Investigations

1st investigations to order

Test
Result
Test

Performed to identify Treponema pallidum.

Can provide a definitive diagnosis of syphilis, but is not usually available outside specialist settings.

The lesion is cleansed and abraded with a gauze pad until serous exudates appear, which are collected onto a glass slide for microscopic analysis.

A single negative result does not exclude infection; ideally 3 negative examinations on different days are required.

Primary syphilis: sensitivity of dark-field microscopy is 74% to 86%, specificity is 85% to 100%.[38]

Secondary syphilis: dark-field microscopy may be positive from ulcerative anogenital lesions.

Gummata in tertiary syphilis have few, if any, identifiable T pallidum organisms.

Result

coiled spirochaete bacterium with a corkscrew appearance and motility

Test
Result
Test

A treponemal serology test.

A patient with a positive treponemal test result will remain positive for life. Therefore, a positive result alone cannot distinguish between an active infection or past (treated) infection.

The most common approach is to use a treponemal test as the initial serological test, followed by a non-treponemal test to confirm diagnosis and provide evidence of active disease or re-infection (i.e., a ‘reverse sequence screening algorithm’).[41] 

False-positive results may occur with other non-sexually transmitted treponemal infection (e.g., yaws, pinta, bejel).

False-negative results may occur in incubating and early primary syphilis. It usually takes 3 weeks for an EIA IgG/IgM test to become positive after infection with Treponema pallidum.

EIA is the test generally used for screening.[3] 

Primary syphilis: EIA sensitivity 82% to 100%, and specificity 97% to 100%.[72]

Secondary syphilis: EIA sensitivity is 100%.[72]

Late latent syphilis: EIA sensitivity is 98% to 100%.[72]

Result

positive

Test
Result
Test

A treponemal serology test.

A patient with a positive treponemal test result will remain positive for life. Therefore, a positive result alone cannot distinguish between an active infection or past (treated) infection.

The most common approach is to use a treponemal test as the initial serological test, followed by a non-treponemal test to confirm diagnosis and provide evidence of active disease or re-infection (i.e., a "reverse sequence screening algorithm").[41]

Primary syphilis: TPPA sensitivity 85% to 100%, and specificity 98% to 100%.[73][74]

Secondary and late latent syphilis: TPPA sensitivity 98% to 100%.[74]

Result

positive

Test
Result
Test

A treponemal serology test.

A patient with a positive treponemal test result will remain positive for life. Therefore, a positive result alone cannot distinguish between an active infection or past (treated) infection.

The most common approach is to use a treponemal test as the initial serological test, followed by a non-treponemal test to confirm diagnosis and provide evidence of active disease or re-infection (i.e., a 'reverse sequence screening algorithm').[75]

Result

positive

Test
Result
Test

A treponemal serology test.

A patient with a positive treponemal test result will remain positive for life. Therefore, a positive result alone cannot distinguish between an active infection or past (treated) infection.

The most common approach is to use a treponemal test as the initial serological test, followed by a non-treponemal test to confirm diagnosis and provide evidence of active disease or re-infection (i.e., a 'reverse sequence screening algorithm').[75]

FTA-ABS is used less often than TPHA and TPPA because it is less specific.

Result

positive

Test
Result
Test

A treponemal serology test.

A patient with a positive treponemal test result will remain positive for life. Therefore, a positive result alone cannot distinguish between an active infection or past (treated) infection.

The most common approach is to use a treponemal test as the initial serological test, followed by a non-treponemal test to confirm diagnosis and provide evidence of active disease or re-infection (i.e., a 'reverse sequence screening algorithm').[75]

Result

positive

Test
Result
Test

A treponemal serology test.

A patient with a positive treponemal test result will remain positive for life. Therefore, a positive result alone cannot distinguish between an active infection or past (treated) infection.

LIA serological tests (e.g., INNO-LIA syphilis test) can be used to confirm syphilis infection following initial serological treponemal testing. A single LIA test can confirm infection, making it more convenient than traditional methods of serological confirmation (which usually require multiple assays). Studies evaluating the performance of LIA tests for syphilis infection have demonstrated higher sensitivity and specificity compared with FTA-ABS and TPHA serology tests.[55][56]

Result

positive

Test
Result
Test

A non-treponemal serology test. 

Provides a quantitative measure of disease activity and can be used to monitor treatment response (RPR titers decrease or become non-reactive with effective treatment).

The most common approach is to use a treponemal test as the initial serological test, followed by a non-treponemal test to confirm diagnosis and provide evidence of active disease or re-infection (i.e., a 'reverse sequence screening algorithm').[75]

A titre of ≥32 is rarely seen in adequately treated infection. 

Despite adequate treatment, some patients maintain a persisting low level positive antibody titre (known as a serofast reaction).[51]

False positives may occur due to the presence of a variety of medical conditions (e.g., pregnancy, autoimmune disorders, and infections).

A false-negative test may occasionally occur in an undiluted specimen (the prozone phenomenon).

Primary syphilis: RPR sensitivity 70% to 73%.[15][76]

Secondary syphilis: RPR sensitivity is 100%.[76]

Preferred test over the serum Venereal Disease Research Laboratory test.

Result

positive

Test
Result
Test

A non-treponemal serology test.

