The classic lesion of primary syphilis is a painless chancre, which identifies the site of inoculation of the bacteria in the body. It occurs between three and 90 days after inoculation (mean 21 days) and develops from a macule to a papule and nodule, which loses its covering epithelium and then becomes an erosion. The loss of deeper tissue produces an ulcer, typically measuring 0.5 to 3 cm in diameter. The central surface of the chancre is clean, smooth, and mucoid and produces a slight serous exudate. The border is usually flat and well-demarcated. Chancres are hardened to the touch due to the surrounding edema and lymphocytic infiltration, giving rise to the name “hard chancre” for this lesion which is usually solitary. The occurrence of two or more lesions may be related to coinfection with the HIV virus (Fig. 3). It is important to note that protosyphiloma can often go unnoticed by the patient due to the painless nature of the lesion.18,20–24

When the chancre is located in an area with excess skin, such as the foreskin, the presence of the “flag sign” or “button sign”, known in English as the “dory flop sign”, is evidenced during a dynamic inspection, which depicts this infiltrate and solid lesion moving en masse.22,24,25

Chancre redux is an uncommon form of recurrent syphilis, in which a primary syphilis lesion, usually a hard chancre, reappears at the site of the original infection after the person has been inadequately treated or has not completed treatment for the disease. This recurrence occurs due to the persistence of the bacterium Treponema pallidum in the body. Chancre redux is a sign that the infection has not been completely eradicated and that treatment should be reassessed to ensure the complete elimination of syphilis. It is currently a less common manifestation since treatments with appropriate antibiotics are usually effective. It should not be confused with pseudochancre redux, a clinical manifestation of tertiary syphilis that presents a gummatous lesion at the site of the original chancre.22,26

Primary infection in the glans penis may present with multiple erosions of treponematous origin characterized by flat, whitish elevations that are easily confused with fungal or irritative etiology. This atypical presentation is named after its first descriptor, “Follmann’s syphilitic balanitis”, and may develop before or after the appearance of the primary chancre.15,21,24,27–29

Another manifestation that has been observed at this stage is the presence of painless, hardened “cord-like” lesions on palpation, located mainly in the balanopreputial sulcus (Fig. 3).15

Fig. 3.

Primary syphilis lesions on the penis. A- Patient with a hard chancre lesion on the glans and two on the foreskin. B- Note the presence of a “cord-like” lesion in the balanopreputial sulcus (which can also be seen in patient A).

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The inguinal lymphadenopathy seen at this stage has been highlighted by secular researchers. It follows the lymphatic drainage chain, preferably unilateral and inflammatory, but may be bilateral: lesions on the penis and vaginal labia tend to show inguinal lymphadenopathy; anal lesions, lymphadenopathy in the pelvic and abdominal cavity; oral and labial lesions, submandibular and cervical lymphadenopathy. The presence of regional lymph node enlargement is so frequent that Fournier stated that this manifestation “follows the chancre as the shadow follows the body”, and it is also recognized as “mayor lymph node” (Fig. 4).21,24

Fig. 4.

Patient with primary syphilis showing left inguinal lymph node enlargement.

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Co-infection of Treponema pallidum and Haemophilus ducreyi, in the same ulcerated lesion, constitutes Rollet's mixed chancre (hard chancre associated with soft chancre). This situation is rarely described in the literature; perhaps not because of the rarity of the condition, but because of the syndromic approach to genital ulcers, with a low frequency of microbial investigation for both agents in the lesion.30

The primary form of syphilis can last between two and eight weeks and tends to disappear spontaneously, regardless of treatment, usually without leaving a scar.21,22,24,31 The chancre is identified in about 15% of patients at the beginning of the secondary stage, and cases that exhibit this concomitant primary and secondary phase should be investigated for immunosuppression as co-infection with the HIV virus.20–22

In untreated individuals, treponemas proliferate in the chancre and migrate via the lymphatic system to the bloodstream, from where they spread throughout the body. Signs and symptoms appear on average between six weeks and six months after infection and last on average between four and 12 weeks.19,22,31

