Table 1.
Summary of the Relevant Data
| Syphilis Screening Algorithms | ||||
|---|---|---|---|---|
| Study, First Author and Year [Ref] | Study Design | Study Population | Gold Standard | Findings |
| Diagnostic implications | ||||
| Aktas 2005 [8] | Cross-sectional comparison of RPR and/or TPHA positive to Serodia TPPA, Syphilis ICE, and Enzywell TP | N = 1876 routine samples ≈4.5% prevalence | Traditional algorithm RPR followed by TPHA | 23 RPR (+), 16 TPHA (+), and 84 both (+). 23 (1.23%) RPR biological false positives that did not confirm with TPHA, Serodia TPPA, the Murex Syphilis ICE, and the Enzywell TP tests. Lower false positives seen if TPHA used for screening 16 (0.85%). Agreement of TPHA (N = 124) with the Serodia TPPA, the Murex Syphilis ICE and the Enzywell TP tests were 96.7%, 100%, and 99.1%, respectively. Regardless of the treponemal test used as the confirmatory test, almost the same number of patients would have been diagnosed as having syphilis. |
| Aktas 2007 [9] | Cross-sectional comparison of FTA-ABS to TPHA, Mastaflourt FTA-ABS, Serodia TPPA, ICE Syphilis Detection Pack, and Enzywell TP | N = 122 FTA-ABS+ samples | FTA-ABS | Agreements of the FTA-ABS with the TPHA test, the TPPA test, ICE test, and TP test were 97.5%, 95.9%, 98.3%, and 98.3%, respectively. Agreements of the WB (n = 42) with TPHA, Serodia TPPA, Murex syphilis ICE, Enzywell TP, and FTA-ABS were 92.8%, 97.6%, 100%, 95.2%, and 92.8%, respectively. 2 FTA-ABS negative sera were positive by TPHA, TPPA, ICE, TP, and WB. |
| Angue 2005 [10] | Cross-sectional comparison of VDRL to Abbot Syfacard-R (RPR card test) | N = 2100 pregnant women 3% prevalence | VDRL | RPR: sensitivity 56.3% and specificity 96.5% High discordance rate between the RPR and VDRL |
| Berry 2016 [11] | Cross-sectional evaluation of signal-to-cutoff ratio | N = 665 (mixed population with 3.8% screen reactive rate) | Reverse algorithm (Bioplex IgG followed by RPR and TPPA) | 99.3% of Bioplex IgG antibody index values of ≥ 8 were confirmed by TPPA, indicating that signal-to-cutoff ratio can be used in lieu of confirmatory testing. Total cost savings of $4825 annually. |
| Binnicker 2011 [12] | Cross-sectional comparison of 7 treponemal assays | N = 303 (203 routine and 100 previously tested samples) | FTA-ABS or consensus 4 of 7 treponemal tests | Agreements of the FTA-ABS with Bioplex 2200 Syphilis IgG, TPPA, Trep-Sure EIA, Trep-Check EIA, Trep-ID EIA, and Treponema ViraBlot IgG were 98.0%, 97.0% 95.4%, 97.7%, 98.4%, and 97.0%, respectively. Consensus 4 of 7 positive (panel) agreement for Bioplex 2200 Syphilis IgG, TPPA, Trep-Sure EIA, Trep-Check EIA, Trep-ID EIA, and Treponema ViraBlot IgG were 99.0%, 98.0% 95.7%, 98.7%, 99.3%, and 98.0%, respectively. Fastest TAT and throughput: Bioplex at 1.75 h for 100 samples and 514 samples for 9-h shift. Slowest TAT and lowest throughput: Trep-ID with 5.7 h for 100 samples and 158 samples in 9-h shift. |
| Binnicker 2012 [13] | Prospective, direct comparison of traditional and reverse algorithms | N = 1000 ≈1.5% prevalence | Traditional and reverse algorithms Discrepant results resolved by clinical data | Traditional algorithm 2 (0.2%) patients with possible latent syphilis missed 0 false reactive samples Reverse algorithm 6 (0.6%) false reactive samples |
