Version May 2024
INTRODUCTION — Syphilis is an infection caused by the bacterium Treponema pallidum. Most new cases of syphilis are sexually acquired. The clinical manifestations depend upon the stage of disease. Studies performed in the preantibiotic era permit a relatively complete understanding of the natural history of untreated syphilis. Information about the natural history of untreated syphilis in humans derives from data collected from several sources:
●In the late 19th century, a Norwegian physician described the evolution of infection in more than 1400 patients with primary and secondary syphilis. Because he believed that the available therapies at the time were highly toxic and of little benefit, patients received no treatment [1].
●Additional data were collected from a study of 382 adults with syphilis who underwent autopsies between 1917 and 1941 [2]. This compilation provided pathologic confirmation of the late manifestations of syphilis.
●Finally, the Tuskegee study conducted between 1932 and 1972 collected data on 431 Black men whose syphilis was untreated [3]. This project was initiated prior to the availability of effective therapy for syphilis, but it profoundly violated ethical standards by not providing study participants with treatment proven to be effective once it became available. Moreover, the study participants were not given sufficient information about the study to provide informed consent. These ethical concerns significantly impacted clinical research by engendering distrust between investigators and potential study participants that persists to this day; efforts to address these concerns have led to major reforms in clinical research standards and requirements.
The epidemiology, pathogenesis, and clinical manifestations of syphilis will be reviewed here. Discussions of the diagnosis and treatment of syphilis, as well as syphilis in special populations, are found elsewhere:
●(See "Syphilis: Treatment and monitoring".)
●(See "Syphilis: Screening and diagnostic testing".)
●(See "Syphilis in pregnancy".)
●(See "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis".)
●(See "Congenital syphilis: Management and outcome".)
MICROBIOLOGY — T. pallidum, the causative organism of syphilis, was first identified in 1905 [4]. It is a bacterium from the order Spirochaetales and is one of several closely related treponemes that cause human disease [5]. T. pallidum is approximately 10 to 13 microns long but only 0.15 microns in width making it too slender to be visualized by direct microscopy. This feature greatly complicates diagnosis.
The organism can be seen with darkfield microscopy, a technique that employs a special condenser that casts an oblique light. When visualized by this method, T. pallidum is a delicate, corkscrew-shaped organism with tightly wound spirals (picture 1). It exhibits a characteristic rotary motion with flexing and back-and-forth movement, features considered sufficiently characteristic to be diagnostic [6].
EPIDEMIOLOGY
●Worldwide – The World Health Organization (WHO) estimates that worldwide in 2016 there were 19.9 million prevalent cases of syphilis in adolescents and adults aged 15 to 49 years and 6.3 million new cases [7]. As of 2014, the median case rate was 17.2 cases per 100,000 females and 17.7 cases per 100,000 males [8]. The highest prevalence was reported in the WHO Western Pacific region (93 cases per 100,000 adult population), followed by the African region (46.6 cases per 100,000 adult population), and the region of the Americas (34.1 cases per 100,000 adult population).
●United States – In the United States, syphilis has been a nationally notifiable disease since 1944. Its unique laboratory diagnostic features ensure that most cases are reported. Although there are relatively accurate statistics on the incidence of new infections [9], some data are still limited by missing demographic information.
In the late 1980s and early 1990s, there was a mini epidemic of early syphilis that produced case rates that were higher than at any time since the introduction of penicillin in 1943. The number of cases peaked in 1990 (20.3 cases per 100,000 population) but subsequently fell to a new nadir in 2000, raising hopes for eradication [10,11]. However, the number of cases has continued to climb almost every year since that time (figure 1). In 2021, 176,713 cases of syphilis (all stages) were reported [12]. The total rate of syphilis increased approximately 32 percent during 2020 to 2021. The United States Centers for Disease Control and Prevention (CDC) states that the increased case counts seen in late-2020 and in 2021 may have been impacted by the COVID-19 pandemic and reflect an increase in health care utilization [13].
In 2021, 53,767 cases of primary and secondary syphilis (the most infectious stages) were reported [12]. The rate of primary and secondary syphilis cases increased 28.6 percent from 2020 to 2021 with 16.2 cases per 100,000 population reported in 2021. Approximately 75 percent of primary and secondary syphilis cases occurred in men [12].
