Diagnostic tests for syphilis test
Syphilis is a sexually transmitted infection caused by Treponema pallidum. A total of 13,106 cases of primary and secondary syphilis were reported in the United States in 2011 and the rate of infection has increased in subgroups, particularly men who have sex with men. The disease is mainly diagnosed through clinical findings and serologic testing. However, no single serologic test of syphilis is sufficient. Hence, the serologic diagnosis of syphilis requires the detection of 2 types of antibodies (nontreponemal antibodies and treponemal antibodies). The paradigm in syphilis testing has recently shifted in many centers to screen with a treponemal antibody test, reflexing to a nontreponemal test if the treponemal antibody test is positive. This reverse of the traditional algorithm may not be widely recognized among clinicians.
Syphilis test is a sexually transmitted infection caused by the spirochete Treponema pallidum. Syphilis has been a major infection in man throughout recorded history and has challenged clinicians with its many clinical manifestations. The rate of primary and secondary syphilis in the United States steadily increased from 2001 to 2009 with a slight decline in 2010.1 Over this time period, the proportion of infections seen in men who have sex with men (MSM) has increased.2 This infection can also be associated with transmission or presence of other sexually transmitted diseases. The total number of cases of syphilis in the United States in 2011 reached 46,042, a slight increase of 0.4% from the previous year.1 The diagnosis is mainly based on clinical findings and serologic tests since the organism cannot be grown in vitro. The clinical manifestations of the disease are classified by stages: primary, secondary, latent, and late or tertiary syphilis, including neurosyphilis and cardiovascular syphilis. Confirmation of the diagnosis is through serologic testing. As no single test is able to diagnose active syphilis, a combination of treponemal and nontreponemal tests is used.3Clinical manifestations of syphilis
Following acquisition of infection, the asymptomatic incubation phase lasts on average 21 days (3–90 days). The patient may then develop a variety of clinical findings, which have classically been divided into clinical stages.
This stage is characterized by a painless genital, anal Syphilis test, or less commonly oral ulcer or chancre. This lesion occurs at the site of inoculation. The ulcer is typically indurated and is usually without exudate. There may be regional lymphadenopathy.
This stage typically develops weeks or a few months after acquisition in a portion of untreated patients. The most common manifestation is a diffuse maculopapular skin rash involving the trunk, extremities, palms, and soles. This is a systemic illness and the rash is often accompanied by fever, malaise, myalgias, sore throat, headaches, and weight loss. Hepatitis, patchy alopecia, and renal insufficiency may also be seen. Ocular manifestations can include uveitis, retinitis, and optic neuritis. Invasion of the CNS is also seen in the early stages of untreated disease and can be associated with aseptic meningitis, cranial neuropathies, or meningovascular manifestations.
This stage is characterized by the absence of any signs or symptoms of infection, but associated with positive serologic tests. Early latent syphilis has been defined as infection of 1 year or less. Other asymptomatic states are classified as late latent syphilis or latent syphilis of unknown duration.
Late syphilis (tertiary)
A progressive dementing illness (general paresis) and tabes dorsalis are considered the classic late neurologic manifestation of the disease. Aortitis and gummatous syphilis (nodular lesions more commonly present in the skin and bones) are other clinical manifestations in this stage.
Diagnostic tests for syphilis
Direct detection methods
Although these methods are not widely available, there are several tests that can be used to directly detect the organism. These include dark-field microscopy, PCR, and direct fluorescent antibody testing for T pallidum. In some cases, these tests may allow the diagnosis of syphilis prior to a serologic response. However, most clinical centers do not have access to these methods and must rely on clinical manifestations and serologic testing.
There are 2 different types of serologic tests classified based on the type of antigen the antibodies are directed against. Treponemal tests detect antibody to T pallidum proteins. Nontreponemal tests detect antibodies directed against lipoidal antigens, damaged host cells, and possibly from treponemes. Both tests are used to confirm the infection and determine whether the disease is active. Figure 1 (adapted from a World Health Organization bulletin in 2004) illustrates the timing of the different serologic responses.4
Timing of serologic responses in syphilis infection
Reproduced with permission (Diagnostic tools for preventing and managing maternal and congenital syphilis: an overview. Bull World Health Organ 2004;82:439–446). FTA-Abs = fluorescent treponemal antibody absorbed; IgM = immunoglobulin M; RPR = rapid plasma reagin; TPHA = T pallidum hemagglutination assay; VDRL = Venereal Disease Research Laboratory.
