untreated, secondary syphilis usually resolves spontaneously within a matter of 4 to 12 weeks without leaving a scar.

The term early latent syphilis describes patients without any signs or symptoms of primary or secondary syphilis, but with positive serologic tests and evidence that the infection was acquired over the past 12 months.5,17,18

• -

  Early (< 2 years): mucocutaneous syphilides, palmoplantar pemphigus, rhinitis, jaundice, lymphadenopathies, meningitis, nephrotic syndrome, hemolytic anemia, prematurity, bone lesions, etc.23,24.

• -

  Late (> 2 years): deafness, interstitial keratitis, dental anomalies, bone lesions, neurological or gummatous involvement, etc.23.

Treponema pallidum is not cultivable in laboratory media, so direct diagnosis is based on detecting it in ulcerated or exudative lesions through dark-field microscopy, which can identify its morphology and motility.25,26 Although this method can be useful for genital ulcers with negative serological screening in centers with a significant volume of samples and experienced microscopists,27 a negative result does not exclude the disease.

This is currently the most widely used technique for direct diagnosis. It is the method of choice for ulcerated or erosive oral, anal, and other exudative lesions where commensal treponemas exist. The PCR is also useful in the newborns’ vitreous humor, placenta, and exudative tissues; however, it has low sensitivity in cerebrospinal fluid (CSF),28 and its yield varies depending on the type of sample and the stage of the infection, being high in primary ulcerative lesions and lower in secondary lesions.29

Commercially available multiple platforms detect different agents causing ulcerative STIs.

Direct immunofluorescence techniques, in situ hybridization, or silver staining techniques are currently not used anymore.30,31

Serological diagnosis is indirect and presumptive, not differentiating among different pathogenic treponemas (T. pertenue, T. endemicum, and T. carateum) .32

Non-treponemal or reagin tests use antigens composed of cardiolipin, lecithin, and cholesterol and are primarily the Rapid Plasma Reagin (RPR) and Venereal Disease Research Laboratory (VDRL) tests. Both are manual, simple, inexpensive, and semi-quantitative techniques to assess disease activity and post-treatment monitoring. They test positive 10-15 days after the appearance of the chancre if left untreated. Titers peak 1 and 2 years after infection and remain low positive in late untreated disease.26 A quantified serum sample should be obtained before treatment (or within the first few hours) to have a baseline test and measure subsequent changes with the same technique (1, A). Ntts are quantified as follows: 1/1 (pure serum), 1/2, 1 /4, 1/8, 1/16, 1/32, 1/64, etc.

Seroreversion is a 4-fold decrease of titers (2 dilutions) between 6 and 12 months after early infection (e.g., from 1/16 to 1/4) and indicates adequate treatment.33 Occasionally, some patients properly treated based on their stage fail to reduce Ntt titers by 4 times (at least, 2 dilutions) at the 6-to-12-month follow-up for early syphilis and at the 12-to-24-month follow-up for late syphilis in the absence of reinfections; this lack of response is called serofast reaction and is influenced by factors, such as the stage of the disease, duration, and initial Ntt titer. Its causes are not entirely clear.34–36 We should think of reinfections or relapses (treatment failures) when Ntt titers increase by 4 times or 2 dilutions after correct treatment.

Ntts can show false positive in 0.2% up to 0.8% of cases and less frequently in treponemal tests (see annexes 1 and 2, supplementary data).37

Treponemal tests are qualitative and earlier than Ntts. They detect specific antibodies 2 to 4 weeks after exposure.32 They are used as confirmatory tests and are not useful to monitor treatment or disease activity as they remain positive in most treated cases.26 The most widely used are T. pallidum hemagglutination (TPHA), T. pallidum microhemagglutination (TP-MHA), fluorescent treponemal antibody absorption (FTA-ABS), IgG or IgM immunoblot, enzyme immunoassay (EIA), and chemiluminescence immunoassay (CLIA).

EIA and CLIA tests are automated and allow testing sera from multiple patients, making them a crucial screening tool.

Although false positive TTs are possible, they are less frequent than Ntts (see annexes 1 and 2).37

Most laboratories use the so-called reverse algorithm38 as a screening test, performing automated EIA or CLIA (both TTs), which are the most efficient; positive tests may be due to past treated disease or an untreated patient with active disease. An initial positive test should be confirmed with another TT, usually TPHA (1, C); if positive, a quantified Ntt should be performed before establishing the baseline titer, which indicates activity and serves as post-treatment control (1, A).

The clinical and epidemiological context should always be considered when interpreting syphilis tests (annex 3).39

CSF evaluation is ill-advised in early syphilis in patients without neurological, ocular, or auditory symptoms (1, A). It is, however, indicated in patients with neurological symptoms,40 regardless of the stage of the disease (1, C), and in syphilis with ocular involvement, it should be individually assessed.36

CSF examination includes total proteins, the number of mononuclear cells, treponemal tests (FTA or TPHA), and non-treponemal tests, preferably VDRL.

No single test per se can confirm the presence of neurosyphilis. While a positive VDRL test in CSF is considered diagnostic of late-stage neurosyphilis in the absence of blood contamination, a negative result does not exclude diagnosis.17,41 PCR in CSF has low sensitivity and specificity rates for neurosyphilis diagnosis.28

Neurosyphilis diagnosis is rare in patients with negative blood Ntts (data provided in the presentation “Syphilis & neurosyphilis update” at the IUSTI 2023 Congress held in Malta, Dr. Nicolas Dupin, Professor of Dermato-Venerology at University Paris Cité, Cochin Hospital, APHP. Head of the National Reference Center of Syphilis, Former president of the French Society of Dermatology).

Benzathine penicillin G (BPG) 2.4 million international units (MIU) intramuscular (IM) (1, B).

If allergic to penicillin, if parenteral treatment is refused, or in the presence of bleeding disorders: doxycycline 100mg orally every 12hours for 14 days (1, C).

Azithromycin is ill-advised due to the potential resistance of Treponema pallidum.28,42–44

Benzathine penicillin G 2.4 MIU IM, weekly dose for 3 weeks (1, C).

If allergic to penicillin, if parenteral treatment is refused, or in the presence of bleeding disorders: doxycycline 100mg orally every 12hours for 4 weeks (2, D).

Sodium penicillin G (also known as benzylpenicillin) 3-4 MIU IV every 4hours for 14 days (1, C) or 18-24 MIU/day in continuous IV infusion for 14 days.

Alternatives: IV ceftriaxone 2g daily for 10-14 days (1, C); procaine penicillin 2.4 MIU IM daily plus probenecid 500mg every 6hours for 10-14 days (1, C).

Desensitization and subsequent treatment with penicillin as the first-line therapy is recommended (1, C). The duration of the recommended and alternative regimens in neurosyphilis is shorter than treatments for latent syphilis, which is why some reports consider additional doses of benzathine penicillin 2.4 MIU IM weekly for 3 weeks after the IV treatment, providing a therapeutic duration comparable to latent forms.18,45

Summary of therapy inTable 1