The Reverse Sequence Syphilis Screening Webinar will begin shortly. The dial-in number for the call is

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1 The Reverse Sequece Syphilis Screeig Webiar will begi shortly The dial-i umber for the call is Questios ca be submitted durig the Webiar via the chat fuctio. Due to the volume of Webiar participats ad the time we have allotted, we may ot be able to provide live aswers to all of the submitted questios. We will compile ad aswer these questios ad will post them olie at as soo as we ca. Natioal Ceter for HIV/AIDS, Viral Hepatitis, STD, ad TB Prevetio Divisio of STD Prevetio Istructios o how to receive CME credits are available at: A archived versio of the Webiar will be available at withi a few days. If you have questios about reverse sequece syphilis screeig followig the Webiar you may submit them to stdtraiig@cdc.gov Natioal Ceter for HIV/AIDS, Viral Hepatitis, STD, ad TB Prevetio Divisio of STD Prevetio 1

2 CME The Dever PTC has collected iformatio from our plaers ad speakers to esure that you are aware of ay potetial coflicts of iterest that may lead to commercial bias. These iclude: Gail Bola, MD No disclosures Ia Park, MD, MS - No disclosures Kare Hoover, MD, MPH - No disclosures Rheta Bares, MSN, MPH No disclosures Hele Burside, MS No disclosures Joh Fitch, LPN No disclosures The Dever STD/HIV Prevetio Traiig Ceter is accredited by the Colorado Medical Society to provide cotiuig medical educatio for physicias. The Dever STD/HIV Prevetio Traiig Ceter desigates this educatioal activity for a maximum of 1 AMA PRA Category 1 Credit TM. Physicias should oly claim credit commesurate with the extet of their participatio i the activity. Reverse Sequece Syphilis Screeig A Overview by CDC Jauary 13, 2011 Natioal Ceter for HIV/AIDS, Viral Hepatitis, STD, ad TB Prevetio Divisio of STD Prevetio 2

3 Gail Bola, MD Director Divisio of STD Prevetio Ceters for Disease Cotrol ad Prevetio Learig objectives Describe the evaluatio ad maagemet of persos with a reactive trepoemal ezyme immuoassay (EIA+) result Idetify three possible explaatios for discordat test results (i.e., EIA+ ad RPR-) with reverse sequece screeig Discuss the maagemet of a perso who has a discordat test result (i.e., EIA+ ad RPR-) that is oreactive by cofirmatory trepoemal testig with a Trepoema pallidum particle agglutiatio (TP-PA) test Compare the performace of the reverse sequece algorithm i populatios with high ad low prevalece of ifectio 3

4 Target Audiece Cliicias who provide screeig, diagosis, ad cliical care for persos at risk for or ifected with syphilis Other health care professioals, such as laboratorias, epidemiologists ad public health program staff, whose work ivolves syphilis screeig or maagemet of persos at risk for or ifected with syphilis Isert Audiece pollig questios here If you are watchig i a group, how may people are i your group? 4

5 What is your primary professio/disciplie (select ONE)? Advaced practice urse Registered urse Licesed practical urse Physicia Physicia assistat Public health professioal Laboratoria Other What is your pricipal employmet settig (select oe)? Academic health ceter College/uiversity Commuity health ceter (federally qualified) Other o-profit health ceter Correctioal facility HMO/maaged care orgaizatio Hospital/Hospital-affiliated cliic Military health system/ Veteras Health Admi facility Private practice (solo/group) State/local health departmet Tribal/Idia Health Service facility Other Not workig 5

6 Preseters Kare Hoover, MD, MPH Medical Epidemiologist Divisio of STD Prevetio Ceters for Disease Cotrol ad Prevetio Ia Park, MD, MS Chief Medical ad Scietific Affairs Uit STD Cotrol Brach Departmet of Public Health Webiar Overview Syphilis screeig with serologic tests Ezyme immuoassays (EIA) ad chemilumiescece immuoassays (CIA) icreasigly used as syphilis screeig tests Large proportio of EIA+/RPR- results Cofusio about patiet maagemet Performace ad cliical data for the use of reverse sequece screeig MMWR 2011 JID 2011 (uder review) CDC recommedatios for the use of EIA/CIA to scree for syphilis Research eeds to provide a evidece basis for future guidelies 6