Rarely, primary manifestations may be absent during the course of the infection, with the first signs of the disease represented by lesions in the secondary phase. This situation is known as “decapitated syphilis”, due to the absence of the primary phase during the course of the disease, or “syphilis d'emblée”, a French word that refers to the immediacy of the infection. It occurs when the treponema is inoculated directly into the bloodstream, such as untested blood transfusions or the sharing of needles.33

Thus, while primary syphilis represents the site of inoculation of the bacteria in the epithelium, secondary syphilis corresponds to the spread of the parasite throughout the host body. The most frequent clinical manifestations are mucocutaneous lesions (90%‒97%), with or without systemic signs and symptoms, such as generalized lymphadenopathy (50%‒85%), malaise (13%‒20%), sore throat (15%‒30%), body aches (6%‒8%), and low-grade fever (5%‒8%).22,26,31,34 Involvement of internal organs such as the lungs, stomach, and intestine has been described, causing a variety of symptoms and clinical presentations.35,36

The cutaneous and mucous lesions of secondary syphilis are called syphilides, and the first cutaneous sign of this stage is a macular rash (“syphilitic roseola”) that is ephemeral, lasting a few days, with a pale erythema (“cupric erythema” or “sad erythema”) and a preference for the trunk and limbs. In melanodermic individuals, the roseola phase may go unnoticed, due to the difficulty in perceiving mild erythema on dark skin (Fig. 5).22,26,31 Residual hypochromic macules (leukoderma) may follow the regression of the roseola stage and are more common in women with dark hair. Because it typically affects the neck and shoulders, it is known as the “necklace of Venus” and may be misdiagnosed as vitiligo.26,34

Fig. 5.

Patients with secondary syphilis; A- Patient presenting with syphilitic roseola; B- Patient with maculopapular exanthema on the trunk.

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The initial macular stage develops into a symmetrical papular eruption including the palms and soles, usually desquamative, with peripheral desquamation called “Biett collarette” (Fig. 6), which may also be smooth, follicular or, rarely, pustular. In this phase, the erythema is more intense and evident (Fig. 5). Vesicles do not usually occur, although vesicopustular lesions are seen on rare occasions and are common on the palms and soles (Fig. 7).22,26,31 Despite the extent of the lesions, pruritus is not a characteristic symptom of the disease. However, recent studies indicate that these eruptive lesions may be associated with this symptom, prominent eosinophilic infiltration on histopathology.37,38

Fig. 6.

Detail of a lesion in a patient with secondary syphilis, showing Biet's collarette.

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Fig. 7.

Palmoplantar involvement of secondary syphilis. A- Erythematous papules and macules on the palmar region; B- Erythematous-violaceous papular lesions on the plantar region.

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With persistence of the skin lesions, regression occurs in the affected body area, localized in segments of the skin, while the elementary lesions increase to nodules and plaques and may acquire a corymbiform aspect (Fig. 8).32,39,40 In skinfold areas, nodular and tumor lesions, called flat condylomas, appear (Fig. 9), which are extremely infectious and can be confused with condyloma acuminata caused by the human papillomavirus (HPV).31,34,41,42 In melanodermic patients, facial lesions may acquire annular and circinate configurations, being called elegant or beautiful syphilides (Fig. 10).26

Fig. 8.

A and B-Patients with secondary syphilis showing nodular lesions in the cervical region; B- Lesions in corymbiform arrangement.

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Fig. 9.

Perianal flat condyloma, clinical manifestation of secondary syphilis that is a differential diagnosis for condyloma acuminata.

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Fig. 10.

Perioral elegant syphilides, clinical manifestation of secondary syphilis in an Afro-descendant patient.

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Mucosal lesions are also common and characteristic of secondary syphilis, occurring in 30% to 40% of patients. Mucosal patches are exudative, oval, well-demarcated erosions with erythematous borders, most commonly manifesting on the tongue and lips; like flat condyloma, these lesions are highly infectious. Occasionally, erosions can coalesce and take on a linear outline, and are called “snail-track ulcers”. In the oral commissures, lesions may appear as papules with transverse erosions called “split papules” (Fig. 11).22,34,43,44

Fig. 11.

Oral mucosal lesions of secondary syphilis. A- linear erosions on the labial mucosa (“snail track ulcers”); B Papules with transverse erosions on the labial commissure (“split papules”).

