Syphilis

Clinical Presentation:

Syphilis, which is caused by the bacterium Treponema pallidum, has often been called the “great imitator” because many of its signs and symptoms are indistinguishable from those of other diseases. Many refugees who are infected do not recall ever having had symptoms. Asymptomatic latent infection is detected through serologic screening.

Typical signs and symptoms of syphilis, listed by stage, include the following:

• Primary stage (generally occurs 10-90 days after exposure):
  Ulcer or chancre at the inoculation site (usually the genitals, rectum, tongue, or lips)
• Secondary stage (generally occurs 2-10 weeks after the chancre appears):
  Skin rash marked by red or reddish-brown macules on the palms and soles or other parts of the body; mucocutaneous lesions; lymphadenopathy; anorexia; fever; headaches; weight loss; fatigue
• Latent stage (early latent and late latent, begin when primary or secondary symptoms disappear and may last for years):
  No signs or symptoms present
• Tertiary stage (generally occurs 10-20 years after infection):
  Cardiac manifestations (e.g., aortitis), ocular manifestations (e.g., optic atrophy, uveitis, pupillary disorder), auditory abnormalities (e.g., asymmetric deafness, tinnitus), neurologic manifestations (e.g., tabes dorsalis, meningitis, dementia), gumma

Neurosyphilis:

Signs and symptoms of neurosyphilis include motor or sensory deficits; cranial nerve dysfunction; or symptoms and signs of meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, and auditory or ophthalmic abnormalities. Neurosyphilis may occur at any stage of disease.

Congenital Syphilis:

Congenital syphilis may present as nonimmune hydrops, jaundice, hepatosplenomegaly, rhinitis, skin rash, or pseudoparalysis of an extremity. In older children, signs of untreated congenital infection include interstitial keratitis (5-20 years of age), cranial nerve deafness (10-40 years of age), Hutchinson teeth (peg-shaped, notched central incisors), anterior bowing of the shins, frontal bossing, mulberry molars, saddle nose, rhagades (linear scars around the mouth), and Clutton’s joints (symmetric, painless swelling of the knees). Prevention and detection of congenital syphilis depends on identification of syphilis in pregnant women by serology. For specific more information on congenital syphilis see CDC congenital syphilis.

Syphilis Serology:

Serologic tests for syphilis require the use of two tests: nontreponemal tests that use a nonspecific cardiolipin antigen and confirmatory tests that use specific T. pallidum antigens (Table 1). A nontreponemal test, such as VDRL or RPR, may be used for screening. Positive results on these nontreponemal tests should be confirmed using a treponemal test (e.g., FTA-ABS, TP-PA, EIAs, chemiluminescence immunoassays). The use of only one type of test is insufficient for diagnosis, since all tests have limitations, including the possibility of false-positive test results. False-positive nontreponemal test results can be associated with various medical conditions unrelated to syphilis, including autoimmune disorders, older age, and injection drug use.

Screening tests, such as the VDRL and RPR, are relatively simple to perform and provide rapid results. Both VDRL and RPR quantitative titer usually correlate with disease activity, and are used to monitor the effect of treatment. If treatment is successful, the antibody titer gradually declines. A four-fold change in titer (e.g., from 1:16 to 1:4) is necessary to demonstrate a clinically significant difference between two nontreponemal tests. Sequential nontreponemal tests should be performed by using the same testing method, because quantitative results from the two tests cannot be compared directly; RPR titers are often slightly higher than VDRL titers. The timing of follow-up testing is dictated by the clinical presentation and stage of infection, as well as the HIV status of the refugee, and is detailed in the current treatment guidelines¹.

Unlike nontreponemal tests, treponemal tests (e.g., FTA) do not usually revert to nonreactivity after successful treatment of syphilis. Screening with treponemal tests is not recommended in high-prevalence settings, because these tests will be reactive in people with previous successful treatment, as well as those with untreated or incompletely treated infection.

