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DAVID L. BROWN, MAJ, MC, USA, and JENNIFER E. FRANK, CPT, MC, USA
DeWitt Army Community Hospital, Fort Belvoir, Virginia
Syphilis is a sexually transmitted disease with varied and often subtle clinical mani-
festations. Primary syphilis typically presents as a solitary, painless chancre, whereas O A patient infor-
secondary syphilis can have a wide variety of symptoms, especially fever, lymph- mation handout on
syphilis, written by
adenopathy, rash, and genital or perineal condyloma latum. In latent syphilis, all clini-
the authors of this
cal manifestations subside, and infection is apparent only on serologic testing. Late or article, is provided
tertiary syphilis can manifest years after infection as gummatous disease, cardiovas- on page 297.
cular disease, or central nervous system involvement. Neurosyphilis can develop in any
stage of syphilis. The diagnosis of syphilis may involve dark-field microscopy of skin
lesions but most often requires screening with a nontreponemal test and confirmation
with a treponemal-specific test. Parenterally administered penicillin G is considered
first-line therapy for all stages of syphilis. Alternative regimens for nonpregnant
patients with no evidence of central nervous system involvement include doxycycline,
tetracycline, ceftriaxone, and azithromycin. In pregnant women and patients with
neurosyphilis, penicillin remains the only effective treatment option; if these patients
are allergic to penicillin, desensitization is required before treatment is initiated. Once
the diagnosis of syphilis is confirmed, quantitative nontreponemal test titers should be
obtained. These titers should decline fourfold within six months after treatment of pri-
mary or secondary syphilis and within 12 to 24 months after treatment of latent or late
syphilis. Serial cerebrospinal fluid examinations are necessary to ensure adequate
treatment of neurosyphilis. (Am Fam Physician 2003;68:283-90,297. Copyright© 2003
American Academy of Family Physicians.)
S
yphilis is a sexually transmitted dis- syphilis is more prevalent in the South, in
ease (STD) caused by the spiro- urban areas, in men, and in blacks.1
chete Treponema pallidum. Previ-
ously known as the “great imitator,” Stages of Syphilis
this disease can have numerous and Primary syphilis most often manifests as a
complex manifestations. Family physicians solitary, painless chancre that develops at the
should understand its presentations, stage- site of infection an average of three weeks after
specific diagnostic testing, and appropriate exposure to T. pallidum.
antibiotic treatments, because missed or inap- Without treatment, blood-borne spread of
propriately treated syphilis can result in devas- T. pallidum over the next several weeks to
tating cardiovascular and neurologic disease, months results in secondary syphilis, which
as well as congenital syphilis. has numerous clinical manifestations. The
most common features are fever, lymph-
Epidemiology adenopathy, diffuse rash, and genital or per-
The incidence of syphilis decreased signifi- ineal condyloma latum.
cantly with the introduction of penicillin in During the latent stage of syphilis, skin
the 1940s but rose sharply again with the lesions resolve, and patients are asympto-
advent of human immunodeficiency virus matic. However, serologic tests are positive for
(HIV) infection in the 1980s. From 1990 T. pallidum.
through 2000, primary and secondary syphilis Tertiary or late syphilis develops years after
infection rates decreased by 89.2 percent. the initial infection and can involve any organ
See page 204 for defi-
Despite the overall decreases, outbreaks of system. The most dreaded complications are
nitions of strength-of- syphilis have recently been reported in men neurosyphilis and involvement of the aortic
evidence levels. who have sex with men. In the United States, valve and root.
JULY 15, 2003 / VOLUME 68, NUMBER 2 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 283
types. Hence, the same nontreponemal test should be used
The usefulness of qualitative nontreponemal tests for follow-up evaluations.
is limited by decreased sensitivity in early primary
TREPONEMAL-SPECIFIC TESTS
syphilis and late syphilis.