| Bosshard 2013 [14] | Retrospective study evaluating IgM syphilis assays | N = 156 syphilis samples | Clinical symptoms and laboratory data (VDRL, TPPA, and Pathozyme Syphilis M Capture) | Overall n = 156 TPPA: sensitivity 100% and specificity 99.2% VDRL: sensitivity 83.3% and specificity 100% Pathozyme IgM: sensitivity 88.5% and specificity 96.0% Primary syphilis n = 59 TPPA: sensitivity 100% VDRL: sensitivity 61.0% Pathozyme IgM: sensitivity 89.8% Secondary syphilis n = 66 TPPA: sensitivity 100% VDRL: sensitivity 97.0% Pathozyme IgM: sensitivity 90.9% Latent syphilis n = 25 TPPA: sensitivity 100% VDRL: sensitivity 96.0% Pathozyme IgM: sensitivity 84.0% |
| CDC 2008 [2] | Retrospective study of 4 New York City laboratories using the reverse algorithm | N = 116 822 2.5% prevalence | Reverse algorithm: EIA followed by RPR | Among the 6548 EIA screen positive, 2884 (44%) were reactive and 3664 (56%) were nonreactive to the RPR test. 433/2079 (20.8%) of reactive EIA screens were non-reactive with a second treponemal assay. When TPPA was used as confirmation, 78/80 (98%) were reactive. |
| CDC 2011 [15] | Retrospective study of 5 laboratories (CA × 3, IL, and NY) using the reverse algorithm | N = 140 176 3 low-prevalence and 2 high-prevalence (Chicago and New York City) locations | Reverse algorithm: EIA/CIA followed by RPR | 56.7% of reactive screens had a nonreactive RPR. 31.6% of reactive EIA screens were nonreactive with a second treponemal assay (FTA-ABS or TPPA). Among discordant sera, the rate of nonreactive confirmatory treponemal tests was 2.9 times higher in a population with low prevalence. |
| Creegan 2007 [16] | Cross-sectional study of primary syphilis | N = 106 primary syphilis | Clinical symptoms and dark field microscopy | VDRL: sensitivity 70.8% TPPA: sensitivity 85.9% RPR (n = 51): sensitivity 72.5% 12% of primary cases were missed by VDRL and TPPA. Similar performance between RPR and VDRL in primary syphilis. Traditional algorithm less sensitive in primary syphilis. |
| Dai 2014 [17] | Retrospective study evaluating signal-to-cutoff ratio of the Architect Syphilis TP assay | N = 8980 cancer patients 3.6% screen reactive rate | European algorithm Architect followed by TRUST and TPPA | 100% of Architect reactive samples with a signal-to-cutoff ratio ≥ 9.9 were reactive by confirmatory testing. |
| Dang 2006 [18] | Cross-sectional evaluation of RPR, TPPA, and WB | N = 67 (20 primary or 47 secondary syphilis | Not defined | Primary syphilis n = 20 RPR: 12/20 (60%) TPPA: 18/20 (90%) WB: 20/20 (100%) Secondary syphilis n = 47 RPR, TPPA, and WB: 47/47 (100%) |
| Gratrix 2012 [19] | Retrospective review of data when changing from the traditional to the reverse screening algorithm | N = 243 969 routine samples | Clinical and laboratory data (RPR and TPPA) | Significant increase in the rate of late latent syphilis diagnoses after switching to the reverse screening algorithm. Rate of late latent syphilis Traditional algorithm: 0.07% (n = 97) Reverse algorithm: 0.14% (n = 137) No significant rise in cases of primary syphilis. Only 3 cases of primary syphilis would have been missed using the traditional algorithm. |
| Gratzer 2014 [20] | Retrospective medical records review | N = 52 suspected primary syphilis STD clinic | Clinical symptoms and laboratory data (FTA-ABS or RPR positive) | Trep-Sure: sensitivity 28/52 (53.8%) RPR: 40/52 (76.9%) |
| Gu 2013 [21] | Cross-sectional study of RPR and TRUST | N = 209 active syphilis stratified by stage N = 247 control sera | Clinical and laboratory data (EIA and TPPA) | RPR kit 1: sensitivity 98.7% and specificity 96.8% RPR kit 2: sensitivity 95.7% and specificity 97.6% TRUST kit 1: sensitivity 99.0% and specificity 98.0% TRUST kit 2: sensitivity 96.7% and specificity 96.8% Nonreactive RPR and TRUST Overall (n = 209): 1%–4.3% Primary (n = 30): 6.7%–10% Secondary (n = 92): 0%–1.1% Latent (n = 39): 0%–5.1% Neurosyphilis (n = 44): 0%–4.5% Biological false positives ranged from 2.0% to 3.2% with the highest rate seen in patients with SLE (10.4%). |
