Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
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CDC laboratory recommendations for syphilis testing, United States, 2024
Papp JR , Park IU , Fakile Y , Pereira L , Pillay A , Bolan GA . MMWR Recomm Rep 2024 73 (1) 1-32 This report provides new CDC recommendations for tests that can support a diagnosis of syphilis, including serologic testing and methods for the identification of the causative agent Treponema pallidum. These comprehensive recommendations are the first published by CDC on laboratory testing for syphilis, which has traditionally been based on serologic algorithms to detect a humoral immune response to T. pallidum. These tests can be divided into nontreponemal and treponemal tests depending on whether they detect antibodies that are broadly reactive to lipoidal antigens shared by both host and T. pallidum or antibodies specific to T. pallidum, respectively. Both types of tests must be used in conjunction to help distinguish between an untreated infection or a past infection that has been successfully treated. Newer serologic tests allow for laboratory automation but must be used in an algorithm, which also can involve older manual serologic tests. Direct detection of T. pallidum continues to evolve from microscopic examination of material from lesions for visualization of T. pallidum to molecular detection of the organism. Limited point-of-care tests for syphilis are available in the United States; increased availability of point-of-care tests that are sensitive and specific could facilitate expansion of screening programs and reduce the time from test result to treatment. These recommendations are intended for use by clinical laboratory directors, laboratory staff, clinicians, and disease control personnel who must choose among the multiple available testing methods, establish standard operating procedures for collecting and processing specimens, interpret test results for laboratory reporting, and counsel and treat patients. Future revisions to these recommendations will be based on new research or technologic advancements for syphilis clinical laboratory science. |
Considerations for endpoint titer determination in syphilis testing using newly marketed, automated rapid plasma reagin instruments
Shukla M , Pereira L , Sun Y , Fakile YF , Kersh EN , Cao W . Public Health Rep 2023 333549231176007 Syphilis is a sexually transmitted disease (STD) caused by the bacterium Treponema pallidum, subspecies pallidum (T. pallidum).1 The resurgence of syphilis in the last 2 decades is a major public health concern in the United States. In 2020, a total of 133 945 cases of all stages of syphilis were reported in the United States, an increase of more than 70% since 2015. The national rate of congenital syphilis has increased 254% since 2016. In 2020, a total of 2148 cases of congenital syphilis were reported, including 149 congenital syphilis–related stillbirths and infant deaths.2 However, syphilis diagnosis is still challenging, partially because of overlapping and ambiguous clinical presentation, particularly during early infection.3 For laboratory testing, darkfield microscopy examinations and direct molecular detection of T. pallidum from clinical specimens are definitive methods for diagnosing early syphilis, but both methods are currently not widely performed at local, reference, or public health laboratories and have challenges in identifying asymptomatic or early-stage infection without the presence of visible lesions for suitable specimen collection.4 Darkfield microscopy requires special equipment and experienced operators for reliable results.5 US Food and Drug Administration (FDA)–cleared molecular tests for syphilis are still not available, and laboratory-developed molecular tests are limited in availability. Therefore, serological tests that detect treponemal and nontreponemal antibodies remain the mainstay for routine laboratory diagnosis of active syphilis infection.6 |
Evaluation of three automated nontreponemal rapid plasma reagin (RPR) tests for the laboratory diagnosis of syphilis
Shukla MR , Pereira L , Gaynor AM , Sun Y , Edwards D , Simmons T , Andrews CW , Park IU , Hong J , Cao W , Kersh EN , Fakile Y . J Clin Microbiol 2023 61 (6) e0016823 Automated nontreponemal rapid plasma reagin (RPR) tests were recently introduced in the United States for syphilis testing and limited performance data are available. In collaboration with the Association of Public Health Laboratories, three public health laboratories (PHL) were chosen through a competitive selection process to evaluate the performance of three FDA-cleared automated RPR test systems: BioPlex 2200 Syphilis Total & RPR assay (Bio-Rad Laboratories), AIX 1000 (Gold Standard Diagnostics), and ASI Evolution (Arlington Scientific). Panels prepared at the CDC included: a qualitative panel comprised of 734 syphilis reactive/nonreactive sera; a quantitative panel of 50 syphilis reactive sera (RPR titer 1:64 to 1:1,024); and a reproducibility panel of 15 nonreactive and reactive sera (RPR titer 1:1 to 1:64). Panels were shipped frozen to the PHL and tested on the automated RPR systems following manufacturers' instructions. Prior test results were blinded to all laboratories. When compared to manual RPR (Arlington Scientific) performed at the CDC as a reference test, the qualitative panel results demonstrated an overall concordance of 95.9% for AIX 1000, 94.6% for ASI Evolution, and 92.6% for Bioplex RPR; quantitative panel showed within range titer of 2-fold for 94% of specimens for AIX 1000, 68% for ASI Evolution, and 64% for BioPlex RPR, and the reproducibility testing panel demonstrated point estimates ranging from 69 to 95%. Automated RPR instruments could reduce turnaround time and minimize interpretation errors. However, additional evaluations with more specimens could assist laboratories with implementing automated RPR tests and understanding their limitations. |