Treponemal-specific tests detect antibodies to antigenic
components of T. pallidum. These tests are used primarily
to confirm the diagnosis of syphilis in patients with a reac-
Diagnosis tive nontreponemal test. However, the enzyme immunoas-
DARK-FIELD MICROSCOPY say (EIA) test for anti-treponemal IgG also may be used for
Dark-field microscopy is the most specific technique for screening.7 Treponemal-specific tests include the EIA for
diagnosing syphilis when an active chancre or condyloma anti-treponemal IgG, the T. pallidum hemagglutination
latum is present.2 However, its accuracy is limited by the (TPHA) test, the microhemagglutination test with T. pal-
experience of the operator performing the test, the number lidum antigen, the fluorescent treponemal antibody-
of live treponemes in the lesion, and the presence of non- absorption test (FTA-abs), and the enzyme-linked
pathologic treponemes in oral or anal lesions.3 immunosorbent assay.
In preparation for dark-field microscopy, the lesion is Treponemal tests have sensitivities and specificities equal
cleansed and then abraded gently with a gauze pad. Once a to or higher than those for nontreponemal tests.2,5 How-
serous exudate appears, it is collected on a glass slide and ever, treponemal-specific tests are more difficult and
examined under a microscope equipped with a dark-field expensive to perform, which limits their usefulness as
condenser.2 T. pallidum is identified by its characteristic screening tests. In addition, false-positive results can occur,
corkscrew appearance.4 Given the inherent difficulties of especially when the FTA-abs test is used in patients with
dark-field microscopy, negative examinations on three dif- systemic lupus erythematosus or Lyme disease.2,8
ferent days are necessary before a lesion may be considered Unlike nontreponemal tests, which show a decline in
negative for T. pallidum.4 titers or become nonreactive with effective treatment,
treponemal-specific tests usually remain reactive for life.
NONTREPONEMAL TESTS Therefore, treponemal-specific test titers are not useful for
Syphilitic infection leads to the production of non- assessing treatment efficacy.
specific antibodies that react to cardiolipin. This reaction is
the basis of traditional nontreponemal tests such as the Stage-Specific Diagnosis and Treatment
VDRL test and rapid plasma reagin test. TREATMENT GUIDELINES
With nontreponemal tests, false-positive reactions can Guidelines from the Centers for Disease Control and Pre-
occur because of pregnancy, autoimmune disorders, and vention (CDC) recommend parenterally administered peni-
infections.5,6 In addition, these tests may show a “prozone” cillin G for the treatment of all stages of syphilis (Figure 1).9
phenomenon in which large amounts of antibody block [Evidence level C, consensus/expert guidelines] Alternative
the antibody-antigen reaction, causing a false-negative test regimens may be used in patients who are allergic to peni-
in the undiluted sample.2 cillin. However, pregnant women and patients with neuro-
Qualitative nontreponemal tests are widely used for syphilis require treatment with penicillin even if they are
syphilis screening. However, their usefulness is limited by allergic to the drug. In these patients, desensitization is nec-
decreased sensitivity in early primary syphilis and during essary before penicillin therapy is initiated.
late syphilis, when up to one third of untreated patients The treatment of syphilis is similar in HIV-positive and
may be nonreactive.3 HIV-negative patients. However, HIV-positive patients
After adequate treatment of syphilis, nontreponemal require more frequent follow-up because of an increased
tests eventually become nonreactive. However, even with risk of treatment failure. In addition, a higher index of sus-
sufficient treatment, patients sometimes have a persistent picion for central nervous system (CNS) involvement
low-level positive nontreponemal test (referred to as a must be maintained.9
serofast reaction). Treatment of syphilis in any stage should take into
Titers are not interchangeable between different test account the risks of acquiring other STDs. HIV testing
284 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 2 / JULY 15, 2003
Syphilis
Treatment of Syphilis
Lumbar puncture
Penicillin G benzathine,
Early latent Late latent 2.4 million units IM
syphilis syphilis (single dose)*
Signs, symptoms, or
CSF findings consistent
with neurosyphilis
Penicillin G benzathine, Penicillin G benzathine,
2.4 million units IM 2.4 million units IM
(single dose)* once a week for
3 weeks (three doses)†
Yes No
Desensitization
*—Alternative treatments for nonpregnant penicillin-allergic patients: doxycycline (Vibramycin), 100 mg taken orally twice daily for
2 weeks, or tetracycline, 500 mg taken orally four times daily for 2 weeks; limited data support efficacy for ceftriaxone (Rocephin), 1 g
once daily IM or IV for 8 to 10 days, or azithromycin (Zithromax), 2 g orally (single dose).