7 Diagosis of syphilis Trepoema pallidum caot be cultured Ideally, early syphilis would be diagosed usig direct detectio methods Darkfield microscopy Polymerase chai reactio (PCR) Direct fluorescet atibody test for T. pallidum (DFA-TP) Direct detectio methods are ot widely available Direct detectio methods ca miss cases Fail to detect up to 30 of primary cases Most persos preset without symptoms or sigs of syphilis Healed early lesios Iapparet lesios Syphilis is usually diagosed with serologic tests Serologic diagosis of syphilis Serologic diagosis always requires detectio of two types of atibodies Notrepoemal atibodies Atibodies directed agaist lipoidal atiges o Damaged host cells o Possibly from trepoemes Trepoemal atibodies Atibodies directed agaist T. pallidum proteis 7

8 Serologic diagosis of syphilis Notrepoemal tests Rapid plasma reagi (RPR) test Veereal Disease Research Laboratory (VDRL) test Toluidie red uheated serum test (TRUST) Trepoemal tests Fluorescet trepoemal atibody absorbed (FTA-ABS) test Trepoema pallidum article agglutiatio (TP-PA) test Ezyme immuoassays (EIAs) Trep-Check Trep-Sure Chemilumiescece immuoassays (CIAs) LIAISON Architect Microbead immuoassays (MBIA) BioPlex 2200 Syphilis IgM ad IgG Commo patters of serologic reactivity i syphilis patiets Peelig et al. / Bulleti of the World Health Orgaizatio / 2004 / Vol. 82 / No. 6 8

9 Syphilis serologic screeig algorithms Traditioal Reverse sequece Quatitative RPR EIA or CIA RPR+ RPR- EIA/CIA+ EIA/CIA- TP-PA or other trep. test Quatitative RPR TP-PA+ Syphilis (past or preset) TP-PA- Syphilis ulikely RPR+ Syphilis (past or preset) RPR- TP-PA TP-PA+ Syphilis (past or preset) TP-PA- Syphilis ulikely MMWR R&R / i preparatio MWR / February 11, 2011 / Vol. 60 / No. 5 Which algorithm? Traditioal algorithm Detects active ifectio High rate of biologic false positives Cofirmatio with trepoemal test o Use of both tests results i a high positive predictive value Ca miss early primary ad treated ifectio Reverse sequece algorithm Detects early primary ad treated ifectio that might be missed with traditioal screeig Notrepoemal test eeded to detect active ifectio Ideally, EIAs ad CIAs should have perfect specificity EIAs ad CIAs are ospecific High rate of false positive results Varies by risk of populatio 9

10 EIA/CIA AS SYPHILIS SCREENING TESTS Syphilis Screeig Paradigm TRADITIONAL No-trepoemal tests (RPR, VDRL) NON-SPECIFIC ANTIBODY AGAINST LIPOIDAL ANTIGENS QUANTITATIVE REACTIVITY DECLINES WITH TIME reflex to Trepoemal tests (TP-PA, FTA-Abs) SPECIFIC ANTIBODY AGAINST T pallidum QUALITATIVE REACTIVITY PERSISTS OVER LIFETIME 10

11 Traditioal Use of Trepoemal Tests Cofirmig reactive o-trepoemal tests Screeig the blood supply Syphilis Screeig Paradigm EMERGING / NEW Trepoemal tests (EIA, CIA, MBIA) SPECIFIC ANTIBODY TO T pallidum QUALITATIVE REACTIVITY PERSISTS OVER LIFETIME reflex to No-trepoemal tests (RPR, VDRL) NON-SPECIFIC ANTIBODY AGAINST LIPOIDAL ANTIGENS QUANTITATIVE REACTIVITY DECLINES WITH TIME 11

12 Trepoemal Immuoassay: A timelie 1980s EIA is FDA cleared for use as cofirmatory test & i blood bak screeig UK Public Health Laboratory Guidelies: EIA appropriate alterative to VDRL/RPR +TPHA EIA is FDA cleared for cliical diagostic use EU Guidelies: EIA/TPPA recommeded for screeig, VDRL ad RPR o loger recommeded CDC-APHL Report: Presets algorithm for screeig with Trep EIA Why switch to EIA/CIA? Automated (high throughput) Low cost i high volume settigs Less lab occupatioal hazard (pipettig) No false egatives due to prozoe reactio Objective results Some EIA/CIAs detect IgM atibodies; potetially useful for diagosis of early syphilis 12