| Hunter 2013 [22] | Retrospective analysis of samples reactive only by Archictect Syphilis TP | N = 18 713 0.005% prevalence | Reverse algorithm Archictect Syphilis TP followed by RPR and TPPA | 82 (9.4%) were reactive only by Archictect Syphilis TP. Chart reviews of 20 of these patients found that 11 (55%) had clinical or serological evidence of previous or subsequent syphilis. |
| Jost 2013 [23] | Cross-sectional comparison of 9 treponemal assays | N = 290 with 109 reactive and 181 nonreactive samples | TPPA | 95 (85%) samples were nonreactive for the confirmatory RPR test. Agreements of the TPPA with FTA-ABS, INNO-LIA, LIASON, Trep-Sure, BioELISA, SD BIOLINE, CAPTIA IgG, Trep-ID, were 97.9%, 99.3%, 99.7%, 99.3%, 99.3%, 99.3%, 98.3%, and 100%. Analytical sensitivity in fold dilutions: FTA-ABS (4), CAPTIA IgG (8), INNO-LIA (16), TPPA (16), SD BIOLINE (64), Trep-ID (64), LIASON (128), BioELISA (128), Trep-Sure (512). Confirmatory test should have the same or better analytical sensitivity. |
| Knaute 2012 [24] | Retrospective study of response to treatment of syphilis | N = 264 (42% HIV positive and 13% with history of syphilis) | Clinical and laboratory data (VDRL, TPPA, and Pathozyme Syphilis M Capture) | VDRL sensitivity stratified by stage: primary 58%, secondary 100%, tertiary 100%, and latent 88%. TPPA sensitivity stratified by stage: primary 93%, secondary 100%, tertiary 100%, and latent 100%. Pathozyme IgM: sensitivity stratified by stage: primary 96%, secondary 91%, tertiary 62%, and latent 79%. For primary syphilis, the VDRL test should not be recommended as first-line screening test because of its lack of sensitivity. |
| Knight 2007 [25] | Cross-sectional evaluation of LIAISON vs CAPTIA Syphilis-G | N = 2645 (51 primary syphilis, 999 routine samples, 200 HIV, 200 pregnant, and 992 negative controls) | Reverse algorithm CAPTIA Syphilis-G followed by RPR Discordant results tested by TPPA | LIAISON agreement with CAPTIA and reverse algorithm, respectively Primary and secondary syphilis: 94.1% and 100% Routine samples: 93.2% and 98.7 HIV patients: 84.5% and 94.0% Pregnant patients: 98.0% and 100% Negative controls: 94.3% and 98.3% Overall LIASON: sensitivity 95.8% and specificity 99.1% 11 of 21 discordant results positive by TPPA. |
| Li 2016 [26] | Retrospective study evaluating signal-to-cutoff ratio of the Architect Syphilis TP assay | N = 20 550 1.3% screen reactive rate | European algorithm Architect followed by RPR and TPPA | 54/267 (20.2%) reactive by RPR 185/267 (69.3%) reactive by confirmatory TPPA 117/117 (100%) of Architect-reactive samples with a signal-to-cutoff ratio >10 were reactive by confirmatory TPPA testing. Only 42/117 (35.9%) were reactive by RPR. |
| Loeffelholz 2011 [27] | Retrospective study evaluating signal-to-cutoff ratio of the Bioplex IgG | N = 6234 Screen reactive rate: incarcerated 7.5%, OB/GYN 1.6%, and delivery 2.6% | NA | An RPR titer of ≥ 1:2 was more likely to confirm by TPPA. Bioplex IgG antibody index > 8 provided highest specificity for TPPA confirmation. |
| Malm 2015 [28] | Cross-sectional comparison of RPR to VDRL | N = 729 (301 Guinea-Bissau, 201 Sweden, 30 performance panels, and 200 blood donors) | Macro-Vue RPR | VDRL: sensitivity 66.3% and specificity 98.5% High discordance rate between the RPR and VDRL |
