Syphilis - Epidemiology, Pathophysiology, and Clinical Manifestations in Patients Without HIV - UpToDate

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Syphilis: Epidemiology, pathophysiology, and clinical

manifestations in patients without HIV
Authors: Charles B Hicks, MD, Meredith Clement, MD
Section Editor: Jeanne Marrazzo, MD, MPH, FACP, FIDSA
Deputy Editor: Jennifer Mitty, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2022. | This topic last updated: Jul 15, 2022.
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.
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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 features and diagnosis".)
● (See "Congenital syphilis: Evaluation, management, and prevention".)
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; in 2020, 133,945 cases of syphilis (all stages) were reported, which is up 52
percent from 2016 ( figure 1) [12].
In 2020, 41,655 cases of primary and secondary syphilis (the most infectious stages)
were reported. The rate of primary and secondary syphilis cases increased 6.8 percent
during 2019 to 2020 with 12.6 cases per 100,000 population reported in 2020 [12].
Approximately 80 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). Although the number of primary and secondary syphilis cases among
MSM decreased by 2.2 percent from 2019 to 2020, MSM are still disproportionately
impacted, accounting for 53 percent of all male primary and secondary syphilis cases in
2020. Risk factors for acquisition of syphilis in MSM include methamphetamine use
( figure 3) and having acquired recent sexual partners via social media [13,14].
Since 2010, the rate of primary and secondary syphilis has increased by over 400
percent, with an increase of 20 percent from 2019 to 2020 (3.9 to 4.7 cases per 100,00)
[12]. The rate was higher in Black women compared with women of Hispanic ethnicity
and White women (12.3, 4.1, and 2.9 per 100,000 population, respectively). A report
from the United States Centers for Disease Control and Prevention (CDC) suggests that
the increased rate of syphilis in women may be due in part to increased drug use [15].
In 2017, the percentages of women with primary and secondary syphilis who used
methamphetamines, injection drugs, or heroin during the previous 12 months were
16.6, 10.5, and 5.8 percent, respectively; these numbers more than doubled during the
period from 2013 to 2017. Similar trends in drug use were seen in men who have sex
with women.
With the increased number of cases in women, there has also been an increase in the
number of cases of congenital syphilis. In 2020, 2148 cases of congenital syphilis were
reported, including 149 congenital syphilis-related stillbirths and infant deaths [12].
(See "Syphilis in pregnancy" and "Congenital syphilis: Clinical features 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 2020 suggest that approximately 46 percent of
MSM with primary and secondary syphilis have HIV, compared with about 8 percent
of men who have sex with women and 6 percent of women [12,16]. (See "Syphilis in
patients with HIV", section on 'Epidemiology'.)
• In men, the highest rates of primary and secondary syphilis in 2020 occurred in
those aged 20 to 34 years [12]. When ranked according to age, the rate was highest
in those aged 25 to 29 years (58 cases per 100,000 population) ( figure 4).
• 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 2020, the rate of reported cases per 100,000 population was 57.7 in
Black men, 23.4 in men of Hispanic ethnicity, and 11.0 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 14.2 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 features 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 [3,17]. 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 [18]. 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 [19]. (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 [5,20]. 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 [21]. 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 [22]. In one study of 23 patients with secondary syphilis,
leukocytes were obtained from syphilitic lesions and peripheral blood mononuclear cells
[23]. 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 [24]. 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
[20].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) [25]. (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 [26]. (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 [27].
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 [28].
Individual lesions are discrete copper, red, or reddish-brown and measure 0.5 to 2
cm in diameter [26,27]. 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) [28].
• Secondary syphilis can also affect mucosal surfaces [27]. 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 [26]. 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) [29]. 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 [30,31]. 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 [32].
Renal abnormalities — Patients with secondary syphilis can have mild transient
albuminuria, nephrotic syndrome, or acute nephritis with hypertension and acute renal
failure [33]. 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 [34]. 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 [35-37]. (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) [35,38]. Posterior uveitis typically presents
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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 [34]. 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 [39]. 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 [40].
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 pulmonary 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:
Evaluation, management, and prevention".)
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".)
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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.
Use of UpToDate is subject to the Terms of Use.
Topic 7584 Version 35.0
GRAPHICS
Treponoma pallidum by darkfield microscopy
Darkfield examination of an exudate from a penile ulcer in a patient