Recently, some clinical laboratories have begun using a “reverse screening” algorithm. The use of this algorithm is acceptable when it is considered the local standard of care. This method can identify persons previously treated for syphilis, those with untreated or incompletely treated syphilis, and persons with false-positive results. Persons with a positive treponemal screening test should have a standard nontreponemal test, with titer performed reflexively by the laboratory to guide patient management decisions. If the nontreponemal test is negative, the laboratory should perform a different treponemal test (preferably one based on different antigens than the original test) to confirm the results of the initial test. If a second treponemal test is negative and the epidemiologic risk and clinical probability for syphilis are low, the initial treponemal test is considered a false positive and further evaluation or treatment is not indicated. People with a history of previous treatment require no further management unless sexual history suggests likelihood of re-exposure. In this instance, a repeat nontreponemal test in 2–4 weeks is recommended to evaluate for early infection. Those without a history of treatment for syphilis should be offered treatment. Unless history or results of a physical examination suggest a recent infection, previously untreated persons should be treated for late latent syphilis. For more information, refer to CDC Sexually Transmitted Diseases Treatment Guidelines.

Cerebrospinal Fluid Examination:

Involvement of the central nervous system can occur during any stage of syphilis; therefore, any person who has syphilis and signs or symptoms of neurologic or ophthalmic involvement should have a cerebrospinal fluid (CSF) evaluation. The diagnosis of neurosyphilis depends on a combination of CSF tests (elevated cell count or protein and a reactive CSF-VDRL), with reactive serologic tests and neurologic signs or symptoms. The treatment guidelines provide in-depth information on diagnosis and treatment, and expert consultation may be needed when deciding how to evaluate an individual or interpret testing¹.

Other Diagnostic Tests:

Because early treatment decreases the possibility of transmission, presumptive treatment of suspected infectious syphilis is recommended on the basis of clinical presentation and epidemiologic circumstances (high incidence of disease among populations or communities and travel history).

Syphilis in children (either congenital or acquired) must be properly evaluated. The diagnosis of congenital syphilis is complicated by transplacental transfer of maternal nontreponemal and treponemal IgG antibodies to the fetus, making it difficult to interpret reactive serologic tests for syphilis in newborns born to mothers seropositive for syphilis. Further information on evaluation for congenital syphilis is available in published guidelines, including a section in CDC’s STD Treatment Guidelines (2015) and the American Academy of Pediatrics Red Book. Infants >1 month of age and children who have a reactive serology should be examined, and have maternal serology and records reviewed to assess whether they have congenital or acquired syphilis.

References

1. Workowski KA, Bolan GA; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2015. MMWR Mortal Morb Wkly Rep 2015;64(RR-03):1-137.

Table 1. Interpretation of Syphilis Serology Tests

Nontreponemal test (e.g., RPR, VDRL)	Treponemal (specific) test (e.g., FTA-ABS, TPPA)	Likely interpretations and comments
Nonreactive*	Nonreactive	No evidence of syphilis
Reactive	Reactive	Untreated syphilis OR Previously treated late syphilis OR Other spirochetal diseases
Reactive	Nonreactive	False-positive result may be seen in certain acute or chronic infections (e.g., tuberculosis, hepatitis, malaria, early HIV infection), autoimmune diseases (e.g., systemic lupus, rheumatoid arthritis), injection drug use, pregnancy, and following vaccination (e.g., smallpox, MMR).
Nonreactive	Reactive	Very early untreated syphilis OR Previously treated syphilis OR Very late untreated syphilis Note: After successful treatment, a positive nontreponemal test usually becomes negative, whereas the treponemal test usually remains positive for life.

*Note: Nontreponemal testing may have a false-negative result during primary syphilis in the very early stages or tertiary syphilis in the very late stages. Suggest presumptive treatment, and retesting if clinical suspicion is high. See CDC Sexually Transmitted Diseases Treatment Guidelines.

Acronyms: Rapid plasma reagin (RPR); venereal disease research laboratory (VDRL) test; fluorescent treponemal antibody absorption (FTA-ABS); treponema pallidum particle agglutination (TPPA) assay.