| Cross-sectional comparison of 4 FDA-cleared treponemal assays | N = 619 (301 Guinea-Bissau, 201 Sweden, 30 performance panels, and 200 blood donors) | TPPA and TrepSure Anti-Treponema EIA Screen | Similar sensitivity (98.7%–100%) and specificity (97.9%–100%) of FDA-cleared TPPA, TrepSure Anti-Treponema EIA Screen, and Liaison Treponema Screen. Architect Syphilis TP: sensitivity 99.5%–99.8% and specificity 87.6%–89.5% | |
| Marangoni 2000 [29] | Cross-sectional comparison of WB, FTA-ABS, MHA-TP, and VDRL | N = 100 clinically characterized samples | Clinical data | WB agreement stratified by stage: primary 96%, secondary 100%, tertiary 100%, and latent 100%. FTA-ABS agreement stratified by stage: primary 65%, secondary 95%, tertiary 100%, and latent 100%. MHA-TP agreement stratified by stage: primary 65%, secondary 85%, tertiary 92%, and latent 100%. VDRL agreement stratified by stage: primary 66%, secondary 100%, tertiary 100%, and latent 100%. |
| Marangoni 2005 [30] | Retrospective and prospective study LIAISON compared to RPR, TPHA, WB | N = 2494 control sera N = 131 syphilis sera N = 96 analytical specificity N = 1800 prospective samples | Clinical and laboratory data | 75 (2.90%) biological false-positive RPRs Characterized syphilis sera n = 131 LIASON: sensitivity 99.2% and specificity 99.9% EIA: sensitivity 95.4% and specificity 99.9% TPHA: sensitivity 94.7% and specificity 99.9% WB: sensitivity 100% and specificity 99.9% RPR: sensitivity 96.3% and specificity 97.1% Prospective study n = 1800 Overall agreement between the LIASON and WB (99.9%), EIA (98.7%), and TPHA (99.3%) were similar. |
| Mishra 2011 [31] | Retrospective review of data when changing from the traditional to the reverse screening algorithm | N = 3 092 938 | Laboratory data | Confirmed positive rates increased by 10.3 per 100 000 population (P < .001) when switching to the reverse algorithm. Nonconfirmed RPR rate 0.13% Nonconfirmed EIA rate 0.26% 0.59% of EIA+/RPR– patients converted to RPR+ within 2 months |
| Park 2011 [32] | Cross-sectional comparison of 6 automated treponemal assays | N = 155 FTA-ABS+/VDRL+ samples | Reverse algorithm (FTA-ABS followed by VDRL) | Agreement, sensitivity, and specificity, respectively Architect Syphilis TP: 99.2%, 96.8%, and 100% Cobas Syphilis: 99.8%, 99.4%, and 100% ADVIA Centaur Syphilis: 99.8%, 99.4%, and 100% HISCL Anti-TP: assay kit, 99.7%, 98.7%, and 100% Immunoticles Auto3 TP: 99.0%, 97.5%, and 99.6% Mediace TPLA: 98.0%, 98.1%, and 98.0% Automated immunoassays generally showed high sensitivities, specificities, and percentages of agreement compared to FTA-ABS. |
| Pope 2000 [33] | Cross-sectional comparison of MHA-TP to Serodia TPPA and CAPTIA Syphilis-G | N = 390 routine samples | MHA-TP | TPPA: agreement 97.4% Captia Syphilis-G: agreement 97.7% |
| Singh 2008 [34] | Cross-sectional study of primary and late latent syphilis cases that were initially nonreactive by RPR screening | N = 2166 | Traditional algorithm RPR followed by MHA-TP or FTA-ABS | Primary syphilis: 224 (26%) nonreactive on initial RPR screening Late latent syphilis: 512 (39%) nonreactive on initial RPR screening |
| Tong 2014 [35] | Cross-sectional comparison of traditional, reverse, and ECDC algorithms | N = 24 124 ≈11.4% prevalence | Clinical symptoms and laboratory data (RPR, TPPA, and CIA) | Traditional algorithm: sensitivity 75.81%, specificity 99.98%, and accuracy 97.22%. Highest negative likelihood ratio (0.24), but lowest sensitivity for primary (75%) and tertiary (68%) syphilis; 71 biological false positives not confirmed by TPPA and CIA. Reverse algorithm: sensitivity 99.85%, specificity 99.82%, and accuracy 99.96%. 81 specimens were positive only by CIA. ECDC algorithm: sensitivity 99.38%, specificity 100%, and accuracy 99.93%. Both the reverse and ECDC had high sensitivity regardless of syphilis stage; 99.7% (665/667) of patients with RPR–/CIA+/TPPA+ were diagnosed with syphilis. |