with syphilis. When viewed in a fresh specimen, Treponema pallidum
moves with a characteristic forward and backward motion with
rotation around the longitudinal axis.
Courtesy of Charles B Hicks, MD.
Graphic 56211 Version 3.0
Syphilis – Rates of reported cases by stage of infection, United States,

2011-2020
* Per 100,000.
Reproduced from: Sexually Transmitted Disease Surveillance, 2020. Centers for Disease Control and Prevention.
Available at: https://www.cdc.gov/std/statistics/2020/figures/SYPH-1.htm (Accessed on June 2, 2022).
Primary and secondary syphilis – reported cases by sex, sex of sex partners,
and HIV status, United States, 2018
MSM: men who have sex with men; MSW: men who have sex with women only.
Reproduced from: Sexually Transmitted Disease Surveillance 2018. Centers for Disease Control and Prevention. Available at:
https://www.cdc.gov/std/stats18/default.htm (Accessed on October 14, 2019).
Reported* injection drug use, methamphetamine use, heroin use, and sex
with a PWID among MSM with primary and secondary syphilis, United
States, 2015-2019
PWID: person who injects drugs; MSM: bisexual, or other men who have sex with men.
* Proportion reporting injection drug use, methamphetamine use, heroin use, or sex with a PWID
within the last 12 months calculated among cases with known data (cases with missing or unknown
responses were excluded from the denominator).
Reproduced from: Sexually Transmitted Disease Surveillance, 2019: Syphilis Surveillance Supplemental Slides, 2015-2019.
Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/std/statistics/2019/syphilis/default.htm
(Accessed on June 2, 2022).
Primary and secondary syphilis – Rates of reported cases by age group and
sex, United States, 2020
NOTE: Total includes all ages.
* Per 100,000.
Reproduced from: Sexually Transmitted Disease Surveillance, 2019. Centers for Disease Control and Prevention. Available at:
https://www.cdc.gov/std/statistics/2019/figures.htm (Accessed on June 2, 2022).
Primary syphilis: Penile chancre
A chancre due to syphilis is an ulcerative lesion that is often painless

and has an indurated character. Chancres arise at the site of initial
inoculation of the organism.
Clinical manifestations and treatment of syphilis in nonpregnant adults
Clinical Monitoring after

Treatment¶
manifestations* treatmentΔ
Early syphilis Primary syphilis: Preferred: Clinical exam and

Typically consists of a Penicillin G serologic testing with a
single painless chancre benzathine 2.4 nontreponemal test (eg,
at the site of inoculation, million units IM RPR) at 6 and 12
accompanied by regional once months.
adenopathy.
Alternatives (choose Titers should be
Secondary syphilis: one):◊ checked more
A systemic illness that Doxycycline 100 frequently if the patient
often includes a rash mg orally twice is HIV infected, follow-
(disseminated and/or daily for 14 days§ up is uncertain, or
involving the palms and reinfection is a concern.
Ceftriaxone 1 g
soles), fever, malaise,
daily IM or IV for
and other symptoms
10 to 14 days
such as pharyngitis,
hepatitis, mucous
patches, condyloma lata,
alopecia.
Early latent:
Refers to the period
when a patient is
infected with Treponema
pallidum as
demonstrated by
serologic testing but has
no symptoms. Early
latent syphilis occurs
within the first year of
initial infection.
Late syphilis Tertiary syphilis: Preferred: Clinical exam and