The rise in the rate of reported primary and secondary syphilis cases has been primarily attributable to increased cases in men who have sex with men (MSM) (figure 2) [12]. Gay, bisexual, and other MSM accounted for 46 percent of all male primary and secondary syphilis cases in 2021. Risk factors for acquisition of syphilis in MSM include methamphetamine use (figure 3) and having acquired recent sexual partners via social media [14,15].
Since 2012, the rate of primary and secondary syphilis in females has increased by over 700 percent, with an increase of 55 percent from 2020 to 2021 (4.7 to 7.3 cases per 100,00) [12]. The rate was higher in Black females compared with females of Hispanic ethnicity and White females (17.2, 6.1, and 4.8 per 100,000 population, respectively). A report from the United States CDC suggests that the increased rate of syphilis in females may be due in part to increased drug use [16]. In 2018, 29.3 percent of females with a diagnosis of primary or secondary syphilis reported recent injection drug use or use of heroin, methamphetamine, or crack/cocaine [17]. This rate of substance use was higher than in men who have sex with women or MSM diagnosed with primary and secondary syphilis (22.7 and 12.4 percent, respectively).
With the increased number of cases in women, there has also been an increase in the number of cases of congenital syphilis. In 2021, 2855 cases of congenital syphilis were reported, including 220 congenital syphilis-related stillbirths and infant deaths [12]. (See "Syphilis in pregnancy" and "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis".)
Other epidemiologic trends include the following:
•There is a high rate of human immunodeficiency virus (HIV) coinfection among MSM with syphilis. Available data from 2021 suggest that approximately 45 percent of MSM with primary and secondary syphilis have HIV, compared with about 7 percent of men who have sex with women and 4 percent of women [12]. (See "Syphilis in patients with HIV", section on 'Epidemiology'.)
•In men, the highest rates of primary and secondary syphilis in 2021 occurred in those aged 25 to 34 years (figure 4) [12].
•The rate of reported primary and secondary syphilis cases remains highest among Black individuals, with the overall rate of syphilis being highest in Black men. As an example, in 2021, the rate of reported cases per 100,000 population was 68.3 in Black men, 27.8 in men of Hispanic ethnicity, and 13.4 in White men [12].
Late syphilis occurs in an uncertain proportion of patients infected by T. pallidum, with the uncertainty due to the lack of reliable systems for reporting late stages of the disease. However, there has also been an upward trend in late syphilis (including late latent syphilis) and syphilis of unknown duration, with the CDC reporting 9.4 cases per 100,000 in 2016 and 20.5 cases per 100,000 in 2020 [12]. This may be due in part to the resurgence in early syphilis that occurred in the United States in the late 1980s and early 1990s. Implementation of the reverse sequence screening method (ie, an initial treponemal test followed by a confirmatory nontreponemal test) in many labs across the country may also contribute to this upward trend in late and late latent syphilis cases. The reverse approach detects cases of late and late latent syphilis in patients whose nontreponemal test has become nonreactive over time. (See "Syphilis: Screening and diagnostic testing", section on 'Serologic testing algorithms'.)
More detailed surveillance data can be found on the CDC website.
TRANSMISSION — Transmission of T. pallidum usually occurs via direct contact with an infectious lesion during sex. In addition, T. pallidum readily crosses the placenta thereby resulting in fetal infection. The acquisition of syphilis through transfused blood is very rare because all donors are screened and T. pallidum cannot survive longer than 24 to 48 hours under blood bank storage conditions. Additional discussions of syphilis transmission during pregnancy and through blood donations are found elsewhere. (See "Syphilis in pregnancy" and "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis", section on 'Transmission' and "Blood donor screening: Laboratory testing", section on 'Syphilis'.)
Sexual transmission requires exposure to open lesions with organisms present, features seen with the primary chancre and with some of the manifestations of secondary syphilis (mucous patches and condyloma lata). These lesions are very infectious, with an efficiency of transmission estimated at approximately 30 percent [3,18]. By contrast, the cutaneous lesions of secondary syphilis contain few treponemes, and the risk of transmission through intact skin is low. Patients with early latent syphilis are considered infectious due to concern for recently active lesions that are no longer present or active lesions that were missed on the initial evaluation.
T. pallidum can initiate infection wherever inoculation occurs. Thus, contact of infected secretions with almost any tissue can lead to a primary syphilis lesion at that site, and syphilis can be spread by kissing or touching a person who has active lesions on the lips, oral cavity, breasts, or genitals. As an example, transmission of syphilis has been identified in men who have sex with men (MSM) who have reported oral sex as their only risk factor for acquisition [19]. Additional information on the pathophysiology of early infection is found below. (See 'Early local infection' below.)
