Narrative
Syphilis is a sexually transmitted disease caused by Treponema pallidum with 6 million new cases annually worldwide. Infection manifests in stages, from painless ulcers (chancres) in primary syphilis to rashes in secondary syphilis. Latent infection, with no symptoms, may progress to tertiary syphilis, which can affect multiple organ systems with potentially devastating consequences.
Diagnosis involves both direct and indirect tests. Direct methods include microscopic examination of fluid from lesions, fluorescent antibody testing, histological examination of tissues, and nucleic acid amplification methods such as polymerase chain reaction (PCR). Indirect tests such as rapid plasma reagin (RPR) and venereal disease research laboratory (VDRL) are called “nontreponemal” because they detect antibody–antigen complexes (in blood or cerebrospinal fluid) and rely on subjective interpretation of quantitative results that can vary among labs.
“Treponemal” tests include fluorescent treponemal antibody absorption (FTA-ABS), T. pallidum particle agglutination (TP-PA), and other immunoassays. These detect antibodies that persist after infection.
Traditional diagnosis involved starting with a nontreponemal test such as RPR, followed by a T. pallidum–specific assay like the TP-PA for confirmation. Recently there has been a shift toward treponemal immunoassays for initial screening, and an algorithm has been proposed starting with an immunoassay followed, if positive, by nontreponemal testing (see Figure 1). The Centers for Disease Control and Prevention (CDC) recommends confirming discordant results with a TP-PA. Sensitivity and specificity of these tests vary by stage (see Table 1).
Figure 1
Syphilis screening algorithm (reverse sequence algorithm) based on Centers for Disease Control and Prevention (CDC) recommendation. CIA, chemiluminescence immunoassay; EIA, enzyme immunoassay; RPR, rapid plasma regain; TPPA, T. pallidum particle agglutination; VDRL, venereal disease research laboratory.
Table 1. Operating characteristics of treponemal tests based on different stages of syphilis.
The reference standards used in the included trials were dark-field microscopy, PCR from lesions with clinical suspicion of syphilis, or both.
, Because of missing data, and the fact that most trials did not report specificity or provide 2 × 2 tables, the two systematic reviews did not pool the data. The aggregate findings for treponemal tests are presented in the Table 1.
Caveats
The two systematic reviews identified numerous limitations in the original trials evaluating the accuracy of syphilis diagnostic tests. These limitations included retrospective designs, small sample sizes, and unclear clinical staging. Additionally, the trials exhibited significant heterogeneity in methodology, patient selection, disease staging, and reference standards. This variability led to wide confidence intervals around the effect sizes, further increasing the uncertainty regarding the validity of the reported results.
Most trials predominantly included patients with positive (reactive) serology, which could bias sensitivity estimates toward 100%, especially in cases of primary syphilis. Additionally, the varying case definitions and reference standards, along with the broad range of results, provided no reliable data on the performance of nontreponemal tests for neurosyphilis. Another limitation was the small number of children enrolled in these trials. Moreover, most trials lacked sufficient data to construct 2 × 2 tables, preventing a comprehensive analysis of the tests' operating characteristics.
In summary, there is insufficient evidence to recommend one treponemal assay over another based on available performance data. The accuracy of each test varies with the stage of the disease. For now, the diagnostic algorithm recommended by the CDC seems to be a reasonable, expert-guided approach. However, more robust diagnostic trials are needed to better refine the approach to syphilis diagnosis at each stage of the disease.
The original manuscript was published in
Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.
Author
Fatima Johari, MD; Michelle Ordoveza Cho, MD
Supervising Editors: Shahriar Zehtabchi, MD
Published/Updated
November 20, 2024
What are Likelihood Ratios?
LR, pretest probability and posttest (or posterior) probability are daunting terms that describe simple concepts that we all intuitively understand.
Let's start with pretest probability: that's just a fancy term for my initial impression, before we perform whatever test it is that we're going to use.
For example, a patient with prior stents comes in sweating and clutching his chest in agony, I have a pretty high suspicion that he's having an MI – let's say, 60%. That is my pretest probability.
He immediately gets an ECG (known here as the "test") showing an obvious STEMI.
Now, I know there are some STEMI mimics, so I'm not quite 100%, but based on my experience I'm 99.5% sure that he's having an MI right now. This is my posttest probability - the new impression I have that the patient has the disease after we did our test.
And likelihood ration? That's just the name for the statistical tool that converted the pretest probability to the posttest probability - it's just a mathematical description of the strength of that test.
Using an online calculator, that means the LR+ that got me from 60% to 99.5% is 145, which is about as high an LR you can get (and the actual LR for an emergency physician who thinks an ECG shows an obvious STEMI).
(Thank you to Seth Trueger, MD for this explanation!)