Patients with late Penicillin G serologic testing with a
syphilis who have benzathine 2.4 nontreponemal test (eg,
symptomatic million units IM RPR) at 6, 12, and 24
manifestations involving once weekly for months.
the cardiovascular three weeks
system or gummatous
Alternatives (choose
disease (granulomatous
one):
disease of the skin and
Doxycycline 100
subcutaneous tissues,
bones, or viscera). mg orally twice
daily for four
Late latent syphilis: weeks§
The period when a
patient is infected with T.
pallidum as Ceftriaxone 2 g
demonstrated by daily IM or IV for
serologic testing but has 10 to 14 days
no symptoms. Late
latent syphilis by
definition is present
more than one year after
initial infection. If the
timing of an infection is
not known, late latent
syphilis is presumed.
Neurosyphilis Neurosyphilis: Preferred: Clinical and serologic

Can occur at any time Aqueous penicillin monitoring with
during the course of G 3 to 4 million nontreponemal tests
infection. units IV every four (eg, RPR). The frequency
hours (or 18 to 24 depends upon the stage
Early neurosyphilis:
million units of disease (eg, early or
Patients with early
continuous IV late).
neurosyphilis may have
asymptomatic infusion) for 10 to CSF monitoring may be
meningitis, symptomatic 14 days¥ warranted.†
meningitis, or less If possible,
commonly patients allergic to
meningovascular penicillin should be
disease (ie, meningitis or desensitized and
stroke). Vision or hearing treated with IV
loss with or without penicillin
concomitant meningitis Alternatives‡ (choose
may also be present, and one):
ocular/otologic syphilis
Penicillin G
is treated as
procaine 2.4
neurosyphilis.
million units IM
Late neurosyphilis: daily plus
The most common probenecid 500
forms involve the brain mg orally four
and spinal cord times daily, both
(dementia [general for 10 to 14 days
paresis] and tabes Ceftriaxone 2 g IV
dorsalis). daily for 10 to 14
days
CSF: cerebrospinal fluid; IM: intramuscular; IV: intravenous; RPR: rapid plasma reagin.
* Refer to the topics that discuss the clinical manifestations of syphilis and neurosyphilis for
more detailed information.
¶ For the treatment of pregnant women and children, refer to the topics that discuss syphilis and
pregnancy and congenital syphilis.
Δ Patients infected with HIV are typically monitored more frequently. Refer to the topic that
discusses the treatment of syphilis in patients with HIV infection.
◊ Amoxicillin 3 g plus probenecid 500 mg, both given orally twice daily for 14 days, is another
alternative but is rarely used given the complexity of the regimen. A single dose of azithromycin
2 g administered orally is also an alternative but only if other options are not possible since
azithromycin resistance is a concern.
§ Tetracycline 500 mg orally four times daily is also an alternative but is harder to take.
¥ For patients with late neurosyphilis, some UpToDate authors administer a single dose of
benzathine penicillin G upon completion of IV penicillin since the total duration of penicillin
treatment for neurosyphilis is shorter than the regimens used for late syphilis.
‡ Limited clinical experience suggests that doxycycline (200 mg orally twice daily) for 21 to 28
days may be effective as an alternative regimen. However, this regimen should be reserved for
exceptional circumstances.
† Refer to the topic on neurosyphilis for a more detailed discussion of monitoring after
treatment.
Primary syphilis
Well-delimited vulvar ulceration with raised, indurated borders and a

clean base in a patient with primary syphilis.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights

reserved.
Penile chancre of primary syphilis

reserved.
Primary syphilis
Penile chancre in primary syphilis. Ulcer with an indurated margin on the penile shaft.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.
Primary syphilis of the oral cavity
Primary syphilis manifesting as a painless tongue ulcer with indurated,