Syphilis is also associated with the transmission and acquisition of other sexually transmitted infections (eg, HIV). As an example, in a study examining the HIV incidence among men with new primary and secondary syphilis, 1 in 20 MSM were diagnosed with HIV within one year of a syphilis diagnosis [20]. (See "Approach to the patient with genital ulcers" and "Syphilis in patients with HIV", section on 'Epidemiology'.)
PATHOPHYSIOLOGY — The understanding of T. pallidum pathophysiology is impeded by the inability to grow the organism in culture. Thus, knowledge of the growth characteristics and metabolism of this bacterium are quite limited. Data in animal models and human subjects form the basis of most of the available information on this pathogen [5,21]. The pathogenesis of neurosyphilis is discussed elsewhere. (See "Neurosyphilis", section on 'Pathogenesis'.)
Early local infection — T. pallidum initiates infection when it gains access to subcutaneous tissues via microscopic abrasions [22]. Despite a slow estimated dividing time of 30 hours, the spirochete evades early host immune responses and establishes the initial ulcerative lesion, the chancre (picture 2). During the period of early local replication, some organisms establish infection in regional draining lymph nodes with subsequent dissemination.
T. pallidum elicits innate and adaptive cellular immune responses in skin and blood. The host immune response begins with lesional infiltration of polymorphonuclear leukocytes, which are soon replaced by T lymphocytes [23]. In one study of 23 patients with secondary syphilis, leukocytes were obtained from syphilitic lesions and peripheral blood mononuclear cells [24]. Compared with peripheral blood, lesional fluids were enriched with CD4+ and CD8+ T cells, activated monocytes, macrophages, and dendritic cells. Many of these dendritic cells also expressed HIV coreceptors (eg, CCR5 and DC-SIGN), which may help explain the epidemiologic link between syphilis and HIV transmission. (See "The natural history and clinical features of HIV infection in adults and adolescents", section on 'Alterations in the CCR5 coreceptor' and "Syphilis in patients with HIV", section on 'Epidemiology'.)
After acquisition of T. pallidum, humoral immune responses are also generated. This leads to the development of a variety of antibodies that can be detected relatively early in the course of syphilis. (See "Syphilis: Screening and diagnostic testing".)
In some respects, the immune response to T. pallidum is paradoxical. On one hand, the various immune responses during early infection appear to be efficacious, since they coincide with resolution of the primary chancre, even in the absence of therapy. However, despite this apparent immune control, widespread dissemination of spirochetes occurs at the same time, leading to subsequent clinical manifestations of secondary or tertiary syphilis in untreated patients. (See 'Clinical manifestations' below.)
Late infection — Cellular immunity is important for control of syphilis in experimental infection and probably contributes to the pathogenesis of late syphilis [25]. The prolonged latent period that is characteristic of most types of late syphilis suggests that immune mechanisms may be involved in one of two ways. Waning immunity with aging may facilitate recrudescence of a small number of treponemes that had survived in sequestered sites. Alternatively, a partially immune hypersensitive host may react to the presence of treponemes, engendering a chronic inflammatory response.
Gummas, or late benign syphilis often involving the skin, viscera, or other tissues (eg, bone, brain, abdominal viscera), are characterized pathologically by the presence of granulomas, a finding that is consistent with a cellular hypersensitivity reaction (see 'Gummatous syphilis' below). Experimental studies with human subjects who were inoculated cutaneously with live T. pallidum found that gummas developed only in those who had previous syphilis [21].This suggests that development of gummas requires an immune response insufficient to be protective but substantial enough to cause tissue damage and granuloma formation in the reinfected host. It is important to note that this study in human subjects was conducted in prisoners in the 1950s and was not subject to rigorous ethical review that would be expected in the current research landscape.
Cardiovascular syphilis with involvement of the ascending arch of the aorta and aortic valve is a consequence of vasculitis of the vasa vasorum ("endarteritis obliterans"). Small vessel vasculitis is a common manifestation of secondary and later stages of syphilis as evidenced by the presence of lymphocytes and plasma cells infiltrating blood vessels and perivascular tissues.