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During the secondary stage, in addition to the involvement of the skin and mucous membranes, changes in the skin appendages may also occur, i.e., hair and nails. Hair loss is also called syphilitic alopecia (SA) which is classified as symptomatic (when lesions occur on the scalp associated with hair loss) and essential, when only hair loss occurs. The latter is subdivided into three patterns: patchy alopecia, diffuse alopecia, and mixed alopecia. Essential patchy SA is the most common and is characterized by the presence of multiple patches of non-cicatricial alopecia, without inflammation or desquamation; it is also called “moth-eaten” or “in clearings” (Fig. 12). It occurs mainly in the parieto-occipital region, but can also appear on the beard, eyelashes, armpits, pubis, trunk and legs. Diffuse essential SA is caused by telogen effluvium-like hair loss (Fig. 13), while mixed essential SA is characterized by small irregular patches that develop together with diffuse alopecia.45,46 In addition to these clinical forms, some authors describe a fourth pattern of essential SA: the alopecia areata-like type (Fig. 13).25

Fig. 12.

Alopecia in secondary syphilis. A - “moth-eaten” pattern; B - “clearing” pattern.

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Fig. 13.

Manifestations of alopecia in secondary syphilisA- Diffuse essential alopecia; B- Alopecia areata-like lesion.

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Changes in the nail apparatus are rare. Changes in the nail plate result from the involvement of the matrix, causing fragility, splitting, fissures, corrosion, onycholysis, Beau's lines, onychomadesis (Fig. 14), and even loss of the nail. The onset of a periungual and/or subungual inflammatory leads to syphilitic paronychia, with erythema and edema in the periungual tissues.22,47

Fig. 14.

A and B- Involvement of the nail apparatus in a patient with secondary syphilis, characterized by onychomadesis.

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Malignant syphilis, or nodular-ulcerative syphilis, is typically characterized by the presence of asymmetric ulcers or round necrotic plaques with lamellar or rupioid crusts located on the scalp, face, trunk, and extremities. Oral ulcers may occur with systemic signs and symptoms; fever, headache, and lymphadenopathy are usually present. It is more common in patients with HIV infection and low CD4 + T lymphocyte counts, malnourished patients, MSM, patients with previous syphilis, diabetes mellitus, tuberculosis, and alcohol abuse.14,18,20,22

In addition to the skin manifestations caused directly by Treponema pallidum infection, there are reports of skin reactions secondary to the bacteria, considered reactive conditions, more common during secondary syphilis. The cases described are more common in patients with HIV coinfection and range from manifestations of Sweet's syndrome to erythema multiforme.16,48,49 They are diagnosed by associating the clinical picture with positive serology for syphilis and a reactive pattern on histopathology, with no evidence of the bacteria by immunohistochemistry. Unlike the Jarisch-Herxheimer condition, where exacerbation of skin lesions occurs after the institution of treatment, these reactive conditions appear before and improve after treatment.

Secondary lesions tend to regress spontaneously after four to 12 weeks. Most lesions do not leave scars, but anetoderma may occur, most commonly reported in patients with positive HIV serology.16,39

Neurosyphilis results from treponemal invasion of the CNS, with an increasing number of cases described in immunocompetent and heterosexual patients.13 Invasion of the meninges by treponema occurs early, 12 to 18 months after infection, but disappears in 70% of the cases without treatment. When the infection persists, which occurs during any stage of the infection, neurosyphilis appears, which may be symptomatic or asymptomatic.26

In asymptomatic neurosyphilis, the patient does not have clinical manifestations, but there is evidence of CNS infection in the analysis of the cerebrospinal fluid (reactive VDRL, elevated protein or leukocyte count).22

In symptomatic neurosyphilis, the clinical picture is usually nonspecific and can develop at any time during the natural history of the disease. In patients with coinfection with the HIV virus, a more fulminant course usually occurs, while in immunocompetent individuals, the disease is more insidious, with nonspecific symptoms.13,22

The most common first symptoms of neurosyphilis are mild meningeal signs, such as headache and nausea. Cranial nerve palsies may occur, with unilateral or bilateral hearing loss, with or without tinnitus and nystagmus. Meningitis can cause fever, meningismus, and photophobia. In meningovascular syphilis, arteritis causes infarctions in the brain or spinal cord. The investigation of recent neurosyphilis should be performed in syphilitic patients with neurological or ocular signs, immunosuppression, or those who do not reduce VDRL levels after treatment.