†—Alternative treatments for nonpregnant penicillin-allergic patients: doxycycline, 100 mg taken orally twice daily for 4 weeks, or tetra-
cycline, 500 mg taken orally four times daily for 4 weeks.
FIGURE 1. Recommended approach to the treatment of syphilis. (IM = intramuscular; HIV = human immunodeficiency
virus; CSF = cerebrospinal fluid; IV = intravenous)
Information from reference 9.
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Patients with human immunodeficiency virus TABLE 1
infection who develop syphilis are at higher risk Selected Differential Diagnosis of Genital Lesions
for treatment failure and neurosyphilis.
Characteristics of
Disorder or disease genital lesion Etiology
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TABLE 2
Stages of Syphilitic Infection
IM = intramuscular; IV = intravenous.
Information from references 2 and 9.
eight to 10 days, or azithromycin (Zithromax), in a single infection and evaluated for neurosyphilis with a cerebro-
2-g dose taken orally, may be effective for the treatment of spinal fluid (CSF) examination.9
primary syphilis, although close follow-up is warranted to
assess treatment efficacy.9 SECONDARY SYPHILIS
At six and 12 months after treatment, patients with pri- Secondary syphilis develops several weeks to months
mary syphilis should be reexamined and undergo repeat after the chancre appears.4 The skin is most often affected.
serologic testing. Treatment failure is defined as recurrent Patients may present with macular, maculopapular, or
or persistent symptoms or a sustained fourfold increase in even pustular lesions, beginning on the trunk and proxi-
nontreponemal test titers despite appropriate treatment. mal extremities. The rash of secondary syphilis may
Patients with treatment failure should be tested for HIV involve all skin surfaces, including the palms and soles.
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Follow-up of Primary or Secondary Syphilis
Infectious diseases
consultation
Lumbar puncture Lumbar puncture findings
negative compatible with neurosyphilis
*—See text for alternative treatment recommendations for nonpregnant penicillin-allergic patients.
†—See text for recommended treatments for neurosyphilis.
FIGURE 2. An approach to follow-up in patients treated for primary or secondary syphilis. (IM = intramuscular; HIV =
human immunodeficiency virus)
Information from reference 9.
Condyloma latum also is associated with secondary The diagnosis of secondary syphilis is confirmed by
syphilis. Involving mainly warm, moist areas such as the nontreponemal and treponemal-specific tests. Treatment
perineum and perianal skin, this soft, verrucous plaque is employs the same antibiotic regimens used for primary
painless but highly infectious. syphilis. Follow-up is the same as that for primary syphilis
Other organs and systems that can be affected in sec- (Figure 2).9
ondary syphilis include the renal system (glomeru-
lonephritis, nephrotic syndrome), the liver (hepatitis), the LATENT SYPHILIS
CNS (headache, meningitis, cranial neuropathy, iritis, and It is important to distinguish between early and late
uveitis), and the musculoskeletal system (arthritis, osteitis, latent syphilis, because relapse to secondary syphilis and
periostitis).4 Patients also may have constitutional symp- recurrent infectivity are possible during the early latent
toms such as fever, malaise, generalized lymphadenopathy, stage. Early latent syphilis encompasses the first year after
arthralgias, and weight loss. infection. This stage can be established only in patients
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Syphilis
who have seroconverted within the past year, who have had
symptoms of primary or secondary syphilis within the past Although a positive cerebrospinal fluid VDRL test
year, or who have had a sexual partner with primary, sec- result is specific for neurosyphilis, a negative
ondary, or early latent syphilis within the past year. Patients
result does not exclude the possibility of central
who do not meet any of these criteria should be presumed
to have late latent syphilis. nervous system infection.