13 Why switch to EIA/CIA? VS 180 tests per hour, o maual pipettig Syphilis Tests by Test Type, ,000 3,500,000 Number of VDRLs ad EIA/CIA Tests 400, , , , , , ,000 50,000 VDRL RPR 3,000,000 2,500,000 2,000,000 1,500,000 1,000, ,000 Number of RPRs Departmet of Public Health, STD Cotrol Brach,

14 Challeges ad limitatios of the EIA/CIA Caot distiguish betwee active disease ad old disease (treated/utreated) Studies to compare test performace with other serologic tests are lackig Studies evaluatig performace of EIA/CIA to detect IgM atibodies i early syphilis are lackig Cofusio re: maagemet of patiets with discrepat serology (e.g., positive EIA/CIA ad a egative RPR) PERFORMANCE AND CLINICAL DATA FOR THE USE OF THESE TESTS 14

15 Discordat Results from Reverse Sequece Syphilis Screeig Five Laboratories, Uited States, MMWR / February 11, 2011 / Vol. 60 / No. 5 Methods Aalyzed data from five laboratories that used reverse sequece screeig durig ,176 sera screeed with a trepoemal EIA/CIA Data from sera with equivocal EIA/CIA test results were ot icluded as reactive tests EIA tests Trep-Chek Trep-Sure CIA test LIAISON Reflex otrepoemal test RPR Cofirmatory trepoemal tests TP-PA FTA-ABS MMWR / February 11, 2011 / Vol. 60 / No. 5 15

16 Methods Three sites served patiet populatios with low prevalece for syphilis Large maaged-care orgaizatios Two sites served patiet populatios with high prevalece MSM HIV-ifected patiets Calculated Reactive EIA/CIAs amog all sera (i.e., EIA+) Discordat sera amog reactive EIA/CIAs (i.e., EIA+/RPR-) Noreactive cofirmatory TP-PA or FTA-ABS tests amog discordat sera (i.e., EIA+/RPR-/TP-PA-) MMWR / February 11, 2011 / Vol. 60 / No. 5 Results of reverse sequece syphilis screeig five laboratories, Uited States, Populatio Test Total N Reactive EIA/CIA total Noreactive reflex RPR EIA/CIA+ Noreactive cofirmatory trepoemal test* RPR Overall 140,176 4, , Low prevalece Souther Norther Souther High prevalece New York City 127,402 2, , Trep-Chek 47,952 1, Liaiso 21, Trep-Sure 57,827 1, ,774 1, Trep-Chek 7,607 1, Chicago Trep-Sure 5, MMWR / February 11, 2011 / Vol. 60 / No. 5 16

17 Results of reverse sequece syphilis screeig five laboratories, Uited States, Populatio Test Total N Reactive EIA/CIA total Noreactive reflex RPR EIA/CIA+ Noreactive cofirmatory trepoemal test* RPR Overall 140,176 4, , Low prevalece Souther Norther Souther High prevalece New York City 127,402 2, , Trep-Chek 47,952 1, Liaiso 21, Trep-Sure 57,827 1, ,774 1, Trep-Chek 7,607 1, Chicago Trep-Sure 5, MMWR / February 11, 2011 / Vol. 60 / No. 5 Results of reverse sequece syphilis screeig five laboratories, Uited States, Populatio Test Total N Reactive EIA/CIA total Noreactive reflex RPR EIA/CIA+ Noreactive cofirmatory trepoemal test* RPR Overall 140,176 4, , Low prevalece Souther Norther Souther High prevalece New York City 127,402 2, , Trep-Chek 47,952 1, Liaiso 21, Trep-Sure 57,827 1, ,774 1, Trep-Chek 7,607 1, Chicago Trep-Sure 5, MMWR / February 11, 2011 / Vol. 60 / No. 5 17