STAGES OF DISEASE — Patients with syphilis can present with a wide range of symptoms depending upon the stage of disease. Others will have serologic evidence of syphilis based upon laboratory testing but will not have symptoms (ie, latent syphilis). (See 'Latent syphilis (asymptomatic)' below.)
Syphilis is generally divided into early and late stages (table 1).
●Early syphilis – Early syphilis comprises primary and secondary syphilis, which typically occur within weeks to months after initial infection as well as early latent syphilis (asymptomatic infection that was acquired within the previous 12 months). (See 'Primary syphilis (chancre)' below and 'Secondary syphilis' below and 'Latent syphilis (asymptomatic)' below.)
●Late syphilis – When patients are untreated during the earlier stages of syphilis, they can progress to late latent disease (which is asymptomatic) or develop major complications of the infection (eg, tertiary syphilis). The clinical events occurring as a consequence of late syphilis may appear at any time from 1 to 30 years after primary infection and can involve a wide variety of different tissues. (See 'Late syphilis' below.)
Patients can present with central nervous system (CNS) manifestations (neurosyphilis) at any time during the course of infection. A detailed discussion of neurosyphilis is found elsewhere. (See "Neurosyphilis".)
CLINICAL MANIFESTATIONS — Patients with signs and symptoms consistent with syphilis should undergo serologic testing to confirm the diagnosis. However, certain patients can be treated empirically based upon the clinical findings (eg, patients with a suspected chancre and a known exposure). Discussions of the diagnosis and treatment of syphilis are found elsewhere. (See "Syphilis: Screening and diagnostic testing" and "Syphilis: Treatment and monitoring".)
Early syphilis
Primary syphilis (chancre) — Following acquisition of T. pallidum, the initial clinical manifestation of infection is a localized skin lesion termed a chancre. The median incubation period before the chancre appears is 21 days (range 3 to 90 days) [26]. (See 'Pathophysiology' above.)
The lesion begins as a papule, which is typically (but not always) painless, appearing at the site of inoculation. This soon ulcerates to produce the classic chancre of primary syphilis, a 1 to 2 centimeter ulcer with a raised, indurated margin (picture 3A-C). The ulcer generally has a nonexudative base and is associated with mild to moderate regional lymphadenopathy that is often bilateral. Such lesions usually occur on the genitalia, but occasionally patients may develop chancres at other sites of inoculation (picture 4). These sites may include areas that may not be noticeable to the patient, including the posterior pharynx, anus, or vagina. Infrequently, multiple chancres occur, particularly in the setting of HIV infection. (See "Syphilis in patients with HIV", section on 'Early syphilis'.)
Chancres heal spontaneously within three to six weeks even in the absence of treatment. Since the ulcer is painless, many patients do not seek medical attention, a feature that enhances the likelihood of transmission. The mechanism of healing is unknown but is thought to be a consequence of local immune responses [27]. (See 'Early local infection' above.)
The chancre represents an initial local infection, but syphilis quickly becomes systemic with widespread dissemination of the spirochete. This dissemination may or may not be associated with concurrent systemic symptoms but is the pathophysiologic basis for subsequent secondary and/or late syphilis, including neurosyphilis.
Secondary syphilis — Within weeks to a few months after the chancre develops, approximately 25 percent of individuals with untreated infection develop a systemic illness that represents secondary syphilis [1]. Patients with secondary syphilis may not have a history of a preceding chancre since the primary infection may have been asymptomatic and/or gone unnoticed.
Similar to primary disease, the acute manifestations of secondary syphilis typically resolve spontaneously, even in the absence of therapy, except in the case of severe cutaneous ulcerations called lues maligna (picture 5A-C). Occasionally, untreated patients experience additional episodes of relapsing secondary syphilis, which can occur for up to five years after their initial episode [1].
Secondary syphilis can produce a wide variety of signs and symptoms, which are described below.
Generalized symptoms
●Constitutional symptoms – Patients with secondary syphilis may develop systemic symptoms including fever, headache, malaise, anorexia, sore throat, myalgias, and weight loss. These clinical manifestations probably reflect the brisk immunologic response resulting from widespread dissemination of T. pallidum.
●Adenopathy – Most patients with secondary syphilis have lymph node enlargement with palpable nodes present in the posterior cervical, axillary, inguinal, and femoral regions (picture 6). The finding of epitrochlear nodes is particularly suggestive of the diagnosis. These nodes are generally minimally tender, firm, and rubbery in consistency.