The available tests in the United States include the microhemagglutination assay for T pallidum, the T pallidum particle agglutination, the T pallidum hemagglutination assay, the fluorescent treponemal antibody absorbed (FTA-ABS) test, and chemoluminescence immunoassays and enzyme immunoassays that detect Treponemal antibodies.5 The results of these tests are typically reported as reactive or nonreactive. Reactivity to a treponemal test implies infection but it does not determine whether the infection is recent or remote or whether it has been treated or not. False-positive results with this type of test can occur and may be due to other infections or other inflammatory diseases, such as systemic lupus erythematosus.6
Three types of nontreponemal tests are available in the United States: the rapid plasma reagin (RPR), the Venereal Disease Research Laboratory (VDRL) test, and the toluidine red unheated serum test. These tests usually react with immunoglobulin M and immunoglobulin G antibodies. The results of these tests are semiquantitative, reflecting the activity of the infection, and are reported as a titer of the antibody reflecting the number of dilutions where activity is still detected. Seroconversion occurs around 3 weeks, but can take up to 6 weeks.7 Consequently, patients can present with primary syphilis and have initially negative serologic tests. Titers will normally decline over time, often to undetectable titers after successful treatment. False-positive nontreponemal tests have been described in systemic infections such as tuberculosis, rickettsial diseases, and endocarditis, and also during pregnancy.8
Testing for syphilis
The paradigm shift
As pointed out above, the clinical manifestations of syphilis vary widely and can be subtle. Syphilis is also a well-known imitator of other systemic illnesses. Consequently, clinicians should have a low threshold to test for syphilis.
In the past, when testing for clinical findings or for screening purposes, the nontreponemal tests (e.g., RPR or VDRL) were used. If a nontreponemal test was positive, a confirmatory treponemal test (e.g., the FTA-ABS) was performed. However, the advent of automated and rapid treponemal testing has allowed the algorithm to be reversed.9 Thus, it is now widely accepted to order a treponemal test as the initial diagnostic tool. In high prevalence settings, this strategy seems to be cost-effective, although this may not apply to public clinics handling patients with high rate of previous infection or laboratories with low specimen volumes.5 More recently, rapid point-of-care syphilis testing based on simultaneous detection of treponemal a`nd nontreponemal antibodies has been reported.10
Interpretation of reactive tests
A reactive treponemal test most likely indicates infection by T pallidum but is not sufficient to determine disease activity and make treatment decisions (table 1). A reactive test can be seen in patients with a history of syphilis who has been treated. Consequently, it is important to determine if disease is active based on history, physical examination, and nontreponemal testing.
Interpretation of serologic tests in syphilis
A negative treponemal test likely indicates the absence of syphilis and generally no further testing is required. However, recent infection cannot be ruled out and repeat testing should be considered in patients who have had a recent high-risk sexual exposure.11 In most cases of active syphilis, the nontreponemal test will be positive and a titer will be performed. A positive titer with a VDRL or RPR indicates active syphilis and follow-up serologic testing is performed to monitor treatment response.
With this new testing algorithm that uses the treponemal test first, some patients may test positive for a treponemal test but test negative with a nontreponemal test. As mentioned above, this will be a usual finding after successfully treating syphilis but may also be seen in some patients who report no history of syphilis treatment. The Centers for Disease Control and Prevention (CDC) has proposed an algorithm for evaluating for syphilis in these patients (figure 2).3 Patients who have a reactive treponemal test on 2 different tests with a negative nontreponemal test are candidates for treatment if they have not been treated in the past.
Algorithm for a positive treponemal test with a nonreactive nontreponemal test
Algorithm for the interpretation of treponemal tests in syphilis infection. RPR = rapid plasma reagin; VDRL = Venereal Disease Research Laboratory.
