Pediatric Syphilis Workup

The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics in their joint publication, Guidelines for Perinatal Care, recommend screening for syphilis at the first prenatal visit for all women and at 32-36 weeks' gestation for women who are at risk. ^[9] In the 2003 Red Book: Report of the Committee on Infectious Diseases, the American Academy of Pediatrics recommends screening early in pregnancy and preferably again at delivery. ^{[10, 11]}  This screening should be performed even if they have been tested previously. ^[12]

CDC policy states that no newborn should leave a hospital without documentation of the mother's serologic status at least once during the pregnancy. Testing of mother's serum is preferred to testing cord blood or the infant's serum because the titers frequently are lower in the infant and may be nonreactive if the mother was infected late in pregnancy. Serologic testing should also be performed at delivery in communities and populations at risk of acquiring congenital syphilis.

Test for syphilis any woman who delivers a stillborn infant after 20 weeks' gestation. Syphilitic stillbirth is considered fetal death after 20 weeks' gestation or when a fetus weighs more than 500 g and the mother had untreated or inadequately treated syphilis at delivery. Report these cases as congenital syphilis.

According the 2009 Red Book, "Darkfield examinations and direct fluorescent antibody (DFA) tests of lesion exudate or tissue are the definitive  methods for diagnosing early syphilis. Serologic tests for syphilis allow for a presumptive  diagnosis of syphilis and for following response to therapy. A nontreponemal serologic test must be confirmed by a treponemal serologic test." ^[13]

Laboratory evaluation of sexually abused children should include serologic testing for syphilis if the assailant is known to have a sexually transmitted infection (STI) or is at high risk of having an STI (eg, previous STI, multiple partners) or has an unknown history. The suspicion of child sexual abuse mandates filing a report with child protective services or law enforcement agencies.

Diseases that cause genital ulcers, including syphilis, may provide vascular portals of entry for HIV. Evaluate any patient with known or suspected syphilis for the possibility of neurosyphilis, which is known to have an increased incidence among individuals with HIV infection.

Concomitant HIV and syphilis is common. Serologic tests for syphilis may be modified by the presence of HIV, usually resulting in extremely high titers and failure to decrease in response to adequate treatment. A serologic response may fail to develop.

Because clinical manifestations of syphilis are protean, serologic testing has the primary role in confirming the diagnosis. Because the causative microorganism cannot be cultured on artificial media and because simple laboratory stains fail to demonstrate the spirochetes, a presumptive diagnosis of syphilis, as well as evaluation of response to therapy, are based on serologic test results.

The 2 types of serologic tests for syphilis are nontreponemal reaginic tests and treponema-specific tests. A positive nontreponemal reaginic test must be confirmed by a treponema-specific test. Depending on the clinical circumstance, treatment can begin before confirmation is received.

Nontreponemal reaginic serologic tests

Nontreponemal reaginic tests include the rapid plasma reagin (RPR) and the Venereal Disease Research Laboratory (VDRL), both of which are useful in routine screening and are equally sensitive, inexpensive, simple to perform, and rapid. These tests are also useful for ongoing measurement of disease activity (eg, measuring response to treatment or testing for reinfection).

These tests measure antibody directed against a lipoidal antigen that results from the interaction of host tissues with Treponema pallidum or to the spirochete itself. Nonspecific antibodies develop 4-8 weeks following infection.

Seroreactivity occurs in 70% of patients within 2 weeks of developing a chancre and in 100% of patients with secondary and latent disease. False -negative results may occur in early primary syphilis, latent acquired syphilis of long duration, and late congenital syphilis.

Quantitative results of these tests tend to correlate with disease activity; thus, they are very helpful for screening. A 4-fold or greater rise in titer may be seen during the evolution of early syphilis. In secondary syphilis, test results are always positive and often at a high titer (ie, at least 1:32).

A prozone phenomenon occurs in approximately 2% of patients, especially in those with secondary syphilis and those who are pregnant. High levels of antibody in undiluted serum cause an obscured positive test result. When clinical findings strongly suggest syphilis (eg, an infant with the appearance of congenital syphilis, despite negative maternal serology), perform appropriate dilutions to exclude this phenomenon.

The quantitative RPR and VDRL tests should become nonreactive one year after successful therapy in primary syphilis, 2 years after successful treatment in secondary or congenital syphilis, and 5 years after successful therapy in late syphilis. Meanwhile, a sustained 4-fold decrease in titer demonstrates adequate therapy. Similarly, a 4-fold increase in titer following therapy suggests reinfection or relapse and necessitates reevaluation.

False-positive test results occur when the antigen recognized in the nontreponemal tests is found in other tissues. When findings become negative within 6 months, the case is termed acute, whereas cases that persist longer are termed chronic. False-positive test findings in acute illness may result from an acute immunologic stimulus (eg, acute bacterial or viral infection, vaccination, early HIV infection).

False-positive test results in chronic syphilis may be due to parenteral drug use, autoimmune or connective tissue diseases (especially systemic lupus erythematosus), aging, and hypergammaglobulinemic states. A false-positive nontreponemal test finding can usually be identified by using treponema-specific tests.

Treponema-specific tests

These tests, which measure antibodies specific for T pallidum, include T pallidum immobilization (TPI), fluorescent treponemal antibody absorption (FTA-ABS), and T pallidum particle agglutination (TPPA). Use these tests in all cases to confirm a positive nontreponemal reaginic test.