raised borders and clean base.
Lues malignaface
Crusted papules, plaques, and nodules on the face.
Image created by Mukesh Patel, MD. Reproduced with permission from VisualDx.
Lues maligna
Large, ulcerated plaques with overlying eschars on the back.
Image created by Mukesh Patel, MD. Reproduced with permission from VisualDx.
Secondary syphilis: Lues maligna
Lues maligna is a severe form of secondary syphilis that occurs in

severely immunocompromised patients and is characterized by non-
resolving ulcerative skin lesions.
Courtesy of Dr. Charles Hicks.
Cervical lymph node in secondary syphilis
Such nodes (arrow) may be found in various locations and are

usually firm, non-tender, and "rubbery" in consistency.
Courtesy of Charles Hicks, MD.
Secondary syphilis plaques on back
Multiple scaly violaceous papules plaques, some annular, on the back.
Secondary syphilis papules on back
Multiple discrete erythematous papules on the back and arms.
Secondary syphilis scaly plaques
Multiple discrete, hyperpigmented scaly plaques on the abdomen.
Secondary syphilis extensive skin involvement
Numerous discrete erythematous papules on the trunk and extremities.
Secondary syphilis
Multiple tiny, discrete, scaly papules on the back and arm.
Trunk rash secondary syphilis
Reproduced with permission from: Dylewski, J, Duong, M. The rash of secondary

syphilis. CMAJ 2007; 176:33. Copyright ©2007 Canadian Medical Association.
Secondary syphilis
Red-brown papules, some with overlying scale, on the palms.
Secondary syphilis palms and soles
Discrete and confluent pink papules, some with collarettes of scale, on the palms, soles, and medial feet
Secondary syphilis palm
Several discrete ham-colored macules on the palm.
Secondary syphilis: Rash
The rash of secondary syphilis characteristically involves the palms

and soles. It may have a variety of appearances but is usually
pigmented and macular.
Secondary syphilis: Mucous patch
The mucous patches of secondary syphilis may appear on a variety of mucous

membranes. They are teeming with organisms and are therefore highly infectious.
Secondary syphilis
Multiple erosions (mucous patches) are present on the tongue in

this patient with secondary syphilis.

reserved.
Secondary syphilis
Multiple erosions (mucous patches) are present on the oral mucosa

in this patient with secondary syphilis.

reserved.
Condylomata lata
Moist, gray papules that resemble condylomata acuminata are

present on the perianal skin.

reserved.
Condylomata lata
Flat condylomata lata lesions which are moist in a woman with

secondary syphilis.
Courtesy of David H Martin and Tomasz F Mroczkowski. The Skin and Infection: A
Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore,
1995.
http://www.lww.com
Condylomata lata
Moist, eroded, pink papules at the perineum.
Condylomata lata
Condylomata lata, showing moist, pink papules on the scrotum and perineum.
Secondary syphilis
A fissured papule is present at the oral commissure in this patient

with secondary syphilis.

reserved.
Secondary syphilis
Multiple slightly scaly, erythematous papules are present on the

trunk of this patient with papular secondary syphilis.

reserved.
Patchy alopecia in secondary syphilis
Scalp hair loss associated with secondary syphilis is usually patchy,

producing a so-called "moth-eaten" appearance.
Alopecia in secondary syphilis
Patchy alopecia referred to as "moth-eaten" alopecia.
Alopecia in secondary syphilis
Patchy alopecia referred to as "moth-eaten" alopecia.
Uveitis and vitritis secondary to syphilis
Photo of retina (color and after intravenous fluorescien dye) in a patient with
uveitis and vitritis secondary to syphilis. The optic nerve is swollen (blurring of
the optic disc margens), there is retinal edema and necrosis (retina appears
white and elevated) as well as retinal vasculitis and tortuous vessels coming
from the optic nerve. In addition, the presence of significant vitritis gives the
picture a general haze (due to inflammatory cells floating in the vitreous).
Photos courtesy of Drs. Mehri McKellar and Michael Cusick.
Chest x-ray of tertiary cardiovascular syphilis
The characteristic lesion is a fusiform aneurysm of the thoracic aorta

which almost always involving the ascending arch.
Gumma in tertiary syphilis
Ulcerated nodule on the lower lip.
Gummatous syphilis
Gumma on the leg of a patient with tertiary syphilis.