Factors associated with syphilis transmission and acquisition among men who have sex with men: Protocol for a multisite egocentric network study
Copen CE , Rushmore J , De Voux A , Kirkcaldy RD , Fakile YF , Tilchin C , Duchen J , Jennings JM , Spahnie M , Norris Turner A , Miller WC , Novak RM , Schneider JA , Trotter AB , Bernstein KT . JMIR Res Protoc 2022 11 (11) e40095 BACKGROUND: In the United States, the rates of primary and secondary syphilis have increased more rapidly among men who have sex with men (MSM) than among any other subpopulation. Rising syphilis rates among MSM reflect changes in both individual behaviors and the role of sexual networks (eg, persons linked directly or indirectly by sexual contact) in the spread of the infection. Decades of research examined how sexual networks influence sexually transmitted infections (STIs) among MSM; however, few longitudinal data sources focusing on syphilis have collected network characteristics. The Centers for Disease Control and Prevention, in collaboration with 3 sites, enrolled a prospective cohort of MSM in 3 US cities to longitudinally study sexual behaviors and STIs, including HIV, for up to 24 months. OBJECTIVE: The Network Epidemiology of Syphilis Transmission (NEST) study aimed to collect data on the factors related to syphilis transmission and acquisition among MSM. METHODS: The NEST study was a prospective cohort study that enrolled 748 MSM in Baltimore, Maryland; Chicago, Illinois; and Columbus, Ohio. NEST recruitment used a combination of convenience sampling, venue-based recruitment, and respondent-driven sampling approaches. At quarterly visits, participants completed a behavioral questionnaire and were tested for syphilis, HIV, gonorrhea, and chlamydia. The participants also provided a list of their sexual partners and described their 3 most recent partners in greater detail. RESULTS: The NEST participants were enrolled in the study from July 2018 to December 2021. At baseline, the mean age of the participants was 31.5 (SD 9.1) years. More than half (396/727. 54.5%) of the participants were non-Hispanic Black, 29.8% (217/727) were non-Hispanic White, and 8.8% (64/727) were Hispanic or Latino. Multiple recruitment strategies across the 3 study locations, including respondent-driven sampling, clinic referrals, flyers, and social media advertisements, strengthened NEST participation. Upon the completion of follow-up visits in March 2022, the mean number of visits per participant was 5.1 (SD 3.2; range 1-9) in Baltimore, 2.2 (SD 1.6; range 1-8) in Chicago, and 7.2 (SD 2.9; range 1-9) in Columbus. Using a community-based participatory research approach, site-specific staff were able to draw upon collaborations with local communities to address stigma concerning STIs, particularly syphilis, among potential NEST participants. Community-led efforts also provided a forum for staff to describe the NEST study objectives and plans for research dissemination to the target audience. Strategies to bolster data collection during the COVID-19 pandemic included telehealth visits (all sites) and adaptation to self-collection of STI specimens (Baltimore only). CONCLUSIONS: Data from NEST will be used to address important questions regarding individual and partnership-based sexual risk behaviors among MSM, with the goal of informing interventions to prevent syphilis in high-burden areas. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/40095. |
Development of a Bead-Based Multiplex Assay for Use in Multianalyte Screening and Surveillance of HIV, Viral Hepatitis, Syphilis, and Herpes.
Yufenyuy EL , Vedapuri S , Zheng A , Cooley G , Danavall D , Mayur S , Kodani M , Chen C , Tun Y , Fakile YF , Martin D , Kamili S , Karem K , Parekh BS . J Clin Microbiol 2022 60 (5) e0234821 Diagnostic assays that can simultaneously determine the presence of infection with multiple pathogens are key for diagnosis and surveillance. Current multiplex diagnostic assays are complex and often have limited availability. We developed a simple, multianalyte, pathogen detection assay for screening and serosurveillance using the Luminex Magpix platform that is high throughput and can be helpful in monitoring multiple diseases. The Luminex bead-based 10-plex immunoassay for the detection of HIV-1, HIV-2, Treponema pallidum, hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus 1 (HSV-1), and HSV-2 infections was accomplished by coupling beads with specific antigens to detect IgG antibodies in plasma or serum samples. Each coupled antigen was systematically optimized, and the performance was evaluated using a panel of