eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Syphilis: Differential Diagnoses & Workup

Author: Muhammad Waseem, MD, Associate Professor of Emergency Medicine in Clinical Pediatrics, Weill Medical College of Cornell University; Consulting Staff, Department of Pediatrics, Bronx Lebanon Hospital; Consulting Staff, Department of Emergency Medicine, Lincoln Medical and Mental Health Center
Coauthor(s): Muhammad Aslam, MD, Instructor in Pediatrics, Harvard Medical School; Staff Physician, Department of Medicine/ Division of Newborn Medicine, Children's Hospital Boston
Contributor Information and Disclosures

Updated: Jul 28, 2009

Differential Diagnoses

Other Problems to Be Considered

Anthrax
Bejel
Granuloma inguinale
Lymphogranuloma venereum
Pinta
Rat-bite fever
Relapsing fever
Sepsis
Venereal warts
Yaws

Workup

Laboratory Studies

• Serologic testing is commonly used to confirm a diagnosis of syphilis. Direct examination for spirochetes is definitive, when positive, and histopathology may also be useful. Ancillary testing is generally required, depending on the clinical circumstance.
• Because the organism cannot be cultured on artificial media, simple laboratory stains fail to demonstrate the spirochetes. Clinical manifestations of infection are protean. Serology has the primary role in confirming the diagnosis. The 2 types of serologic tests for syphilis are nontreponemal reaginic tests and treponema-specific tests.
• Nontreponemal reaginic serologic 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 tests include the rapid plasma reagin (RPR), the Venereal Disease Research Laboratory (VDRL), and the automated reagin test (ART), all 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 T 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. The tests may have false-negative findings 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, VDRL, or ART 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 microhemagglutination assay for antibodies to T pallidum (MHA-TP).
• 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 tests are not quantified.
• The immunoglobulin M (IgM) FTA-ABS measures antibody specific to the infant born to an infected mother. However, this test is less specific than once thought and is available only at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia so its general usefulness is questionable.
• Direct examination for spirochetes is as follows:
• An uncommon method to achieve definitive diagnosis is to identify spirochetes by microscopic darkfield examination or by direct fluorescent antibody tests on exudate or 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 organism's presence can be demonstrated by histopathology (see Histologic Findings) and by the following ancillary tests:
• Cerebrospinal fluid (CSF) 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/μL (10 × 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.
• CBC 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.
• LFT
• 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 STDs: Any patient diagnosed with either syphilis or HIV should also be tested for Chlamydia species, gonorrhea, hepatitis B, and hepatitis C infection.

Imaging Studies

• Chest radiography: Syphilitic pneumonia is common in congenital syphilis and appears as a fluffy diffuse infiltrate termed pneumonia alba.
• Long bone radiography
  • Bone involvement 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.
• Neuroradiography: 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.

Other Tests

• LIAISON Treponema Assay (DiaSorin; Saluggia, Italy), a one-step sandwich chemiluminescent immunoassay (CLIA), was compared with conventional tests.⁶ The test demonstrated higher sensitivity and specificity as a screening and confirmatory tool compared with conventional methods.
• 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.⁷
• Real-time polymerase chain reaction (PCR) is an effective and sensitive assay used to detect T pallidum in the vitreous in patients with syphilitic chorioretinitis.
  
  

Procedures

• Lumbar puncture: In addition to serology (VDRL test), direct examination of CSF by darkfield microscopy may be diagnostic.

Histologic Findings

• 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.

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