Syphilis Workup

T pallidum cannot be cultivated in vitro and is too small to be seen under the light microscope. Serologic testing is considered the standard method of detection for all stages of syphilis. (Note, however, that serologic tests cannot be used to differentiate the different species of the treponeme family—for example, yaws.)

In suspected acquired syphilis, first perform nontreponemal serology screening using the Venereal Disease Research Laboratory (VDRL), rapid plasma reagin (RPR), or the recently developed ICE Syphilis recombinant antigen test.

Sensitivity of the VDRL and RPR tests are estimated to be 78-86% for detecting primary syphilis, 100% for detecting secondary syphilis, and 95-98% for detecting tertiary syphilis. Specificity ranges from 85-99% and may be reduced in individuals who have coexisting conditions (ie, collagen vascular disease, pregnancy, intravenous drug use, advanced malignancy, tuberculosis, malaria, viral and rickettsial diseases).^[19]

VDRL test results turn positive 1-2 weeks after chancre formation. Nontreponemal tests usually become nonreactive with time after treatment. However, in some patients, nontreponemal antibodies can persist, sometimes for the life of the patient.^[20]

Because of the possibility of false-positive results, confirmation for any positive or equivocal nontreponemal test result should follow with a treponemal test, such as the fluorescent treponemal antibody-absorption (FTA-ABS), quantitative VDRL/RPR, microhemagglutination assay T pallidum (MHA-TP), T pallidum hemagglutination (TPHA), and T pallidum particle agglutination (TPPA) tests.^{[21, 22]} Treponemal enzyme immunoassay (EIA) for immunoglobulin G (IgG) and immunoglobulin M (IgM) may be performed.

FTA-ABS is commonly used as a confirmatory test following positive VDRL or RPR test findings. FTA-ABS has a sensitivity of 84% for detecting primary syphilis infection and almost 100% sensitivity for detecting syphilis infection in other stages. Its specificity is 96%.^[19]

Some labs have adopted reverse sequence screening in order to reduce time, labor, and costs. Reverse screening test sera first by automatable treponemal enzyme and chemiluminescence immunoassays (EIA/CIA), followed by testing of reactive sera with a nontreponemal test. Results of the first direct comparison of traditional and reverse screening suggest reverse screening may not be as inferior to traditional testing as previously thought. Six out of 1000 patients tested were falsely reactive by reverse screening, compared to none by traditional testing. However, reverse screening identified 2 patients with possible latent syphilis that were not detected by RPR.^[23] The CDC recommends traditional testing, but if reverse screening is used all sera that produce reactive EIA/CIA results should be reflexively tested with a quantitative nontreponemal test. Sera with discordant results should be reflexively tested with a confirmatory TPPA test.

Testing must be performed more than once in patients diagnosed with latent syphilis in order to exclude laboratory error.

Dark-field microscopy is essential in evaluating moist cutaneous lesions, such as the chancre of primary syphilis or the condyloma lata of secondary syphilis (see the image below).

When dark-field microscopy is not available, direct immunofluorescence staining of fixed smears (direct fluorescent antibody T pallidum [DFA-TP]) is an option. Both procedures detect the causative organism at a rate of approximately 85-92%.

Slit-lamp examination and ophthalmic assessment can be used to differentiate between acquired and congenital syphilis (presence of interstitial keratitis) in patients with latent infection of uncertain duration.

Diagnosis of neurosyphilis can be challenging. The VDRL test for cerebrospinal fluid (VDRL-CSF) is highly specific but has low sensitivity. Therefore, the diagnosis of neurosyphilis usually depends on a combination of reactive serologic test results, CSF cell count, CSF protein, and clinical manifestations with or without a reactive VDRL-CSF. Some specialists recommend performing an FTA-ABS test on CSF. The CSF FTA-ABS is less specific for neurosyphilis than the VDRL-CSF, but it is highly sensitive.^[20]

Infants with suspected congenital syphilis and positive VDRL or FTA-ABS test results can undergo 19S IgM FTA-ABS serologic testing (maternal IgM is not passed to the fetus in utero). However, the false-negative rate is 35%, and the false-positive rate is 10%. The Captia Syphilis-M enzyme-linked immunosorbent assay is an option.

