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, the traditional approach has been to 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). 
VDRL test results turn positive 1-2 weeks after chancre formation. Nontreponemal tests usually become nonreactive with time after treatment. Serology values in patients with HIV infection may take longer to fall than in patients without HIV infection. In some patients, nontreponemal antibodies can persist, sometimes for life, a conditioned referred to as ”serofast.” 
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), microhemagglutination assay T pallidum (MHA-TP), T pallidum hemagglutination (TPHA), and T pallidum particle agglutination (TPPA) tests. [20, 21] 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%. 
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.  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. If the result is positive, the patient should be offered treatment if no treatment history can be elucidated.
Darkfield microscopy is a possible mode of evaluating moist cutaneous lesions, such as the chancre of primary syphilis or the condyloma lata of secondary syphilis. If darkfield 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 CSF (VDRL-CSF) is highly specific but has low sensitivity. Therefore, the diagnosis of neurosyphilis usually depends on a combination of 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. A negative CSF FTA-ABS test result effectively rules out neurosyphilis. 
Patients with confirmed syphilis infections should be tested for other STDs, including HIV infection. If the HIV test is negative, the patient should be retested for HIV in 3 months except in areas with low HIV prevalence. 
Diagnosis of syphilis in pregnant women
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 STDs, 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. 
According to the 2015 CDC STD treatment guidelines, pregnant women who are seropositive should be considered infected unless there is evidence of adequate treatment in the medical records and sequential serologic antibody titers have decreased by 4-fold.  Serologic titers should be checked monthly if the patient is at risk for reinfection or lives in an area with high syphilis prevalence.
Per CDC guidelines, any woman who delivers a stillborn infant after 20 weeks’ gestation should also be tested for syphilis. No infant should leave the hospital without the maternal serologic status having been determined at least once during pregnancy.
For further information, see the 2015 CDC guidelines for syphilis and pregnancy.
Diagnosis of congenital syphilis
Consider congenital syphilis and sexual abuse in all children who present with syphilis.
Most infants with congenital syphilis are born to mothers with syphilis who were either not treated in pregnancy or treated too late during pregnancy. Treponemal tests (ie, TPPA, FTA-ABS, EIA, CIA) using neonatal serum are not recommended owing to passive transfer of IgG antibodies, which react with the reagents in these tests. All infants born to mothers with syphilis should be evaluated with a quantitative nontreponemal serologic test (RPR or VDRL) performed using the neonate’s serum.
The treatment algorithm below is provided in the 2015 CDC congenital syphilis guidelines for determining the need for further diagnostic workup and/or treatment
Proven or highly probable congenital syphilis
Proven or highly probably congenital syphilis is defined as any one of the following:
Abnormal physical examination findings that are consistent with congenital syphilis
A serum quantitative nontreponemal serologic titer that is fourfold higher than the mother’s titer
A positive darkfield test result or positive PCR result using lesions or body fluid(s)
The recommended evaluation in proven or highly probable congenital syphilis includes the following:
CSF analysis for VDRL, cell count, and protein
Complete blood cell (CBC) count with differential and platelet count
Other tests as clinically indicated (eg, radiography of long bones, chest radiography, liver function tests, neuroimaging, ophthalmologic examination, and auditory brain stem response)
Possible congenital syphilis
Congenital syphilis should be considered possible in any neonate who has normal physical examination findings and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer in addition to one of the following:
Mother was not treated, inadequately treated, or has no documentation of having received treatment
Mother was treated with erythromycin or a regimen other than those recommended in these guidelines (ie, a non–penicillin G regimen)
Mother received recommended treatment less than 4 weeks before delivery
The recommended evaluation in possible congenital syphilis is as follows:
CSF analysis for VDRL, cell count, and protein
CBC count, differential, and platelet count
Less-likely congenital syphilis
Congenital syphilis is considered less likely in any neonate who has normal physical examination findings and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer and both of the following:
Mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered more than 4 weeks before delivery
Mother has no evidence of reinfection or relapse
No evaluation is recommended in these cases.
Unlikely congenital syphilis
Congenital syphilis is considered unlikely in any neonate who has normal physical examination findings and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer and both of the following:
Mother’s treatment was adequate before pregnancy
Mother’s nontreponemal serologic titer remained low and stable (ie, serofast) before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4)
No evaluation is recommended in these cases.
For more information, see the 2015 CDC guidelines for congenital syphilis treatment.
Imaging studies should be performed depending on the organ system involved. For example, granulomatous disease of the liver can be seen on computed tomography (CT) of the abdomen.
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.
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 2015 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. 
Current guidelines state that physicians should evaluate CSF in individuals with late latent syphilis if treatment fails or if neurologic or ocular symptoms are present. It is also indicated if there are other changes indicative of tertiary syphilis (eg, gumma, aortitis).
LP should be performed in patients suspected of having neurosyphilis with no contraindication. There is no single test available for the definitive diagnosis of neurosyphilis; rather, the clinical symptoms, serology, and CSF values (CSF cell count or protein and a reactive CSF-VDRL) must be used in combination to determine the diagnosis. CSF examination is the only means by which the occurrence of asymptomatic neurosyphilis in latent syphilis can be excluded; however, it is not recommended unless the patient is asymptomatic or fails to respond serologically to treatment.
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. A positive VDRL test result is highly sensitive for active syphilis. Among persons with HIV infection and active syphilis, the CSF leukocyte count is usually elevated (>5 WBCs/µL), so more than 20 cells/µL should be considered positive. 
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.
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