Provides a quantitative measure of disease activity and can be used to monitor treatment response (VDRL titres decrease or become non-reactive with effective treatment).

The most common approach is to use a treponemal test as the initial serological test, followed by a non-treponemal test to confirm diagnosis and provide evidence of active disease or re-infection (i.e., a 'reverse sequence screening algorithm').[75]

A titre of ≥32 is rarely seen in adequately treated infection.

Despite adequate treatment, some patients maintain a persisting low level positive antibody titre (known as a serofast reaction).[51]

False positives may occur due to the presence of a variety of medical conditions (e.g., pregnancy, autoimmune disorders, and infections).

A false-negative test may occasionally occur in an undiluted specimen (the prozone phenomenon).

Primary syphilis: VDRL sensitivity 44% to 76%.[76]

VDRL is positive in 77% of cases of late latent syphilis.[15]

VDRL sensitivity in secondary syphilis is 100%.[76]

Result

positive

Investigations to consider

Test
Result
Test

Indicated for any patient with clinical evidence of neurological involvement (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsy, features of meningitis).

Indicated if syphilis of unknown duration exists in the presence of HIV co-infection.

Indicated in any child with congenital syphilis and neurological symptoms or signs.[5]

An elevated CSF WBC count and positive CSF Venereal Disease Research Laboratory (VDRL) suggests neurological involvement.[29] 

Some patients with neurosyphilis have an isolated elevated CSF WBC count and negative rapid plasma reagin/VDRL.

Neurosyphilis is unlikely at CSF Treponema pallidum haemagglutination assay (TPHA)/T pallidum particle agglutination assay (TPPA) titres <1:320.

A non-reactive CSF-TPHA test result usually excludes neurosyphilis.


Diagnostic lumbar puncture in adults: animated demonstrationDiagnostic lumbar puncture in adults: animated demonstration

Result

WBC count >10 cells/mm³; CSF protein >50 mg/dL (0.50 g/L); CSF VDRL positive; CSF TPHA/TPPA/FTA-ABS positive

Test
Result
Test

May detect possible thoracic aortic aneurysm or aortic calcification.

Required in people with symptoms or signs of aortic regurgitation, heart failure, or aortic aneurysm.

Result

possible widened thoracic aorta, aortic calcification

Test
Result
Test

Required if cardiovascular syphilis is strongly suspected (e.g., a patient has symptoms or signs of aortic regurgitation, heart failure, or aortic aneurysm).

Result

may show evidence of heart failure, aortic regurgitation, or thoracic aortic aneurysm

Test
Result
Test

Performed before lumbar puncture to exclude elevated intracranial pressure, to ensure that undertaking a lumbar puncture will be safe.

Elevated intracranial pressure is rarely caused by syphilis itself.

Result

usually normal

Test
Result
Test

Performed before lumbar puncture to exclude elevated intracranial pressure, to ensure that undertaking a lumbar puncture will be safe.

Elevated intracranial pressure is rarely caused by syphilis itself.

Result

usually normal

Test
Result
Test

All patients with syphilis should be tested for HIV.

In geographical areas in which the prevalence of HIV is high, patients who have primary syphilis should be re-tested for HIV after 3 months even if the first HIV test result is negative.[5]

Result

positive or negative

Test
Result
Test

Should be performed on all pregnant women with syphilis or suspected of having syphilis.

Presence of fetal or placental syphilis indicates a greater risk of treatment failure for congenital syphilis.[70]

Result

may show hepatomegaly, ascites, hydrops fetalis, intrauterine growth retardation

Test
Result
Test

Performed in infants with possible congenital syphilis.

Result

may show anaemia, thrombocytopenia, leukopenia, possible neutrophilia

Test
Result
Test

May be indicated in infants with suspected congenital syphilis.[5]

Performed if cranial abnormalities suspected.

Result

may demonstrate craniofacial malformation

Test
Result
Test

May be indicated in infants with suspected congenital syphilis.[5]

Performed if osteochondritis suspected.

Result

may demonstrate osteochondritis

Test
Result
Test

May be indicated in infants with suspected congenital syphilis.[5]

Performed if clinical findings suggestive of liver involvement (e.g., hepatomegaly).

Result

aspartate aminotransferase and alanine aminotransferase may be elevated

Test
Result
Test

May be indicated in infants with suspected congenital syphilis.[5]

Performed if clinically indicated.

Result

may detect deafness

Test
Result
Test

Neurosyphilis may involve cranial nerves (particularly the 8th cranial nerve).

Result

may detect hearing deficit

Emerging tests

Test
Result
Test

T pallidum PCR has been shown to have moderate sensitivity (70% to 80%) and high specificity >90% in the diagnosis of primary or secondary syphilis, when compared with adequate reference tests (e.g., serology, dark-field microscopy).[57]

The US Centers for Disease Control and Prevention considers PCR testing a valid method for diagnosing primary and secondary syphilis, and its use is likely to increase.[58]

Result

positive

Test
Result
Test

POC syphilis testing has been assessed in the setting of high-risk regions, where rapid and early diagnosis may be more important than accuracy. Several clinical trials have shown promise[59] and POC testing has been recommended as part of the Pan American Health Organization strategy to diagnose and treat syphilis.[60]

Result

positive; however, a positive result for treponemal antibodies alone does not distinguish between current, past, or treated infection

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