CNS involvement may be asymptomatic. Therefore, the
possibility of neurosyphilis should be considered in
patients with early or late latent syphilis. response to treatment varies and depends on the type and
Early latent syphilis is treated in the same way as primary location of gummatous or cardiovascular lesions.9
and secondary syphilis. Late latent syphilis is treated with
2.4 million units of penicillin G benzathine administered NEUROSYPHILIS AT ANY STAGE OF SYPHILIS
intramuscularly once a week for three weeks. Alternative Neurologic involvement occurs in up to 10 percent of
regimens in nonpregnant patients with penicillin allergy patients with untreated syphilis.14 Neurosyphilis should be
include doxycycline, in a dosage of 100 mg taken orally considered in patients with signs or symptoms of neuro-
twice daily for four weeks, or tetracycline, in a dosage of logic involvement at any stage of T. pallidum infection and
500 mg taken orally four times daily for four weeks.9 in all patients with late latent or tertiary syphilis, although
After treatment of early or late latent syphilis, quantita- asymptomatic neurosyphilis is the most common presen-
tive nontreponemal titers should be measured at six, 12, tation.4 Neurologic involvement also should be suspected
and 24 months. Neurosyphilis should be strongly consid- in patients who previously have been treated for neuro-
ered in patients who show a fourfold increase in titers, syphilis, patients who have not responded to treatment for
patients who have an initially high titer (1:32 or greater) primary, secondary, or latent syphilis, and patients who
that fails to decline at least fourfold, patients who have HIV have HIV infection or other conditions that compromise
infection, and patients who develop signs or symptoms of immune status.
neurosyphilis.9 Lumbar puncture is required to establish the diagnosis
of neurosyphilis. The CSF should be tested for white
TERTIARY SYPHILIS blood cell count and protein level, and for reactivity on a
Tertiary or late syphilis is classified into gummatous VDRL test.5,15 Although a positive CSF VDRL test result is
syphilis, cardiovascular syphilis, and neurosyphilis. Gum- specific for neurosyphilis, a negative result does not
mas are granulomatous-like lesions; they are clinically sig- exclude the possibility of this infection, because sensitivity
nificant because they cause local destruction.4 These is less than 100 percent. A CSF white blood cell count
lesions may affect any organ system but most commonly greater than 10 per mm3 (10 106 per L) or a CSF pro-
occur in the skin, mucous membranes, and bones. tein level greater than 50 mg per dL (0.50 g per L) indi-
Cardiovascular syphilis results from destruction of the cates possible neurosyphilis.
elastic tissue of the aorta, which leads to aortitis and the Treponemal-specific testing (e.g., TPHA) is helpful
formation of aneurysms that rarely rupture. The ascend- only when the result is negative (i.e., it rules out neu-
ing aorta is most often affected, with the potential com- rosyphilis). Because IgG can cross the blood-brain bar-
plications of aortic valve insufficiency and coronary artery rier, a positive test may falsely imply CNS involvement.5
stenosis. A diagnostic clue is the presence of linear calcifi- TPHA testing to compare serum and CSF values (TPHA
cations of the aorta on a chest radiograph. Approximately index) may prove beneficial in establishing the diagnosis
11 percent of untreated patients progress to cardiovascu- of neurosyphilis. Testing for spirochete DNA via poly-
lar syphilis.14 merase chain reaction methods is an evolving technique
Antibiotic therapy for gummatous and cardiovascular that may be helpful because it detects organisms, rather
syphilis is the same as that for late latent syphilis, provided than antibodies, in the CSF.16
no evidence of neurologic involvement is present. Consen- In late neurosyphilis, both vascular lesions (meningo-
sus is lacking on the appropriate follow-up in patients who vascular neurosyphilis) and neuronal degeneration
have tertiary syphilis with no CNS involvement. Clinical (parenchymatous neurosyphilis) are possible.4 The clinical
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Syphilis
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