This content is taken from: Peeling, R., Mabey, D., Kamb, M. et al. Syphilis. Nat Rev Dis Primers 3, 17073 (2017). https://doi.org/10.1038/nrdp.2017.73
Can syphilis be diagnosed based on clinical symptoms?
Syphilis has varied and often subtle manifestations that make clinical diagnosis difficult and can lead to many infections being unrecognized. The classically painless lesions of primary syphilis can be missed, especially in hidden sites of exposure such as the cervix. The rash and other symptoms of secondary syphilis can be faint or mistaken for other conditions. Therefore, clinical symptoms alone should not be used to diagnose syphilis.
What type of diagnostic tests can be used to diagnose syphilis?
Microscopy of exudates from lesions had been used for direct detection and diagnosis since 1920 but nowadays, serological testing has become the most common means to diagnose syphilis. A limitation of all syphilis serological tests in some settings where non-venereal treponemal diseases are endemic is their inability to distinguish between infection with the bacteria Treponema pallidum subspecies pallidum, which causes syphilis, and other Treponema pallidum subspecies that cause yaws, pinta, or bejel. The subspecies are morphologically and serologically indistinguishable.
Serodiagnostic tests for syphilis can be broadly categorized into nontreponemal tests (NTTs) and treponemal tests (TTs).
What is the difference between nontreponemal tests (NTTs) and treponemal tests (TTs)?
Nontreponemal tests (NTTs) measure immunoglobulins (IgM and IgG) produced in response to material released from damaged host cells. NTTs are useful in detecting active syphilis. However, because individuals with an infection do not become positive until 10–15 days after the onset of the primary lesion, 25–30% of primary syphilis cases may be missed. Although simple and inexpensive, most NTTs must be performed by trained workers on serum and rely on a subjective interpretation. These tests also require specialized reagents and equipment, especially the Venereal Disease Research Laboratory test, and, therefore, do not fulfil the criteria for tests that can be used at the point-of-care.
New simple point-of-care NTTs are increasingly available.
The most frequently used NTTs are:
- Rapid plasma reagin (RPR) test
- Venereal Disease Research Laboratory (VDRL) test
Treponemal tests (TTs) detect antibodies directed against Treponema pallidum proteins and are theoretically highly specific. As most individuals infected with syphilis develop treponemal antibodies that persist throughout life, TTs cannot be used to distinguish an active from a past or previously treated infection and are not useful in evaluating treatment effectiveness.
However, in patients with no history of syphilis or syphilis treatment, the detection of treponemal antibodies should be considered as a possible infection and in pregnant women, treated.
Laboratory based TTs are used in typical screening algorithms as confirmatory assays following a positive NTT result. TT results become positive 6–14 days after the primary chancre appears (~5 weeks after infection) and, therefore, may be useful to detect early syphilis missed by NTT testing.
The most common laboratory based TTs include:
- Fluorescent treponemal antibody absorbed (FTA-ABS) test
- Treponema pallidum passive particle agglutination (TPPA)
- Treponema pallidum hemagglutination (TPHA) assays
These tests also require trained personnel in a laboratory setting, are more expensive and technically complex than NTTs and involve specialized reagents and equipment. For these reasons, in lower resource settings, laboratory based TTs are not widely available in primary care, hence limiting their utility as assays for confirming NTT results.
Rapid POC TTs, also known as rapid syphilis tests (RST), enable onsite screening and treatment and are particularly useful in settings with limited laboratory capacity. RST use a finger-prick whole blood sample, serum, or plasma, and are typically immuno-chromatographic strip-based treponemal assays using components that can be stored at room temperature, require no equipment and minimal training, and give a result in less than 20 minutes.
RSTs play an important part when delayed diagnosis is problematic, such as in pregnant women in whom delayed or no treatment poses substantial risks to the fetus that far outweigh the risks of overtreatment for the mother.
At least one test has been developed that enables the simultaneous detection of nontreponemal and treponemal antibodies in a single POC device. Additionally, rapid, dual syphilis and HIV tests are available to screen for HIV and treponemal antibodies using a single lateral-flow immuno-chromatographic strip.
What does the World Health Organization recommend for testing syphilis in pregnant women?
The WHO Guideline recommends screening all pregnant women for syphilis during the first antenatal care visit. Some countries recommend that women at high risk have repeat screening in the third trimester and again at delivery to identify new infections.
In settings with low coverage of syphilis screening and treatment for pregnant women, high loss to follow-up of pregnant women, or limited laboratory capacity, the Guideline suggests on-site tests rather than the standard off-site laboratory-based screening and treatment strategy.
In settings with a low prevalence of syphilis (below 5%), the Guideline suggests a single on-site RST be used to screen pregnant women rather than a single on-site RPR test.
In settings with a high prevalence of syphilis (5% or greater), the Guideline suggests an on-site rapid syphilis test and, if positive, immediate provision of a first dose of treatment and a RPR test, and then, if the RPR test is positive, provision of further treatment according to the duration of syphilis (< 2 years or > 2 years/ unknown). The Guideline suggests this sequence of tests and treatment rather than a single on-site RST or a single on-site RPR test.
In November 2019, the WHO issued new policy recommendations supporting dual HIV/syphilis RDTs as the first test for pregnant women receiving antenatal care. These simple tests can be used at the point-of-care and are cost-saving compared to standard testing in antenatal care. They enable more women to be diagnosed with HIV and syphilis so that they can access treatment and prevent transmission to their children.
Countries introducing the dual HIV/syphilis RDT as the first test in ANC will need to revise their HIV testing strategy for pregnant women. It is important not to use the rapid dual HIV/syphilis test for:
- Women with HIV taking antiretroviral therapy (ART)
- Women already diagnosed with and treated for syphilis during their current pregnancy
- Retesting for HIV
All women whose dual HIV/syphilis test results include a reactive TP (syphilis) result should be treated using benzathine penicillin and referred for further testing to provide final diagnosis of active syphilis.
The Policy Brief can be accessed here.
How can countries maximize the impact of dual HIV/syphilis rapid diagnostic tests?
In line with The Policy Brief, the WHO lays out following steps:
- Step 1 – Verification: Countries introducing dual HIV/syphilis RDTs as the first test in antenatal care will need to verify that the new test works well in combination with the other two HIV tests in the algorithm.
- Step 2 – Product selection: Countries should review and consider WHO-prequalified products listed here.
- Step 3 – Guideline change: Use of the dual HIV/syphilis RDT as the first test in antenatal care allows for integration and improved service delivery coverage. Programs should consider how they can integrate service delivery in antenatal care and other settings, such as outreach to key populations at risk for both HIV and syphilis, to maximize public health impact. Opportunities to offer rapid HBsAg testing alongside the use of dual HIV/syphilis RDTs in pregnancy should also be considered.
- Step 4 – Quantification: As use of the dual-purpose RDTs leads to diagnosis of more syphilis cases, national Programs should prepare for additional procurement of benzathine penicillin to ensure adequate treatment supply and to prevent stock-outs. The increase in demand for benzathine penicillin can be estimated using The WHO Congenital Syphilis Estimation Tool.
- Step 5 – In-country planning: When introducing dual HIV/syphilis RDTs, staff, including testers, implementers, procurement specialists and other related staff, will need training and support. Programs should plan to update training manuals, information and counselling messages, standard operating procedures, quality assurance, operational guidance and tools and procurement planning to include HIV/syphilis RDTs.
- Step 6 – Surveillance updates