Late symptomatic neurosyphilis, rare in the antibiotic era, most commonly causes general paresis (also called general paresis of the insane or paralytic dementia), which can manifest with dementia, seizures, and other psychiatric manifestations. Tabes dorsalis may also occur, which can manifest as fulminant pain, urinary incontinence, and erectile dysfunction, ataxia, Argyll-Robinson pupil (reacting to accommodation/focusing, but not to light), loss of reflexes, and impaired vibratory sensation.22 In a review of 137 articles, reporting on 286 patients with neurosyphilis, only 10% had coinfection with HIV. The most relevant clinical presentations were general paresis (49% of cases), manifested by cognitive impairment and psychiatric changes, followed by syphilitic meningitis (22%), meningovascular syphilis (11.5%), tabes dorsalis (11.5%), parenchymal gummas (3.5%) and epilepsy (2%).13

Ocular syphilis is considered a type of neurosyphilis. While most cases of syphilitic meningitis are accompanied by ocular involvement, ocular syphilis is not always accompanied by syphilitic meningitis.13,50 Therefore, ocular syphilis should be suspected in any case of unexplained ocular inflammation. The disease can occur up to six weeks after transmission and be the only presenting feature of systemic syphilis. The most common findings are panuveitis and posterior uveitis, but ocular involvement can manifest in a variety of ways, affecting both the anterior segment of the eye (conjunctiva, cornea, and sclera) and the posterior segment (choroid and retina). These manifestations rarely occur in the primary stage, except as hard chancres located on the eyelid and conjunctiva. Keratitis, iris nodules, iridocyclitis, episcleritis, and scleritis may occur early in secondary syphilis, and chorioretinitis and vitritis may occur later in the secondary stage. However, ocular involvement is even more frequent in the late, latent, and tertiary stages of syphilis.50,51

Latent syphilis occurs when serological tests are positive but there is no clinical evidence of infection. The period of up to one year after contamination is classified as early latent syphilis, and from this date onwards, late latent syphilis begins.51

The diagnosis is generally based on situations in which tests are requested for patients without clinical symptoms, such as sexual partners or contacts of patients diagnosed with syphilis, routine or screening tests.

Based on studies that monitored the natural progression of syphilis, one-third of patients who had regression of secondary lesions achieve clinical and serological cure, one-third will develop no symptoms but will maintain positive non-treponemal serological tests, and the last third will have the disease progress to tertiary syphilis years to decades after the infection.52,53

Tertiary syphilis is rare and may manifest with mucocutaneous, cardiac, ophthalmological, neurological, skeletal, or gastric alterations.54–57 The incidence of this phase of the disease decreased drastically with the use of penicillin in the treatment of the initial phases.58

The skin is the most affected organ. Cutaneous tertiary syphilis is classified as nodular and gummatous; the former shows dermo-epidermal involvement and the latter, hypodermal involvement.54,57 The lesions of the nodular form are generally asymmetrical, chronic in appearance, painless, and slowly progressive in growth. The nodules are usually located on the face, interscapular areas, and extremities. These lesions may remain isolated, coalesce to form plaques or tumors, be distributed in an arciform pattern, or ulcerate.54,58–61 The gummatous form presents as firm and painless subcutaneous nodules, usually solitary, which later develop ulcerations and drain solid necrotic material. These are destructive lesions that can invade deep into the tissue and bone, healing with deeply retracted scars. Due to the frequent involvement of the cardiovascular system, especially the ascending aorta, adequate cardiac investigation is recommended.13,22,54,58,62,63

It is known that syphilis can increase the risk of acquiring and transmitting HIV by two to ninefold, mainly due to genital ulcers; while HIV infection and antiretroviral therapy (ART) can, in additionally facilitate infection due to a decrease in the immune response mediated by T cells, and alter the natural history and clinical presentation of syphilis.64,65

In patients living with HIV, syphilis can present concomitant clinical manifestations of two different clinical stages, in addition to a greater predisposition to the formation of atypical, larger, and deeper lesions. Multiple primary chancres, a greater number of ulcerated lesions, and early malignant syphilis in the secondary form, systemic manifestations such as uveitis, aortitis, encephalitis, arthritis, gastric and hepatic involvement can be observed. The rate of neurological involvement is high, and this involvement is often early and asymptomatic.66–68