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Syphilis: Epidemiology, pathophysiology, and clinical

The epidemiology, pathogenesis, and clinical manifestations of syphilis will be reviewed

● (See "Syphilis: Treatment and monitoring".)

Other epidemiologic trends include the following:

Late syphilis occurs in an uncertain proportion of patients infected by T. pallidum, with

More detailed surveillance data can be found on the CDC website.

transmission estimated at approximately 30 percent [3,17]. By contrast, the cutaneous

The understanding of T. pallidum pathophysiology is impeded by the inability to grow the

Late infection — Cellular immunity is important for control of syphilis in experimental

Primary syphilis (chancre) — Following acquisition of T. pallidum, the initial clinical

● Constitutional symptoms – Patients with secondary syphilis may develop systemic

● Alopecia – So-called "moth-eaten" alopecia is occasionally seen among patients

● Hepatitis – Syphilitic hepatitis is characterized by a high-serum alkaline phosphatase

● Gastrointestinal abnormalities – The gastrointestinal tract may become extensively

Musculoskeletal abnormalities — Synovitis, osteitis, and periostitis can occur but

Neurologic findings — The early clinical manifestations of neurosyphilis are reviewed

● Headache – Invasion of the cerebrospinal fluid is common in early untreated disease,

● Meninges and vascular manifestations – Patients may present with meningitis,

● Ocular syphilis – A sometimes-underappreciated manifestation of syphilis is eye

as multifocal chorioretinitis; however, other manifestations include retinal necrosis and

● Otosyphilis – Otosyphilis typically presents with cochleo-vestibular symptoms, such as

Late syphilis — Approximately 25 to 40 percent of patients with untreated syphilis can

The most common manifestations include:

● Cardiovascular syphilis (especially aortitis)

Cardiovascular — Cardiovascular syphilis classically involves the ascending thoracic

Gummatous syphilis — Gummatous syphilis is very uncommon. However, several

LATENT SYPHILIS (ASYMPTOMATIC)

infection is not known, late latent syphilis is presumed.

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topic (see "Patient education: Syphilis (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Microbiology – Syphilis is an infection caused by the bacterium Treponema pallidum. T.

● Pathophysiology – T. pallidum gains access to subcutaneous tissues via microscopic

• Primary syphilis – Following acquisition of T. pallidum, the initial clinical

• Secondary syphilis – Weeks to months later, approximately 25 percent of

• Neurosyphilis – Neurosyphilis can occur at any time following infection. A detailed

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges P Frederick Sparling,

Use of UpToDate is subject to the Terms of Use.

Topic 7584 Version 35.0

Treponoma pallidum by darkfield microscopy

Darkfield examination of an exudate from a penile ulcer in a patient

Courtesy of Charles B Hicks, MD.

Graphic 56211 Version 3.0

Syphilis – Rates of reported cases by stage of infection, United States,

Graphic 138824 Version 1.0

Graphic 88975 Version 4.0

Graphic 138825 Version 1.0

NOTE: Total includes all ages.

Graphic 138826 Version 1.0

Primary syphilis: Penile chancre

A chancre due to syphilis is an ulcerative lesion that is often painless

Courtesy of Charles B Hicks, MD.

Graphic 75291 Version 3.0

Clinical manifestations and treatment of syphilis in nonpregnant adults

Clinical Monitoring after

Early syphilis Primary syphilis: Preferred: Clinical exam and

Late syphilis Tertiary syphilis: Preferred: Clinical exam and

Neurosyphilis Neurosyphilis: Preferred: Clinical and serologic

Graphic 50435 Version 10.0

Well-delimited vulvar ulceration with raised, indurated borders and a