Treponema-specific tests are not completely specific for syphilis because false-positive reactions can occur with other spirochetal diseases (eg, yaws, pinta, leptospirosis, rat-bite fever, relapsing fever, Lyme disease [which causes a negative VDRL test result]).

These test findings become positive soon after infection and typically remain positive for life, despite adequate treatment. Test results do not correlate with disease activity and are not quantified.

The immunoglobulin M (IgM) measures antibodies specific to T pallidum, and polymerase chain reaction tests are not yet widely available.

Direct examination for spirochetes provides a definitive diagnosis, when positive, and histopathology may also be useful. Examination by dark field microscopy or by direct fluorescent antibody testing visualizes spirochetes in an exudate or a tissue. Examination of a serous transudate from moist lesions (eg, the primary chancre, condyloma latum, mucous patch, placenta) is most productive because these lesions have the largest numbers of treponemes.

Darkfield microscopy is particularly helpful early in the disease, prior to development of seroreactivity.

Consider a suspicious lesion to be nonsyphilitic only after 3 competent examinations with negative findings have been performed.

Specimens from the oral cavity cannot be used because nonpathogenic treponemes are part of the normal oropharyngeal flora.

The following ancillary tests may be indicated in patients with suspected syphilis:

• Cerebrospinal fluid (CSF) analysis

• Complete blood count (CBC)

• Liver function tests (LFTs)

• HIV testing

• Testing for other sexually transmitted diseases (STDs)

Cerebrospinal fluid analysis

The CNS becomes involved in as many as 40% of patients because of seeding during the inevitable spirochetemia. Asymptomatic involvement can be detected only by CSF analysis for pleocytosis, increased protein concentration, and a VDRL test. A CSF WBC count greater than 10/uL (10 X 10⁶/L) or a CSF protein level greater than 50 mg/dL (0.50 g/L) indicates possible neurosyphilis.

CSF examination is essential in evaluating any seropositive patient with neurologic signs or symptoms and is recommended for all untreated patients who have had syphilis more than one year or when duration is unknown.

Although the only specific diagnostic test for CNS disease in congenital syphilis is a reactive CSF VDRL test result, newborns may have a negative CSF VDRL test result and still develop signs of neurosyphilis. Therefore, all those with presumptive congenital syphilis should be treated for neurosyphilis.

A nonquantitative VDRL test is the only serologic test that should be performed on CSF. Because this test is highly specific, but relatively insensitive, a negative result does not exclude neurosyphilis.

Go to Neurosyphilis for more complete information on this topic.

Complete blood count

Congenital syphilis is characterized by anemia, thrombocytopenia, and either leukopenia or leukocytosis. Monocytosis is common. Evidence of Coombs-negative hemolytic anemia or a leukemoid reaction may be present.

Liver function tests

Syphilitic hepatitis is characterized by a disproportionately high alkaline phosphatase level and a normal or moderately elevated serum bilirubin level but no cholestasis. Aspartate aminotransferase and alanine aminotransferase levels are often elevated. Prothrombin time may be increased.

HIV testing

Fifteen percent of adolescents and adults with syphilis are co-infected with HIV. All patients who present with syphilis should be offered HIV testing, and all patients with HIV infection should be regularly screened for syphilis.

Testing for other sexually transmitted diseases

Any patient diagnosed with either syphilis or HIV should also be tested for the following STDs:

• Chlamydia infection

• Gonorrhea

• Hepatitis B

• Hepatitis C

Syphilitic pneumonia is common in congenital syphilis and appears as a fluffy diffuse infiltrate and is called pneumonia alba (white-out). Radiographs of long bones may disclose bone involvement, which is common in congenital syphilis. Radiologic abnormalities are exceedingly common in early syphilis and are found in 95% of symptomatic infants and as many as 20% of infants with asymptomatic disease.

Bone involvement includes multiple sites of osteochondritis at the wrists, elbows, ankles, and knees and periostitis of long bones and, rarely, the skull. Lesions are symmetric and involve multiple bones. The lower extremities almost always are affected. Metaphyseal lesions (ie, osteochondritis) vary from punctate lucencies to more destructive changes.

Neuroradiological findings in patients with neurosyphilis are nonspecific and may mimic herpes simplex virus and limbic encephalitides infection. MRI may reveal cerebral hypertrophy and hyperintensity in the temporal lobes.

LIAISON Treponema Assay (DiaSorin; Saluggia, Italy), a one-step sandwich chemiluminescent immunoassay (CLIA), has demonstrated higher sensitivity and specificity as a screening and confirmatory tool compared with conventional methods. ^[14]

If discrepancies are noted between enzyme-linked immunoassay (ELISA) immunoglobulin G (IgG) test findings and T pallidum hemagglutination (TPHA) test findings, the Captia SelectSyph-G test (Trinity Biotech; Jamestown, NY) is a highly sensitive and specific test that can be used as a confirmatory test. ^[15]

Real-time polymerase chain reaction (PCR) is an effective and sensitive assay. PCR has been used to detect T pallidum in the vitreous in patients with syphilitic chorioretinitis and to detect T pallidum in a diagnostically challenging case of syphilitic osteomyelitis. ^[16]

The presence of obliterative endarteritis, which consists of concentric endothelial and fibroblastic proliferative thickening, strongly suggests syphilis. These pathologic changes are found in all stages of syphilis.

In the primary chancre, polymorphonuclear leukocytes and macrophages can often be revealed to be ingesting treponemes.

In biopsy specimens, the spirochete may be visualized with specific immunofluorescence or immunoperoxidase staining.