well-characterized specimens (n=417) that contained antibodies to HIV-1, HIV-2, T. pallidum, HBV, HCV, HSV-1, and HSV-2. The multiplex assay had a sensitivity of 92.2% (95% Clopper-Pearson confidence interval [CI], 90.2 to 94.0%) and a specificity of 98.1% (95% CI, 97.6 to 98.7%). The sensitivities and specificities for disease-specific biomarker detection ranged from 68.7 to 100% and 95.6 to 100%, respectively. The results showed that the 10-plex immunoassay had an overall agreement of 96.7% (95% CI, 96.7 to 97.3%) with reference tests and a corresponding kappa value of 0.91 (95% CI, 0.90 to 0.93). Kappa values for the individual pathogens ranged from 0.69 to 1.00. The assay is robust and allows the simultaneous detection of antibodies to multiple antigens using a small sample volume in a high-throughput format. This assay has the potential to simplify disease surveillance by providing an alternative to expensive and highly specialized individual tests. |
Evaluation of the effect of extended refrigerated storage of serum and plasma specimens on syphilis serologic test results
Sun Y , Shukla MR , Deutsch J , Cao W , Fakile Y , Kersh EN , Pereira LE . Diagn Microbiol Infect Dis 2022 102 (2) 115588 The effect of extended refrigerated storage of 14 serum and plasma specimens on 5 syphilis serologic tests was evaluated for 16 weeks. Higher stability of nontreponemal and treponemal antibodies in serum was recorded compared to plasma. Described work may provide insights on refrigerated specimens' stability and suitability for syphilis tests. |
Sensitivity and specificity of treponemal-specific tests for the diagnosis of syphilis
Park IU , Tran A , Pereira L , Fakile Y . Clin Infect Dis 2020 71 S13-s20 We conducted a systematic review of relevant syphilis diagnostic literature to address the question, "What is the sensitivity and specificity of the treponemal tests currently approved by the Food and Drug Administration (FDA) for the diagnosis of syphilis (by stage)?" There were 16 treponemal assays evaluated: 13 immunoassays and 3 manual assays (fluorescent treponemal antibody absorbed test [FTA-ABS], microhemagglutination assay for Treponema pallidum antibodies [MHA-TP], Treponema pallidum particle agglutination assay [TP-PA]). MHA-TP and FTA-ABS were less sensitive in primary and secondary syphilis than TP-PA; TP-PA is the most specific manual treponemal assay. There is insufficient evidence to recommend one particular treponemal immunoassay (eg, enzyme immunoassays, chemiluminescence immunoassays, microbead immunoassays) over another based on published performance data. For diagnosis of neurosyphilis, cerebrospinal fluid (CSF) TP-PA has similar performance to CSF FTA-ABS in studies with patients with definitive or presumptive neurosyphilis. However, CSF treponemal testing has limitations in its sensitivity and specificity and should be interpreted within the context of the clinical scenario, additional CSF test results and syphilis prevalence. |
Development of a novel magnetic particle-based agglutination immunoassay for anticardiolipin antibody detection in syphilis
Shukla MR , Deutsch JW , Pereira LE , Kersh EN , Fakile YF . Sex Transm Infect 2020 96 (6) 411-416 OBJECTIVES: Serological tests of non-treponemal and treponemal types are the most frequently used for syphilis diagnosis. Treponemal tests are available in wide variety of assay formats; however, limited advances have been made for the improvement of conventional non-treponemal tests. The objective of this work was to develop a novel non-treponemal magnetic particle-based agglutination assay (NT-MAA) and evaluate its feasibility for syphilis testing. METHODS: Cardiolipin was modified and coupled to magnetic microbeads. Serum diluted in phosphate-buffered saline was mixed with cardiolipin-coupled beads and incubated in a round bottom microplate for 90-120 min followed by visual inspection. A panel of reported syphilis (n=127) and non-reactive (n=244) specimens was prepared to evaluate the NT-MAA performance in comparison to conventional rapid plasma reagin (RPR). Treponema pallidum particle agglutination (TP-PA) assay and enzyme immunoassay (EIA) were included. Analytical sensitivity and reproducibility of NT-MAA were also determined. RESULTS: The non-treponemal NT-MAA and RPR showed sensitivity of 90.6% and 88.2% and specificity of 96.7% and 100%, respectively. The treponemal TP-PA and EIA yielded sensitivity of 100% and 99.2%, respectively, and 100% specificity by both assays. The per cent agreement between NT-MAA and RPR was 97% (kappa=0.931, 95% CI 0.891 to 0.971). Analytical sensitivity determined with IgM anticardiolipin antibody (ACA) was 2.6 microg/mL for both NT-MAA and RPR, while IgG ACA yielded 0.9 microg/mL and 1.7 microg/mL for NT-MAA and RPR, respectively. Qualitative results of intra-assay and interassay reproducibility revealed 100% consistency for NT-MAA. CONCLUSION: Preliminary evaluation of the novel NT-MAA validated proof of concept using laboratory-characterised syphilis sera and demonstrated performance comparable to RPR. Further validation of NT-MAA using additional specimens with better clinical staging may broaden the scope of developed test for syphilis diagnosis. |
Qualitative Variation Among Commercial Immunoassays to Detect Measles-Specific IgG.