Dermatologic findings
●Rash – Rash is the most characteristic finding of secondary syphilis. However, in one series of 105 patients with secondary syphilis, more than 20 percent had lesions that were not appreciated by the patient [28].
The rash can take almost any form, although vesicular lesions are uncommon. As examples:
•The rash is classically a diffuse, symmetric macular or papular eruption involving the entire trunk and extremities (picture 7A-F) including the palms and soles (picture 8A-D). Although involvement of the palms and soles is an important clue to the diagnosis of secondary syphilis, localized lesions can also occur [29].
Individual lesions are discrete copper, red, or reddish-brown and measure 0.5 to 2 cm in diameter [27,28]. Although lesions are often scaly, they may be smooth. In addition, nodular lesions also may be seen. On occasion, the rash may be pruritic.
•Pustular syphilis can take the form of small pustular syphilide, large pustular syphilide, flat pustular syphiloderm, and pustular-ulcerative syphilide (ie, malignant syphilis) [29].
•Secondary syphilis can also affect mucosal surfaces [28]. Patients may develop mucous patches, whitish erosions on the oral mucosa or tongue (picture 9A-C), and split papules at the oral commissures. Large, raised, gray to white lesions called condylomata lata may develop in warm, moist areas such as the mouth and perineum (picture 10A-D). Condylomata lata occur most often in areas proximate to the primary chancre and may reflect direct spread of organisms from the primary ulcer [27]. Mucous patches and condylomata lata contain large numbers of T. pallidum organisms (picture 11).
•In patients with HIV, a more severe ulcerative form of secondary syphilis termed "lues maligna" has been reported (picture 5A-D) [30]. It occurs principally in persons with severely compromised immune systems and presents with nonresolving severe ulcerative skin lesions. (See "Syphilis in patients with HIV", section on 'Secondary syphilis'.)
●Alopecia – So-called "moth-eaten" alopecia is occasionally seen among patients presenting with secondary syphilis (picture 12A-C). This may be noted on the scalp, eyebrows, or beard and is usually reversible with treatment.
Gastrointestinal findings
●Hepatitis – Syphilitic hepatitis is characterized by a high-serum alkaline phosphatase level on laboratory examination, often with normal or only slightly abnormal transaminases [31,32]. Mild clinical hepatitis resolves with treatment.
●Gastrointestinal abnormalities – The gastrointestinal tract may become extensively infiltrated or ulcerated; this can be misdiagnosed as lymphoma.
Musculoskeletal abnormalities — Synovitis, osteitis, and periostitis can occur but usually resolve after treatment [33].
Renal abnormalities — Patients with secondary syphilis can have mild transient albuminuria, nephrotic syndrome, or acute nephritis with hypertension and acute renal failure [34]. Pathologically, membranous glomerulonephritis or diffuse endocapillary glomerulonephritis, sometimes with crescents, can be seen. Resolution of renal abnormalities follows treatment for syphilis.
Neurologic findings — The early clinical manifestations of neurosyphilis are reviewed below and described in detail separately. (See "Neurosyphilis".)
●Headache – Invasion of the cerebrospinal fluid is common in early untreated disease, especially secondary syphilis.
●Meninges and vascular manifestations – Patients may present with meningitis, cranial nerve deficits, meningovascular disease, or stroke.
Visual/auditory findings — Ocular or otic infection can occur at any stage of disease but is most commonly identified during the early stages [35]. Otosyphilis is diagnosed less often than ocular syphilis.
Although these findings can present with or without additional central nervous system (CNS) involvement, these types of infections are managed the same way as CNS infections. (See "Syphilis: Treatment and monitoring", section on 'Treatment of neuro/ocular/otic syphilis'.)
●Ocular syphilis – A sometimes-underappreciated manifestation of syphilis is eye involvement, which has been increasingly reported in the last several years and may be more common among persons with HIV [36-38]. One report suggests ocular syphilis may be associated with certain strains of T. pallidum [39]. (See "Syphilis in patients with HIV", section on 'Neurologic/ocular syphilis'.)
Patients can develop anterior uveitis, posterior uveitis, or panuveitis, which is often granulomatous. Most patients with ocular syphilis develop diminished visual acuity secondary to posterior uveitis (picture 13) [36,40]. Posterior uveitis typically presents as multifocal chorioretinitis; however, other manifestations include retinal necrosis and optic neuritis.