Dark-field treponema testing is performed using samples obtained from primary or secondary syphilis lesions in adults or children. Collecting material from lesions in the oral cavity is not recommended due to the presence of other saprophytic spirochetes, which may result in false reactive tests. The test should be performed on fresh serous exudate from the lesion, avoiding erythrocytes, other organisms, and tissue debris. The collected sample should be immediately analysed on a microscope with a dark-field condenser to look for T. pallidum.

To identify T. pallidum using this technique, it is important to observe its morphology, size and typical movements. The spirochete consists of a thin organism (0.10 to 0.18 μm wide), 6 to 20 μm long, and with 8 to 14 regular spirals. T. pallidum moves quickly, and it is possible to identify elongation and shortening movements; it rotates relatively slowly around its longitudinal axis, in addition to performing syncopated flexions and twists in its central region. In dark-field microscopy, the spirochetes appear as bright, white spiral bodies, illuminated against a black background.72

Sample collection for this examination should be performed in the same manner as is done for direct examination of fresh material. The available methods are:

• •

  Fontana-Tribondeau method: the sample is smeared and allowed to dry on the slide and then stained with silver nitrate, which will impregnate the cell wall of the treponema, thus allowing the parasite to be seen under the microscope;

• •

  Burri method: this technique is performed with Indian ink;

• •

  Giemsa staining method: T. pallidum is stained faintly (palely), making it difficult to observe the spirochetes;

• •

  Levaduti method: uses silver in histological sections.

The sensitivity of the examination of stained material is lower than that of dark-field treponema testing.72

CSF puncture is indicated in cases of suspected neurosyphilis and is recommended in specific situations for syphilis diagnosis and patient follow-up after treatment has been implemented. It is worth emphasizing that the CSF analysis should include cytology, biochemical profile, and VDRL in the material.

Lumbar puncture is indicated for neurosyphilis screening in the following cases: presence of neurological or ophthalmological symptoms; in case of evidence of active tertiary syphilis and after clinical treatment failure without sexual re-exposure. For PLHIV, lumbar puncture is indicated after treatment failure, regardless of sexual history.

In the follow-up of a patient initially treated without neurosyphilis, the procedure is recommended when there is suspected treatment failure, that is, failure of the non-treponemal test to decrease in outpatient serological follow-up. The puncture is also indicated for patients diagnosed with neurosyphilis; the test should be performed every six months for laboratory monitoring of their infection. Treated patients who do not show the expected reduction in VDRL titers should be investigated through cerebrospinal fluid puncture for the possibility of neurosyphilis.

Although it is not considered a criterion by the Ministry of Health, some authors indicate the test for all patients coinfected with syphilis and HIV, regardless of the clinical stage, who meet at least one of the following criteria:71

• •

  Neurological or ophthalmological signs or symptoms;

• •

  Evidence of active tertiary syphilis (aortitis, syphilitic gummas, among others);

• •

  After clinical treatment failure.

The first-line antibiotic is benzathine penicillin G, at a total dose of 2,400,000 IU, administered intramuscularly, in a single dose – 1,200,000 IU is administered in each buttock. Doxycycline, 100 mg, orally, twice a day for 15 days, can be used as an alternative drug (except for pregnant women).

Benzathine penicillin G is administered at a dose of 2,400,000 IU intramuscularly once a week for three weeks, totaling 7,200,000 IU. The alternative drug is doxycycline, 100 mg, orally, twice a day for 30 days (except for pregnant women). For pregnant women proven to be allergic to penicillin, desensitization is recommended in a tertiary service, according to existing protocols.

Individuals with a confirmed diagnosis of syphilis, whose disease duration cannot be determined, should be treated as having late latent syphilis.

Since penicillin G benzathine is not able to cross the blood-brain barrier, treatment of neurosyphilis is hospital-based, carried out with crystalline penicillin, 18-24 million units per day, intravenously, administered in doses of 3-4 million IU, every four hours, for 14 days. Ceftriaxone, 2 g, administered intravenously, once a day, can be used as an alternative drug, for ten to 14 days.