| Wang 2016 [36] | Cross-sectional | N = 3962 routine samples ≈0.48% prevalence | Architect syphilis TP, RPR and TPPA Discrepant treponemal results resolved by WB | Traditional algorithm 19/3962 (0.48%) positive samples 11/3692 (0.28%) nonreactive by confirmatory by Architect and TPPA Reverse algorithm 20/3962 (0.66%) positive samples 5/3692 (0.13%) nonreactive confirmatory TPPA |
| N = 36 000 routine samples ≈0.48% prevalence | European algorithm Architect Syphilis TP followed by TPPA Discrepant results resolved by WB | 252/36000 (0.7%) positive by the Architect screen. 172/252 (68.3%) of Architect samples positive by TPPA. Among the 80 discrepant results, only 6 were reactive by WB. 100% of Architect reactive samples with a signal-to-cutoff ratio > 10 were reactive by confirmatory TPPA. | ||
| Wellinghausen 2011 [37] | Prospective and retrospective evaluation of LIASON to TPPA as a syphilis screen | Prospective N = 577 (318 pregnant) Retrospective N = 32 syphilis samples | Not defined | Prospective study LIAISON: sensitivity 100% and specificity 100% Architect Syphilis TP: sensitivity 100% and specificity 99.8% TPPA: sensitivity 100% and specificity 100% Retrospective study LIAISON, Architect, and TPPA all 100% sensitive |
| Wong/ 2011 [38] | Cross-sectional comparison of Trep-Sure EIA to VDRL and TPPA | N = 674 ≈9.4% prevalence | VDRL | Trep-Sure: sensitivity 87.7% and specificity 93.0% Trep-Sure EIA missed 6 VDRL+/TPPA+/WB+ specimens, and 6 (0.89%) reactive Trep-Sure EIAs were not confirmed by VDRL and TPPA. Among 269 specimens with a Trep-Sure EIA index score of ≥ 8.0, 268 (99.6%) were reactive by TPPA, indicating signal-to-cutoff ratio can be used to limit confirmatory testing. VDRL: 33 (4.9%) biological false positives |
| Yen-Lieberman 2011 [39] | Cross-sectional study to identify false-positive antibody results | N-142 Bioplex SyphG reactive samples ≈3% prevalence | Bioplex SyphG | Trep-Sure: agreement 77% Among the 27 RPR+ samples Trep-Sure had 100% agreement. All Bioplex SyphG samples above an antibody index value of 6.0, were confirmed by Trep-Sure indicating signal-to-cutoff ratio can be used for confirmation. |
| Young 2009 [40] | Retrospective and prospective study | N = 129 active syphilis stratified by stage N = 1107 prospective samples | Clinical and laboratory data | Characterized syphilis sera n = 129 Overall agreement with characterized syphilis sera: Architect CLIA 98.4%, Murex immune capture enzyme 86.0%, TPPA 98.4%, IgM EIA 86.8%, VDRL 83.7% Agreement with primary syphilis: Architect CLIA 97.5%, Murex immune capture enzyme 77.2%, TPPA 97.5%, IgM enzyme immunoassay 93.7%, VDRL 78.5% Prospective study n = 1107 Overall agreement between Architect and TPPA was 98.9% (1095/1107) Architect CLIA: sensitivity 100% and specificity 99.1% Murex immune capture enzyme: sensitivity 97.9% and specificity 99.9% |
| Zhang 2012 [41] | Cross-sectional evaluation of the analytical sensitivity of 5 treponemal assays (Bioplex IgG, LIAISON, Trep-Sure, Captia Syphilis-G, TPPA) | N = 10 (4 active and 6 past syphilis infections) | Laboratory data | Similar analytical sensitivities for Bioplex IgG, LIAISON, and CAPTIA Syphilis-G. Trep-Sure more sensitive by three 2-fold dilutions, and TPPA was the most sensitive by six 2-fold dilutions. The relative analytical sensitivities differ between treponemal assays and the confirmatory test should be at least as sensitive as the screening test. |