Latner DR , Sowers SB , Anthony K , Colley H , Badeau C , Coates J , Wong P , Fakile Y , Interiano C , Pannell KB , Leung-Pineda V , Patel MM , Rota PA , Limbago BM , Hickman CJ . J Clin Microbiol 2020 58 (6) Measurement of measles virus-specific IgG is used to assess presumptive evidence of immunity among immunocompetent individuals with uncertain immune or vaccination status. False-negative test results may lead to unnecessary quarantine and exclusion from activities such as employment, education, and travel or result in unnecessary re-vaccination. In contrast, false-positive results may fail to identify susceptible individuals and promote spread of disease by those who are exposed and unprotected. To better understand the performance characteristics of tests to detect measles IgG, we compared five widely used, commercially available measles IgG test platforms using a set of 223 well characterized serum samples. Measles virus neutralizing antibodies were also measured by in vitro plaque reduction neutralization (PRN), the gold standard method and compared to IgG test results. Discrepant results were observed for samples in the low-positive ranges of the most sensitive tests, but there was good agreement across platforms for IgG negative sera and for samples with intermediate to high levels of IgG. False negative test results occurred in approximately 11% of sera, which had low levels of neutralizing antibody. |
Successful isolation of Treponema pallidum strains from patients' cryopreserved ulcer exudate using the rabbit model.
Pereira LE , Katz SS , Sun Y , Mills P , Taylor W , Atkins P , Thurlow CM , Chi KH , Danavall D , Cook N , Ahmed T , Debra A , Philip S , Cohen S , Workowski KA , Kersh E , Fakile Y , Chen CY , Pillay A . PLoS One 2020 15 (1) e0227769 Clinical isolates of Treponema pallidum subspecies pallidum (T. pallidum) would facilitate study of prevalent strains. We describe the first successful rabbit propagation of T. pallidum from cryopreserved ulcer specimens. Fresh ulcer exudates were collected and cryopreserved with consent from syphilis-diagnosed patients (N = 8). Each of eight age-matched adult male rabbits were later inoculated with a thawed specimen, with two rabbits receiving 1.3 ml intratesticularly (IT), and six receiving 0.6 ml intravenously (IV) and IT. Monitoring of serology, blood PCR and orchitis showed that T. pallidum grew in 2/8 rabbits that were inoculated IV and IT with either a penile primary lesion specimen (CDC-SF003) or a perianal secondary lesion specimen (CDC-SF007). Rabbit CDC-SF003 was seroreactive by T. pallidum Particle Agglutination (TP-PA) and Rapid Plasma Reagin (RPR) testing, PCR+, and showed orchitis by week 6. Euthanasia was performed in week 7, with treponemal growth in the testes confirmed and quantified by qPCR and darkfield microscopy (DF). Serial passage of the extract in a second age-matched rabbit also yielded treponemes. Similarly, rabbit CDC-SF007 showed negligible orchitis, but was seroreactive and PCR+ by week 4 and euthanized in week 6 to yield T. pallidum, which was further propagated by second passage. Using the 4-component molecular typing system for syphilis, 3 propagated strains (CDC-SF003, CDC-SF007, CDC-SF008) were typed as 14d9f, 14d9g, and 14d10c, respectively. All 3 isolates including strain CDC-SF011, which was not successfully propagated, had the A2058G mutation associated with azithromycin resistance. Our results show that immediate cryopreservation of syphilitic ulcer exudate can maintain T. pallidum viability for rabbit propagation. |
Evaluation of the WHO/CDC Syphilis Serology Proficiency Programme to support the global elimination of mother-to-child transmission of syphilis: an observational cross-sectional study, 2008-2015
Hopkins AO , Trinh T , Fakile YF , Pillay A , Taylor MM , Kersh E , Kamb M . BMJ Open 2020 10 (1) e029434 OBJECTIVES: Syphilis morbidity is high among pregnant women in lower income countries with limited laboratory capacity. We evaluated a long-standing global Syphilis Serology Proficiency Programme (SSPP) that supports testing quality in national reference laboratories to determine if participation affects congenital syphilis elimination strategies. DESIGN: In this observational cross-sectional study, we calculated coverage on type, frequency and quality of syphilis testing reported by laboratories enrolled in the SSPP from 2008 to 2015. We used country-reported data to WHO on four congenital syphilis (CS) indicators and World Bank country economic data to compare coverage and completeness of reporting of indicators in lower income countries with and without an SSPP-enrolled laboratory. PARTICIPANTS: From 2008-2015, 78 laboratories from 51 countries participated in >1 SSPP evaluation; 56% were national reference laboratories, of which most (93%) participated for >3 years and 11 (22%) in all 24 cycles. RESULTS: Median proficiency performance score was >95% regardless of test conducted. Of the 51 countries with an SSPP-enrolled laboratory, 22 (43%) were lower-income countries, of which 21 reported CS data during 2008-2015. Comparing CS data from 87 (90% of total) lower income countries with and without an SSPP-enrolled laboratory, countries with an SSPP-laboratory had stronger reporting on antenatal syphilis testing (p=0.04). For 2015, an estimated 74% of prenatal syphilis tests and 63% of positive tests reported to WHO from countries with an SSPP-enrolled laboratory. CONCLUSION: The SSPP has focused well on national reference laboratories, but has been only partially successful in recruiting laboratories from lower income countries. The finding that over half of syphilis infections in pregnant women living in countries with SSPP-enrolled laboratories suggests wide reach of the current quality assurance programme. However, reach could expand with focussed recruitment of laboratories from lower income countries. |