Involvement of the eye in patients with syphilis should be evaluated and managed emergently, especially when retinal involvement is present. Vision loss can occur with ocular syphilis and may be rapidly progressive; however, it can be prevented or minimized with early therapy. (See "Syphilis: Treatment and monitoring", section on 'Treatment of neuro/ocular/otic syphilis'.)
●Otosyphilis – Otosyphilis typically presents with cochleo-vestibular symptoms, such as tinnitus, vertigo, and sensorineural hearing loss [35]. Hearing loss can have a sudden onset and be unilateral or bilateral. Symptoms can progress rapidly and in some patients may result in permanent hearing loss.
Late syphilis — Approximately 25 to 40 percent of patients with untreated syphilis can develop late disease. The clinical events may appear at any time from 1 to 30 years after primary infection [2]. It is not necessary for individuals to have experienced clinically symptomatic primary or secondary syphilis prior to developing late syphilis.
The clinical manifestations of late syphilis are highly variable and may involve a wide variety of different tissues. However, a strong index of suspicion is essential for the proper clinical diagnosis since the classic descriptions may be altered by antimicrobial therapy administered for other diagnoses.
The most common manifestations include:
●Cardiovascular syphilis (especially aortitis)
●Gummatous syphilis (granulomatous, nodular lesions that are rare, can occur in a variety of organs, usually skin and bones)
●CNS involvement (particularly general paresis and tabes dorsalis)
A confirmed case of late syphilis with clinical manifestations requires the demonstration of T. pallidum in late syphilitic lesions by special stains (eg, Warthin-Starry silver and immunofluorescent staining), polymerase chain reaction, or equivalent direct molecular methods. A probable case is diagnosed when characteristic abnormalities or lesions are noted along with a reactive treponemal serological test. A detailed discussion of diagnostic testing for syphilis is found elsewhere. (See "Syphilis: Screening and diagnostic testing" and "Neurosyphilis", section on 'Diagnosis'.)
Tertiary syphilis — Tertiary syphilis describes patients with late syphilis who have symptomatic manifestations involving the cardiovascular system or gummatous disease (granulomatous disease of the skin and subcutaneous tissues, bones, or viscera).
Cardiovascular — Cardiovascular syphilis classically involves the ascending thoracic aorta resulting in a dilated aorta and aortic valve regurgitation. The disorder is thought to be a consequence of vasculitis in the vasa vasorum leading to a weakening of the wall of the aortic root [41]. The onset is typically insidious; most patients present with an asymptomatic murmur or with left heart failure. Clinical manifestations typically occur 15 to 30 years from initial infection in the untreated patient. Syphilitic aneurysms rarely lead to dissection.
Physical examination may reveal a high-pitched "tambour" second sound, but this finding is neither specific nor sensitive. Chest films often show a calcified ascending arch of the aorta, reflecting the chronic inflammation of the intima; this finding is not usually seen in arteriosclerotic disease (image 1). Syphilis may also involve the coronary arteries, resulting in coronary artery narrowing and thrombosis. Coronary ostial stenosis may sometimes be found on catheterization [42].
Gummatous syphilis — Gummatous syphilis is very uncommon. However, several cases of gummas have been reported in individuals with HIV. Most of these have involved internal organs. (See "Syphilis in patients with HIV", section on 'Neurosyphilis'.)
Gummas can occur anywhere, including skin, bones, or internal organs. On the skin, gummas may present as ulcers or heaped up granulomatous lesions with a round, irregular, or serpiginous shape (picture 14A-B). They range from small to very large and may be severe in malnourished individuals ("rupial" lesions). Visceral gummas may present as a mass lesion. If a biopsy shows granulomas, lesions may be mistaken for a number of other diseases, including sarcoidosis, which is characterized by granulomas. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Neurologic sarcoidosis" and "Evaluation of the adult patient with hepatic granuloma".)
Central nervous system — There are many forms of CNS syphilis, some of which may occur as many as 25 years after the initial infection (eg, general paresis and tabes dorsalis). A detailed discussion of the CNS manifestations of late-stage syphilis is found elsewhere. (See "Neurosyphilis", section on 'Late neurosyphilis'.)
LATENT SYPHILIS (ASYMPTOMATIC) — Latent syphilis refers to the period when a patient is infected with T. pallidum (as demonstrated by serologic testing) but has no symptoms. The diagnosis of latent syphilis is based only upon the results of serological testing, which is discussed elsewhere. (See "Syphilis: Screening and diagnostic testing", section on 'Latent syphilis'.)