| Cost-effectiveness implications | ||||
| Chuck 2008 [7] | Simulation model comparing European and traditional algorithm | N = 89 647 (51 523 prenatal ≈0.076% prevalence and 38 124 routine ≈1.94% prevalence) | European algorithm EIA followed by INNO-LIA Traditional algorithm: RPR followed by TPPA or FTA-ABS | Prenatal cohort Cost: Can$9504 more using reverse algorithm Effectiveness: 1 new case and 6 correctly identified true negatives using reverse algorithm Cost-effectiveness ratio: Using the traditional algorithm will save Can$1358 Routine cohort Cost: Can$86 053 more using traditional algorithm Effectiveness: 3 new cases and 156 correctly identified true negatives using reverse algorithm Cost-effectiveness ratio: Using the reverse algorithm will save Can$541 When the cost for a false negative (Can$17 445) and false positive ($2962) are taken into account, the EIA followed by INNO-LIA is cost-effective in both prenatal and nonprenatal populations and will generate more correct diagnoses. |
| Owusu-Edusei 2011 [6] | Cohort decision analysis model to estimate cost and health outcomes of traditional and reverse algorithms | N = 200 000 with 1000 active and 1000 past infections 0.5% prevalence | NA | Net costs were $1.6 m for reverse algorithm and $1.4 m for traditional algorithm. Cost-effectiveness ratios were $1671 for the reverse algorithm and $1621 for the traditional algorithm per case treated. The cost-effectiveness of the traditional algorithm was lower as long as the treponemal test was > $4.10. Reverse algorithm identified 118 more cases leading to more follow-ups, which would result in identifying 1 additional case of tertiary syphilis. Reverse algorithm costs slightly more and leads to more unnecessary treatment. |
| Owusu-Edusei 2011 [5] | Cohort decision analysis model to estimate cost and health outcomes of traditional and reverse algorithms | N = 10 000 0.5% and 10% prevalence | NA | Low-prevalence setting: Reverse algorithm led to ≈2 times the number of confirmatory tests and was only cost-effective when the test was < $5.80. Traditional algorithm more cost-effective per adverse outcome ($1400 vs $1500). High-prevalence setting: Reverse algorithm led to ≈3 times the number of confirmatory tests and was only cost-effective when the test was < $1.80. Both algorithms detected the same number of syphilis cases in low- and high-prevalence settings. Reverse algorithm leads to overtreatment of uninfected patients. |
Abbreviations: CA, California; Can$, Canadian dollars; CIA, chemiluminescence assay; CLIA, chemiluminescence immunoassay; ECDC, European Centre for Disease Prevention and Control; EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; FDA, United States Food and Drug Administration; FTA-ABS, fluorescent treponemal antibody absorption test; HISCL, high-sensitivity chemiluminescence enzyme immunoassay; HIV, human immunodeficiency virus; ICE, immune capture EIA; IgG, immunoglobulin G; IgM, immunoglobulin M; IL, Illinois; m, million; MHA-TP, microhemagglutination assay for Treponema pallidum antibodies; NA, not applicable; NY, New York; OB/GYN, obstetrics/gynecology; RPR, rapid plasma reagin; SLE, systemic lupus erythematosus; STD, sexually transmitted disease; TAT, turnaround time; TP, Treponema pallidum; TPHA, Treponema pallidum hemagglutination assay; TPLA, Treponema pallidum latex agglutination; TPPA, Treponema pallidum particle agglutination; TRUST, toluidine red unheated serum test; VDRL, Venereal Disease Research Laboratory; WB, Western blot.