Development of a syphilis serum bank to support research, development, and evaluation of syphilis diagnostic tests in the United States
Shukla M , Sun Y , McCormick J , Hopkins A , Pereira L , Gaynor A , Kersh E , Fakile Y . Diagn Microbiol Infect Dis 2019 96 (1) 114913 The Centers for Disease Control and Prevention's (CDC) Division of STD Prevention, in collaboration with the Association of Public Health Laboratories (APHL), is developing a nationally available syphilis serum repository for research of Food and Drug Administration (FDA)-cleared or investigational syphilis diagnostic assays in the United States. State and local public health laboratories (PHL) submitted de-identified residual sera with information on collection date, volume, storage conditions, freeze-thaw cycles, PHL serology results, reported syphilis stage and demographic details if available. Previous test results were blinded and sera (N = 152 reported syphilis stage, N = 131 unknown status) were tested at CDC using five FDA-cleared and one investigational syphilis tests. Treponemal and nontreponemal test sensitivity ranged from 76.3-100% and 63.2-100%, respectively, among staged specimens. The conventional treponemal assays showed high concordance of 95.4%. By providing syphilis stage and comprehensive serological test data, developed repository may serve as a valuable resource for diagnostic test validation studies. |
A nonhuman primate model for rectally transmitted syphilis
Tansey C , Zhao C , Hopkins A , Ritter JM , Fakile YF , Pillay A , Katz SS , Pereira L , Mitchell J , Deyounks F , Kersh EN , McNicholl JM , Vishwanathan SA . J Infect Dis 2018 217 (7) 1139-1144 Among men who have sex with men (MSM), those with a diagnosis of syphilis or other rectal sexually transmitted infections (STIs) are at a higher risk for human immunodeficiency virus acquisition, which is concerning given the large increase in recently reported syphilis cases in the United States. We have developed the first nonhuman primate model for rectally transmitted syphilis by exposing simian/human immunodeficiency virus-infected and naive rhesus macaques to Treponema pallidum in the rectum. All animals showed mucosal lesions, systemic dissemination, and seroconversion (treponemal antibodies). This model would be valuable for studying the manifestations of and interventions for T. pallidum infection, with and without human immunodeficiency virus coinfection. |
Evaluation of a rapid syphilis test in an emergency department setting in Detroit, Michigan
Fakile YF , Markowitz N , Zhu W , Mumby K , Dankerlui D , McCormick JK , Ham DC , Hopkins A , Manteuffel J , Sun Y , Huang YA , Peters PJ , Hoover KW . Sex Transm Dis 2019 46 (7) 429-433 BACKGROUND: Syphilis transmission can be prevented by prompt diagnosis and treatment of primary and secondary infection. We evaluated the performance of a point-of-care rapid syphilis treponemal test (RST) in an emergency department (ED) setting. METHODS: Between June 2015 and April 2016, men aged 18-34 years seeking services in a Detroit ED, and with no history of syphilis, were screened for syphilis with the RST, rapid plasma reagin (RPR) test, and Treponema pallidum particle agglutination assay (TP-PA). A positive reference standard was both a reactive RPR and a reactive TP-PA. We compared test results in self-reported MSM to non-MSM. RESULTS: Among 965 participants, 10.9% of RSTs were reactive in MSM and only 1.5% in non-MSM (p<0.001). Sensitivity of the RST was 76.9% and specificity was 99.0% (PPV 50.0%) compared to the positive reference standard. Three discordant specimens found negative with the RST but positive with the reference standard had an RPR titer of 1:1, compared with 10 specimens with concordant positive results that had a median RPR titer of 1:16. The RST sensitivity was 50.0% (PPV 68.4%) compared to the TP-PA test alone. Among men seeking care in an ED, the RST detected 76.9% of participants with a reactive RPR and TP-PA. CONCLUSIONS: The RST detected all of the participants with an RPR titer > 1:2 but less than 20% of participants with a positive TP-PA and negative RPR. The RST was useful to detect a high proportion of participants with an active syphilis in an urban ED.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
Performance of the Syphilis Health Check in clinic and laboratory-based settings