Recent phase: penicillin G benzathine, 50,000 IU/kg, intramuscularly, in a single dose.

Late phase: 50,000 IU/kg of body weight, intramuscularly, once a week, for three weeks.73

According to the Brazilian Ministry of Health, given the current epidemiological scenario, immediate treatment with benzathine benzylpenicillin is recommended, after only one reactive test for syphilis (treponemal or non-treponemal test) for the following situations (regardless of the presence of signs and symptoms of syphilis): pregnant women, victims of sexual violence, individuals with a chance of loss to follow-up, individuals with signs and/or symptoms of primary or secondary syphilis and individuals without a previous diagnosis of syphilis.

In PLHIV, treatment should be carried out in a similar way to that of non-co-infected individuals. To date, in Brazil, there is no evidence of T. pallidum resistance to benzathine penicillin.

In PLHIV with early syphilis, there may be an increased risk of neurological complications and higher rates of inadequate serological response following the use of recommended regimens. Although data are limited, no syphilis treatment regimen has been shown to be more effective in preventing neurosyphilis in PLHIV than the syphilis regimens recommended for the general population.74

Careful follow-up after therapy is essential, and the use of antiretroviral therapy according to current HIV guidelines may improve clinical outcomes among people co-infected with HIV and syphilis. Differences in treatment response in HIV-syphilis co-infected patients may not apply to those with virological suppression of HIV.75

The Jarisch-Herxheimer reaction is characterized by the exacerbation of pre-existing skin lesions, associated with pain or pruritus, general malaise, fever, chills, headache, and arthralgia. This clinical picture is due to the massive destruction of treponemes by treatment, which causes an antigen storm in the host that induces an inflammatory response in the same proportions. Thus, it is more common in the treatment of secondary forms, mainly those with high titers in non-treponemal tests, and can occur during the 24 hours after the first dose of penicillin. This picture usually regresses spontaneously in 24 to 48 hours. If necessary, analgesics can be used.75

The main differential diagnosis is allergy to benzathine penicillin. However, this condition is rare and is usually characterized by the presence of urticarial lesions.

Non-treponemal tests are important in monitoring the cure of patients and should be performed three, six and 12 months after treatment.

An adequate immunological response to treatment is accepted when there is a decrease in the titer of two dilutions of non-treponemal tests within six months in individuals with recent syphilis, and two dilutions within twelve months in cases of late syphilis.76 Seroreversion (non-reactive non-treponemal test) or progression to serological scarring may occur. Negative treponemal tests are not expected after the patient is cured.

Patients, including people living with HIV, should be monitored after completing treatment for syphilis using a non-treponemal test, preferably the same diagnostic method, every three months until the 12th month of patient follow-up, and every six months until the 24th month for patients whose tests were not negative. Pregnant women should be tested monthly.

One of the pillars of the control actions for acquired syphilis is the continuous encouragement of educational activities for all STIs, encouraging their prevention through the use of condoms. Early diagnosis of the disease should be encouraged by expanding the supply of rapid tests in the public health system. It is also important that health professionals, especially those working in primary care, receive continous training for early diagnosis, correct treatment, adequate follow-up, and reporting of syphilis cases.77

Evaluation and treatment of sexual partners are crucial for interrupting the chain of syphilis transmission. For partners that report exposure to a person with syphilis, within 90 days, it is recommended that these sexual partners be offered presumptive treatment (regardless of the clinical stage or signs and symptoms), with a single dose of benzathine benzylpenicillin 2.4 million IU, IM (1.2 million IU in each buttock).

In addition to promoting safe sex based on condom use, other prevention measures are important and complementary to safe sexual practices, such as immunization for hepatitis B, C, and HPV; knowledge of the HIV serological status of the sexual partner(s); regular testing for HIV and other STIs; testing of all PLHIV; performing preventive exams for cervical cancer; performing pre-exposure prophylaxis (when indicated); access to contraception and conception and performing post-exposure prophylaxis (when indicated).72

It should be noted that, in the case of suspected syphilis or when unprotected sexual contact is referred, testing should be indicated, in endemic areas, not only for treponematosis but also for other detectable STIs such as HIV, hepatitis and HTLV.