Neurosyphilis due to T pallidum can occur at any time after the initial infection. The clinical manifestations may vary widely and can include asymptomatic meningitis, ocular syphilis, otosyphilis, meningovascular syphilis, tabes dorsalis, and general paresis depending on the stage (table 2). The diagnosis of neurosyphilis is often initially suspected based on clinical findings coupled with positive serologic tests. Neurosyphilis is confirmed through lumbar puncture (LP).
CSF profiles in different neurosyphilis stages
Abnormalities in the CSF consistent with disease include pleocytosis, often lymphocytic predominant, mild protein elevation, and a positive CSF VDRL. Even though a CSF VDRL was shown to be insensitive (positive only in 57% of the patients) in a study conducted by Hooshmand et al.,12 this study was called into question and thus, CSF VDRL test results are considered to be positive in the great majority of cases of neurosyphilis.13 CSF FTA-ABS can be used but is not specific. No single or combined CSF abnormalities make or rule out the diagnosis of neurosyphilis. Every result should be placed in context with the clinical scenario and the pretest probability.
The manifestations of neurosyphilis will depend on the stage of the disease (table 2). During early syphilis, neurologic involvement may be asymptomatic, although symptomatic meningitis can be seen. Ocular involvement and involvement of cranial nerves (II through VIII) is also well-documented. Other common findings include hearing loss, tinnitus, and facial weakness. After the first year of infection, meningovascular and stroke-like symptoms can develop. These symptoms include hemiparesis, hemiplegia, seizures, and aphasia.14 During the late stage, usually after 10 years, the classic manifestations of general paresis or tabes dorsalis can be seen. General paresis presents with changes in the affect, sensorium, and personality, hyperactive reflexes, slurred speech, pupillary disturbances, and optic atrophy tremors. Tabes dorsalis presents with lancinating pain to the lower extremities, ataxia, pupillary disturbances, bowel or urinary incontinence, a positive Romberg sign, peripheral neuropathy, and cranial nerve involvement.14 It is worthwhile to mention that a substantial clinical overlap can occur among the different stages.
Any abnormal neurologic finding without a clear etiology should be considered a potential manifestation of neurosyphilis. Confirmation of diagnosis is based on serologic testing. A serum treponemal test is obtained first. A negative test makes neurosyphilis unlikely. If the initial treponemal test is inconclusive, another treponemal-specific test should be obtained (figure 2). Following a positive serum treponemal test, a nontreponemal test should be ordered (e.g., RPR). A negative serum RPR makes neurosyphilis unlikely but does not exclude the diagnosis. If the RPR is positive and the clinical scenario is consistent with neurosyphilis, LP should be performed. A CSF examination is usually indicated with neurologic, otologic, or ophthalmologic manifestations, tertiary syphilis, clinical relapse, and serologic failure to appropriate therapy.3 Other indications such as in asymptomatic individuals with HIV coinfection or with nontreponemal titers >1:32 are not widely accepted.15 A positive CSF VDRL makes the diagnosis of neurosyphilis. If nonreactive, consider treatment in HIV-uninfected individuals if CSF leukocytes >5 cells/µL or protein >45 mg/dL with a reactive CSF FTA-ABS. A CSF FTA is frequently false-positive, but in the setting of a consistent clinical scenario, treatment should be given. If both CSF-VDRL and CSF-FTA are negative, neurosyphilis is unlikely, but evaluation should be performed based upon CSF leukocytes, protein, and clinical scenario. We suggest treatment if ultimately neuroinvasion cannot be ruled out.
Syphilis as part of the dementia workup
Based on the epidemiologic features of patients developing tertiary manifestations of syphilis, we suggest prioritizing testing for neurosyphilis in patients with early-onset dementia and in those without other possible identifiable risk factors for cognitive impairment. We recommend using a treponemal test for screening. These tests are sensitive, specific, and long-lasting even after treatment. If a treponemal test is negative, neurosyphilis is unlikely to be present. If positive, a nontreponemal test should be performed and many laboratories will automatically reflex to this test if a treponemal antibody test is positive. If the nontreponemal test is negative, neurosyphilis is very unlikely. However, treatment for latent syphilis should be offered if therapy cannot be elicited from history. If the nontreponemal test is positive, LP should be performed.