Fakile YF , Brinson M , Mobley V , Park IU , Gaynor AM . Sex Transm Dis 2019 46 (4) 250-253 BACKGROUND: In this study, we evaluate the performance of the Syphilis Health Check (SHC) in clinical and laboratory settings using fingerstick whole-blood and serum. METHODS: Fingerstick whole-blood and serum specimens from adult patients (n=562) without prior syphilis history presenting at two county health department STD clinics in North Carolina were tested. Fingerstick specimens were tested with the SHC in clinic, and serum specimens were tested at the North Carolina State Laboratory of Public Health with: 1) qualitative rapid plasma reagin (RPR), 2) treponemal EIA and 3) SHC. Sensitivity and specificity were calculated with 95% confidence intervals. RESULTS: The fingerstick whole-blood had a sensitivity of 100% (7/7) and specificity of 95.7% (531/555), compared to consensus reference testing - CRT (RPR and EIA reactive), but a sensitivity of 50% (8/16), and specificity of 95.9% (523/546), when compared to the treponemal EIA. Both laboratory-based SHC on serum and whole-blood SHC performed similarly, compared to CRT, and the treponemal EIA alone. Twenty-four specimens SHC reactive on whole-blood were nonreactive by CRT. In 8/24 of these cases STD clinic staff reported difficulty reading the test line for the SHC. Of the fingerstick whole-blood SHC reactive specimens, only 14/31 were also serum SHC reactive. CONCLUSION: The SHC on whole-blood appears to be sensitive at detecting patients likely to have syphilis, and could be an option for testing among high-risk populations. However, given challenges in interpreting SHC test results, adequate training of persons performing testing and ongoing quality assurance measures are key. |
Laboratory evaluation of a commercially available rapid syphilis test
Pereira LE , McCormick J , Dorji T , Kang J , Sun Y , Shukla M , Hopkins A , Deutsch J , Kersh EN , Bernstein K , Fakile YF . J Clin Microbiol 2018 56 (10) Serological diagnosis of syphilis depends on assays that detect treponemal and non-treponemal antibodies. Laboratory certification and trained personnel are needed to perform most of these tests, while high costs and long turnaround time can hinder treatment initiation or linkage to care. A rapid treponemal syphilis test (RST) that is simple to perform, accessible and inexpensive would be ideal. The Syphilis Health Check (SHC) assay is the only Food and Drug Administration (FDA)-cleared and Clinical Laboratory Improvement Amendments (CLIA)-waived RST in the US. In this study, 1,406 archived human sera were tested using SHC and traditional treponemal and non-treponemal assays. Rapid test results were compared with treponemal data alone, and with a laboratory test panel consensus defined as being reactive by both treponemal and non-treponemal assays for a given specimen, or nonreactive by both types of assays. Sensitivity and specificity of SHC when compared with treponemal tests alone were 88.7% (86.2-90.0%) and 93.1% (90.0-94.9%), respectively, while comparison with the laboratory test panel consensus showed 95.7% (93.6-97.2%) sensitivity and 93.2% (91.0-95.1%) specificity. The data were further stratified based on age, sex, pregnancy and HIV status. Sensitivity and specificity of SHC ranged from 66.7% (46.0-83.5%) to 91.7% (87.7-94.7%) and 88% (68.8-97.5%) to 100% (47.8-100%), respectively, across groups when compared to traditional treponemal assays, generally increasing for all groups except the HIV+ population when factoring the laboratory test panel consensus. These data contribute to current knowledge of SHC performance for distinct populations and may guide use in various settings. |
Performance of treponemal tests for the diagnosis of syphilis
Park IU , Fakile YF , Chow JM , Gustafson KJ , Jost H , Schapiro JM , Novak-Weekley S , Tran A , Nomura JH , Chen V , Beheshti M , Tsai T , Hoover K , Bolan G . Clin Infect Dis 2018 68 (6) 913-918 Background: Treponemal immunoassays are increasingly used for syphilis screening with the reverse sequence algorithm. There are little data describing performance of treponemal immunoassays compared to traditional treponemal tests in patients with and without syphilis. Methods: We calculated sensitivity and specificity of seven treponemal assays: 1) ADVIA Centaur (chemiluminescence immunoassay-CIA), 2) Bioplex 2200 (microbead immunoassay-MBIA), 3) fluorescent treponemal antibody absorption test (FTA-ABS), 4) INNO-LIA (line immunoassay), 5) LIAISON CIA, 6) TP-PA (Treponema pallidum particle agglutination assay), and 7) Trep-Sure (enzyme immunoassay-EIA), using a reference standard combining clinical diagnosis and serology results. Sera were collected between May 2012-January 2013. Cases were characterized as: 1) current clinical diagnosis of syphilis: primary, secondary, early latent, late latent 2) prior treated syphilis only, 3) no evidence of current syphilis, no prior history of syphilis and at least 4/7 treponemal tests negative. Results: Among 959 participants, 262 had current syphilis, 294 had prior syphilis, and 403 did not have syphilis. FTA-ABS was less sensitive for primary syphilis [78.2% (65.0-88.2%)], than the immunoassays or TP-PA (94.5-96.4%) (all p</=0.01). All immunoassays were 100% sensitive for secondary syphilis, 95.2-100% sensitive for early latent disease, and 86.8-98.5% sensitive in late latent disease. TP-PA had 100% specificity (99.0-100%). Conclusion: Treponemal immunoassays demonstrated excellent sensitivity for secondary, early latent, and seropositive primary syphilis. Sensitivity of FTA-ABS in primary syphilis was poor compared to the immunoassays and TP-PA. Given its high specificity and superior sensitivity, TP-PA is a better test to adjudicate discordant results with the reverse sequence algorithm than the FTA-ABS. |