Latent syphilis is typically divided into early (if initial infection occurred within the previous 12 months) and late (if initial infection occurred >12 months ago) [9]. If the timing of an infection is not known, late latent syphilis is presumed.
It is important to differentiate between early and late latent syphilis to understand the risk of transmission to others. As examples:
●Patients with late latent disease are not considered infectious to their recent sexual contacts since they do not have lesions that can transmit disease.
●In contrast, patients with early latent syphilis may have transmitted T. pallidum to their sexual partners through lesions that were recently active but are no longer present. It is also possible that patients with early latent syphilis were not diagnosed because of an obscure or painless lesion that was present but not discovered on physical exam. (See 'Primary syphilis (chancre)' above.)
●Pregnant women with latent syphilis can transmit T. pallidum to their fetus for up to four years after acquisition. (See "Syphilis in pregnancy" and "Congenital syphilis: Management and outcome".)
Differentiating early from late latent disease also has implications for treatment (eg, one versus three doses of intramuscular [IM] penicillin G benzathine) (table 1). (See "Syphilis: Treatment and monitoring", section on 'Treatment of early syphilis' and "Syphilis: Treatment and monitoring", section on 'Treatment of late syphilis'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sexually transmitted infections".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Syphilis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Microbiology – Syphilis is an infection caused by the bacterium Treponema pallidum. T. pallidum is a delicate, corkscrew-shaped organism with tightly wound spirals, which exhibits a characteristic rotary motion seen on darkfield microscopy. (See 'Microbiology' above.)
●Epidemiology – The number of cases of syphilis in the United States has been increasing. The increase in rates of primary and secondary syphilis has occurred among both men and women in every region of the country. Syphilis also remains an important problem in other areas of the world. (See 'Epidemiology' above.)
●Transmission – Virtually all new syphilis infections are sexually acquired via contact with mucocutaneous syphilitic lesions, except for cases resulting from vertical transmission (ie, infection acquired in utero or during delivery). Syphilis is transmissible during primary or secondary syphilis with an efficiency of transmission estimated at approximately 30 percent. Patients with early latent syphilis are considered infectious due to lesions that were recently active but are no longer present or were missed on the initial evaluation. (See 'Transmission' above.)
●Pathophysiology – T. pallidum gains access to subcutaneous tissues via microscopic abrasions. Despite a slow estimated dividing time of 30 hours, the spirochete evades early host immune responses and establishes the initial ulcerative lesion (the chancre). During the period of early local replication, some organisms establish infection in regional draining lymph nodes with subsequent dissemination. (See 'Pathophysiology' above.)
●Clinical features – Patients with syphilis can present with a wide range of signs and symptoms depending upon the stage of disease (primary, secondary, tertiary) (table 1). These include:
•Primary syphilis – Following acquisition of T. pallidum, the initial clinical manifestations of primary syphilis consist of a painless chancre at the site of inoculation, which usually heals within a few weeks, even if untreated (picture 3A-C). (See 'Primary syphilis (chancre)' above.)
•Secondary syphilis – Weeks to months later, approximately 25 percent of individuals with untreated primary infection develop secondary syphilis, which is characterized by systemic symptoms including fever, rash, headache, malaise, anorexia, and diffuse lymphadenopathy (picture 7A-F). (See 'Secondary syphilis' above.)
•Late syphilis – When patients are untreated during the earlier stages of syphilis, they are at risk for major complications involving the central nervous system (CNS), cardiovascular structures, or skin and bones (picture 14A-B). (See 'Late syphilis' above.)
•Neurosyphilis – Neurosyphilis can occur at any time following infection. A detailed discussion of neurosyphilis is presented in a separate topic review. (See "Neurosyphilis".)
●Latent syphilis – Latent syphilis refers to the period when a patient is infected with T. pallidum (as demonstrated by serologic testing) but has no symptoms. Latent syphilis is typically divided into early (if initial infection occurred within the previous 12 months) and late (if initial infection occurred >12 months ago). If the timing of an infection is not known, late latent syphilis is presumed. (See 'Stages of disease' above and 'Latent syphilis (asymptomatic)' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges P Frederick Sparling, MD, who contributed to an earlier version of this topic review.
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