Recently, a number of outbreaks of primary and secondary syphilis have been seen in HIV-infected patients. The presence of syphilis increases the likelihood of acquisition of HIV and may be associated with increases in the HIV viral load and decreases in the CD4 count in coinfected patients.16 CNS invasion and ocular including posterior uveitis manifestations are more commonly present among patients infected with HIV. Secondary syphilis with symptomatic early neurosyphilis can mimic the signs and symptoms of acute HIV infection. Historically, HIV-infected persons also have had an increased risk for serious complications of syphilis including greater constitutional symptoms, organ injury, atypical rashes, secondary stage chancre, and multiple genital ulcers.17 Thus, there may be clinical overlap among different syphilis stages. It is likely that the risk of severe complications with syphilis is less in persons who are on successful HIV treatments with restored immune function. Yet there are no distinct or unique clinical manifestations of syphilis among HIV-infected individuals. Because of the high prevalence of syphilis among MSM and HIV-infected individuals, semiannual screening with a treponemal test is recommended (or even every 3 months in high-risk individuals).3,11 Similar to persons without HIV infection, CSF examination should be performed in patients with neurologic manifestations, auditory or ophthalmic signs or symptoms, active tertiary syphilis, or serologic treatment failure.18 Nontreponemal titers ≥1:32, CD4 <350 cells/µL, and syphilis duration greater than a year have been considered indications for LP as well. Because HIV infection itself can produce a mild mononuclear CSF pleocytosis (6–15 cells/mm3), specificity may be improved using CSF leukocyte cutoff of >20 leukocytes/mm3. Also, if the HIV-infected patient is on antiretroviral therapy (ART), has a CD4 count ≤200 cells/µL, or has an undetectable serum HIV viral load, the pleocytosis is more likely due to neurosyphilis rather than HIV.19 Symptomatic HIV coinfected individuals may have higher CSF protein levels compared to coinfected patients without symptoms.20 The workup starts with a serum treponemal test; if negative, neurosyphilis can be ruled out. If reactive, LP should be performed under the indications listed above. Confirmation of disease is done through a reactive CSF VDRL. One approach19 is if the CSF VDRL is not reactive consider treatment for neurosyphilis if CSF leukocytes are >20 cells/µL or between 6 and 20 cells/µL in patients on ART, with plasma HIV <50 copies/mL or CD4 ≤200 cells/µL. A CSF FTA-ABS should be obtained in patients with a nonreactive CSF VDRL and a CSF leukocyte count between 6 and 20 cells/µL in patients off of ART, plasma HIV >50 copies/mL, or CD4 >200 cells/µL. Treat for neurosyphilis if CSF FTA-ABS is reactive. However, we suggest considering treating any HIV+ patient with a pleocytosis or elevated protein on CSF examination, regardless of CSF serology results.Treatment
The treatment of syphilis varies based on the clinical stage. Penicillins are the first line of therapy for all stages. Table 3, adapted from the 2010 CDC STD Treatment Guidelines, summarizes the most common treatments used.
List of syphilis treatment options per disease stage
The diagnosis of syphilis must always rely on a high level of clinical suspicion and routine screening for populations at increased risk. Recently, the availability of rapid, automated treponemal tests has led to a reversal of the typical screening algorithm for syphilis.
No targeted funding reported.
A.F. Henao-Martínez reports no disclosures. S.C. Johnson serves on Scientific Advisory Boards for Gilead Sciences, ViiV Healthcare, Merck, and Bristol-Myers Squibb. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.
1. Sexually Transmitted Diseases Surveillance. 2012. Available at:Accessed April 15, 2013.
2. Taylor MM, Aynalem G, Olea LM, He P, Smith LV, Kerndt PR. A consequence of the syphilis epidemic among men who have sex with men (MSM): neurosyphilis in Los Angeles, 2001-2004. Sex Transm Dis 2008;35:430–434.
3. Workowski KA, Berman S; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recom Rep 2010;59:1–110. [PubMed] [Google Scholar]
4. Peeling RW, Ye H. Diagnostic tools for preventing and managing maternal and congenital syphilis: an overview. Bull World Health Organ 2004;82:439–446. [
5. Sena AC, White BL, Sparling PF. Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century. Clin Infect Dis 2010;51:700–708. [