Evaluation of a rapid point-of-care HIV screening program in an emergency department setting in Detroit, Michigan
Zhu W , Mumby K , Dankerlui D , Manteuffel J , Ham C , Huang YLA , Peters PJ , Fakile YF , Markowitz N , Hoover KW . J Clin Virol 2018 106 11-12 In October 2013, Detroit’s only sexually transmitted disease (STD) clinic, at the Herman Kiefer Health Complex, was closed, which decreased access to HIV testing for many persons at substantial risk for acquiring infection [1]. Emergency departments (EDs), like STD clinics, often serve as a safety net for underinsured individuals but integrating additional services can be difficult given time and space constraints. This journal previously published an evaluation of a rapid point-of-care (POC) HIV antigen/antibody (Ag/Ab) test using stored specimens [2] and here we present an evaluation of this test to identify undiagnosed HIV infection in young men who sought emergency care. |
Correlation of treponemal immunoassay signal strength values with reactivity of confirmatory treponemal testing
Fakile YF , Jost H , Hoover KW , Gustafson KJ , Novak-Weekley SM , Schapiro JM , Tran A , Chow JM , Park IU . J Clin Microbiol 2017 56 (1) Automated treponemal immunoassays are used for syphilis screening with the reverse sequence algorithm; discordant results (e.g., enzyme immunoassay [EIA]-reactive, reactive plasma reagin [RPR]-non-reactive) are resolved with a second treponemal test. We conducted a study to determine automated immunoassay signal strength values consistently correlating with reactive confirmatory treponemal testing.We conducted a cross-sectional analysis of four automated immunoassays: BioPlex 2200 microbead immunoassay (MBIA), LIAISON chemiluminesence immunoassay (CIA), ADVIA-Centaur CIA, and TrepSure EIA, and three manual assays: Treponema Pallidum Particle Agglutination (TP-PA), Fluorescent Treponemal Antibody-Absorption (FTA-ABS) test, INNO-LIA line immunoassay. We compared signal strength values of automated immunoassays and positive and negative agreement. Among 1995 specimens, 908 (45.5%) were true positives (≥4/7 tests reactive) and 1087 (54.5%) were true negatives (≥4/7 tests non-reactive). Positive agreement ranged from 86.1% (83.7-88.2%) for FTA-ABS to 99.7% (99.0-99.9%) for ADVIA-Centaur CIA; negative agreement ranged from 86.3% (84.1-88.2%) for TrepSure EIA to 100% for TP-PA (99.6-100%). Increasing signal strength values correlated with increasing reactivity of confirmatory testing (ptrend <0.0001 for all automated immunoassay). All automated immunoassays had signal strength cutoffs corresponding to ≥4/7 reactive treponemal tests. Bioplex MBIA and LIAISON CIA had signal strength cutoffs correlating with ≥99% and 100% TP-PA reactivity, respectively. ADVIA-Centaur CIA and TrepSure EIA had signal strength cutoffs correlating with at least 95%TP-PA reactivity. All automated immunoassays had signal strength cutoffs correlating with at least 95% FTA-ABS reactivity. Assuming that a 95% level of confirmation is adequate, these signal strength values can be used in lieu of confirmatory testing with TP-PA and FTA-ABS. |
What is the use of rapid syphilis tests in the United States?
Peterman TA , Fakile YF . Sex Transm Dis 2016 43 (3) 201-3 Syphilis testing is complicated. Rapid syphilis tests may change screening practices in the United States, but first more studies are needed to demonstrate the advantages and disadvantages in the field. |
Serologic testing for syphilis: benefits and challenges of a reverse algorithm
Soreng K , Levy R , Fakile Y . Clin Microbiol Newsl 2014 36 (24) 195-202 Syphilis is a human infection of global importance. Its diagnosis can be challenging, requiring construction of a serologic profile based on the results of at least two types of antibody tests: treponemal and nontreponemal. The traditional approach to the serodiagnosis of syphilis has been the use of a nontreponemal screening assay followed by the performance of a treponemal confirmatory test if the initial nontreponemal screening test was reactive. With the increasing availability of automated, easier-to-perform, and rapid treponemal assays, an increasing number of laboratory testing sites are adopting reverse sequence screening for the serodiagnosis of syphilis: screening with a treponemal assay first, then confirmation with a nontreponemal assay and, when necessary, discrepant resolution using another treponemal test. In addition to offering automation and increased throughput, a reverse algorithm can increase disease detection, especially in late latent and early primary stages of infection when the nontreponemal antibody test may be nonreactive. However, a disadvantage to this approach is that there can be an increase in false-positive test results. This article reviews the clinical and workflow benefits and limitations of a reverse testing algorithm and discusses current guidance available from the Centers for Disease Control and Prevention. |