The United States Preventive Services Task Force (USPSTF) has reaffirmed its recommendation for screening all pregnant women for syphilis infection at the first prenatal visit. High-risk women (eg, uninsured women, women living in poverty, sex workers, illicit drug users, those with other sexually transmitted diseases, those living in communities with high syphilis morbidity) should also be tested in the third trimester and at delivery.

If the test results are positive for syphilis, the treatment of choice is parenteral benzathine penicillin G. Dosage and the length of treatment depend on the stage and clinical manifestations of the disease.^[24]

Patients with confirmed syphilis infections should be tested for other sexually transmitted diseases, including HIV.

According to the 2010 CDC STD guidelines, there is insufficient evidence to establish whether infants who have congenital syphilis and whose mothers are coinfected with HIV need different evaluation, treatment, or follow-up for syphilis than is recommended for all infants.^[18]

Imaging studies should be performed depending on the organ system involved. For example, granulomatous disease can be seen on computed tomography (CT).

Obtain chest radiography in patients with tertiary syphilis to screen for aortic dilatation. Linear calcification of the ascending aorta on chest films suggests asymptomatic syphilitic aortitis. Radiologic abnormal findings commonly seen with advanced gummas of bone include periostitis, destructive osteitis, or sclerosing osteitis.

Angiography may be useful to distinguish between abdominal aneurysms of syphilitic versus arteriosclerotic origin. About 10% of syphilitic aneurysms occur superior to the renal arteries, while arteriosclerotic abdominal aneurysms usually are found inferior to the renal arteries.

CT scanning and magnetic resonance imaging (MRI) of the head and body may be used to document the complications of tertiary syphilis.

Invasion of the central nervous system (CNS) by treponemes occurs in 30-40% of patients with primary or secondary syphilis; however, no studies show this to be a predictor of poor neurologic outcome. According to the 2010 CDC STD treatment guidelines, CSF laboratory abnormalities are common in persons with early syphilis, even when clinical neurological findings are absent. If clinical evidence of neurological involvement is found, a CSF examination should be performed.^[18]

Current guidelines in clinical infectious diseases state that physicians should evaluate CSF in individuals with latent syphilis of unknown duration or with late latent syphilis if (1) treatment fails, (2) neurologic or ocular symptoms are present; or (3) the patient has underlying HIV infection. LP is only relatively indicated in patients with high titers on serological tests (≥1:32). It is also indicated if there are other changes indicative of active syphilis (eg, gumma, aortitis).

LP should be performed on patients suspected of having neurosyphilis with no contraindication. CSF examination is the only means by which the occurrence of asymptomatic neurosyphilis in latent syphilis can be excluded.

Examination of the CSF should include the VDRL test, cell count, and protein level. Abnormalities of any of these measurements combined with a suggestive history and examination strongly indicate the presence of neurosyphilis. Derangements of these values are consistently found in neurosyphilis. A positive VDRL test result indicates active syphilis. A positive polymerase chain reaction (PCR) test finding is sensitive in detecting past invasion of the CNS but does establish whether the T pallidum organisms are still alive.

The primary lesion of syphilis is a chancre. Histologically, skin and mucosal lesions show a perivascular and perijunctional infiltrate of lymphocytes, plasma cells, and macrophages. At times, capillary endothelial proliferation and subsequent obliteration of small blood vessels may be appreciable. Focal erosion or ulceration is common.

The inflammatory reaction of secondary syphilis is histologically similar to that of the primary chancre but is less intense. Skin lesions are typified by a “lichenoid-psoriasiform” configuration with a perijunctional infiltrate of lymphocytes, histiocytes, and plasmacytes (see the image below). Often the histiocytic component of the infiltrate is prominent, and thus the biopsy may assume a “lichenoid-granulomatous” configuration.

Small numbers of neutrophils may be included in the perijunctional infiltrate, and neutrophils may also be present in an expanded overlying stratum corneum. Organisms are readily demonstrable using T pallidum immunoperoxidase staining during the secondary stage (see the image below).

In tertiary syphilis, histological examination shows gummas consisting of granulomatous inflammation with central necrosis flanked by plump or palisaded macrophages and fibrocytes surrounded by large numbers of mononuclear leukocytes, including many plasma cells. Treponemes are rare in these lesions and typically cannot be cultured or visualized.

Aortitis reveals inflammatory scarring of the tunica media, secondary to obliterative endarteritis of the vasa vasorum. Uneven loss of the medial elastic fibers and muscle cells may be evident. See the images below.