Increased susceptibility to vaginal SHIV transmission in pigtail macaques coinfected with Chlamydia trachomatis and Trichomonas vaginalis
Henning T , Butler K , Hanson D , Sturdevant G , Ellis S , Sweeney EM , Mitchell J , Deyounks F , Phillips C , Farshy C , Fakile Y , Papp J , Secor WE , Caldwell H , Patton D , McNicholl J , Kersh E . J Infect Dis 2014 210 (8) 1239-47 BACKGROUND: Sexually transmitted infections (STIs) are associated with increased HIV infection risk, but their biological effect on HIV susceptibility is not fully understood. METHODS: Female pigtail macaques, inoculated with C. trachomatis and T. vaginalis (n=9) or media (controls, n=7), were repeatedly intravaginally challenged with SHIVSF162p3. Virus levels were evaluated by real-time PCR, plasma and genital cytokine levels by Luminex assays, and STI clinical signs by colposcopy. RESULTS: SHIV susceptibility was enhanced in STI-positive macaques (p=0.04, log rank; 2.5-times as high relative risk of infection, 95% CI 1.1, 5.6). All STI-positive macaques were SHIV-infected, while n=3 (43%) of controls remained uninfected. Moreover, relative to non-STI, infections occurred earlier in the menstrual cycle in STI-positive macaques (p=0.01, Wilcoxon). Inflammatory cytokines were higher in STI-positive macaques during STI inoculation (IFN-gamma, IL-6, and G-CSF) and SHIV exposure periods (G-CSF) (p≤0.05, Wilcoxon). CONCLUSIONS: C. trachomatis and T. vaginalis increase susceptibility to SHIV, likely due to prolonged genital tract inflammation. These novel data demonstrate a biological link between these non-ulcerative STIs and (S)HIV risk, supporting epidemiological observations. This study establishes a macaque model for high-risk HIV transmission and prevention studies. |
A comparison of the analytical level of agreement of nine treponemal assays for syphilis and possible implications for screening algorithms
Castro A , Jost H , Cox D , Fakile Y , Kikkert S , Tun Y , Zaidi A , Park M . BMJ Open 2013 3 (9) e003347 OBJECTIVE: The serological diagnosis of syphilis requires the detection of two distinct antibodies, the non-treponemal and trepomenal. Center for Disease Control and Prevention (CDC) recommends screening first with a non-treponemal test such as (Rapid Plasma Reagin/Venereal Disease Research Laboratory), and then confirming those results with one of the several treponemal tests (Fluorescent Treponemal Antibody-Absorption (FTA-ABS), Enzyme Immunoassay, chemiluminescence, treponema pallidum particle agglutination (TP-PA) or Point of Care). Owing to the high volume of samples processed by some laboratories using automated systems, the screening with treponemal assays and confirming with non-treponemal tests is becoming the established norm. The purpose of this study was to evaluate eight treponemal assays using TP-PA as the predicate assay. METHODS: 290 stored serum samples were tested qualitatively according to the manufacturer's directions. RESULTS: Concordance with specimens tested as reactive or non-reactive using TP-PA was: FTA-ABS 94.5-100%, Trep-Sure 100-98.9%, BioELISA 100-98.9%, INNO-LIA 99.1-99.4%, BIOLINE 100-98.9%, CAPTIA IgG 100-97.2%, Trep-ID 100-100% and LIAISON 100-99.4%. In order to properly evaluate the performance of these assays, the analytical sensitivity was determined by endpoint titration of serial dilutions of the reactive serum samples in normal sera. The median endpoint titre varied from 1:4 for FTA-ABS to 1:512 for Trep-Sure. CONCLUSIONS: The performance of the treponemal serological assays was comparable while using medium and high-titre sera. However, the varying performance on specimen dilutions suggests that there may be differences in sensitivity with low-titre sera that are more prevalent in primary and late syphilis cases. |
Development of a pigtail macaque model of sexually transmitted infection/HIV coinfection using Chlamydia trachomatis, Trichomonas vaginalis, and SHIV(SF162P3)
Henning T , Fakile Y , Phillips C , Sweeney E , Mitchell J , Patton D , Sturdevant G , Caldwell HD , Secor WE , Papp J , Hendry RM , McNicholl J , Kersh E . J Med Primatol 2011 40 (4) 214-23 BACKGROUND: Sexually transmitted infections (STIs) are associated with an increased risk of HIV infection. To model the interaction between STIs and HIV infection, we evaluated the capacity of the pigtail macaque model to sustain triple infection with Trichomonas vaginalis, Chlamydia trachomatis, and SHIV(SF162P3) . METHODS: Seven SHIV(SF162P3) -infected pigtail macaques were inoculated with T. vaginalis only (n = 2), C. trachomatis only (n = 1), both T. vaginalis and C. trachomatis (n = 2), or control media (no STI; n = 2). Infections were confirmed by culture and/or nucleic acid testing. Genital mucosa was visualized by colposcopy. RESULTS: Characteristic gynecologic signs were observed for both STIs, but not in control animals. Manifestations were most prominent at days 7-10 post-infection. STIs persisted between 4 and 6 weeks and were cleared with antibiotics. CONCLUSIONS: These pilot studies demonstrate the first successful STI-SHIV triple infection of pigtail macaques, with clinical presentation of genital STI symptoms similar to those observed in humans. |
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