18 Results of reverse sequece syphilis screeig five laboratories, Uited States, Populatio Test Total N Reactive EIA/CIA total Noreactive reflex RPR EIA/CIA+ Noreactive cofirmatory trepoemal test* RPR Overall 140,176 4, , Low prevalece Souther Norther Souther High prevalece New York City 127,402 2, , Trep-Chek 47,952 1, Liaiso 21, Trep-Sure 57,827 1, ,774 1, Trep-Chek 7,607 1, Chicago Trep-Sure 5, MMWR / February 11, 2011 / Vol. 60 / No. 5 Results of reverse sequece syphilis screeig five laboratories, Uited States, Populatio Test Total N Reactive EIA/CIA total Noreactive reflex RPR EIA/CIA+ Noreactive cofirmatory trepoemal test* RPR Overall 140,176 4, , Low prevalece Souther Norther Souther High prevalece New York City 127,402 2, , Trep-Chek 47,952 1, Liaiso 21, Trep-Sure 57,827 1, ,774 1, Trep-Chek 7,607 1, Chicago Trep-Sure 5, MMWR / February 11, 2011 / Vol. 60 / No. 5 18

19 Results of reverse sequece syphilis screeig five laboratories, Uited States, Populatio Test Total N Reactive EIA/CIA total Noreactive reflex RPR EIA/CIA+ Noreactive cofirmatory trepoemal test* RPR Overall 140,176 4, , Low prevalece Souther Norther Souther High prevalece New York City 127,402 2, , Trep-Chek 47,952 1, Liaiso 21, Trep-Sure 57,827 1, ,774 1, Trep-Chek 7,607 1, Chicago Trep-Sure 5, MMWR / February 11, 2011 / Vol. 60 / No. 5 Reasos for discordat test results (i.e., EIA/CIA+ / RPR-) False-positive EIA/CIA EIAs ad CIAs are very sesitive But have lower specificity Treated syphilis Trepoemal atibodies are detected by sesitive EIAs ad CIAs Seroreversio of otrepoemal atibodies Early primary syphilis Trepoemal atibody titer rises before otrepoemal atibody titer MMWR / February 11, 2011 / Vol. 60 / No. 5 19

20 Coclusios EIA/CIA have high sesitivity but lower specificity All reactive EIA/CIA must be reflexly tested with a quatitative RPR Cofirm reactive EIA/CIA Detect active ifectio Although test performace varies by prevalece of syphilis i the populatio, all discordat specimes (EIA+/RPR-) must be cofirmed with a cofirmatory trepoemal test Cofirmatory trepoemal test must have at least equivalet sesitivity ad higher specificity compared to the screeig trepoemal test TP-PA recommeded FTA-ABS ot recommeded MMWR / February 11, 2011 / Vol. 60 / No. 5 Screeig for syphilis with the trepoemal immuoassay: Aalysis of discordat serology results ad implicatios for cliical maagemet JID 2011, uder review 20

21 Methods Cross sectioal aalysis of idividuals tested with Diasori LIAISON chemilumiescece immuoassay (CIA) at Kaiser Permaete Norther Regioal Laboratory from Aug-Oct 2007 Data abstracted from electroic medical records (laboratory ad cliical) usig stadardized protocol HIV-status, sexual orietatio, pregacy status, prior syphilis history ad CIA idex values were compared for all CIA-positive, RPR-egative patiets accordig to TP-PA status =151 2 =439 RPR CIA Testig Results CIA = N=21,623 specimes CIA+ = 2 CIA+ / RPR = 1.3 Maaged like prior RPR screeig algorithm 72 =184 TPPA =255* =71 * 33 duplicate or ifat tests 21

22 Demographics CIA+/RPR- TPPA+ (N=184) CIA+/RPR- TPPA- (N=71) Mea age ( SD)* 50 ( 14) 42 ( 16) Males* 149 (81) 33 (47) MSM* 60 (33) 7 (10) Heterosexual 15 (8) 8 (11) Females 35 (19) 38 (53) Pregat 12 (34) 16 (42) HIV-positive* 86 (47) 14 (20) Prior syphilis* 105 (57) 6 (9) *P= < Maagemet based o iitial serology ad syphilis history CIA+ / RPR- / TP-PA+ N=184 Prior treated syphilis N=105 (57) 10 (9) received repeat treatmet 95 (91) o atibiotic treatmet No prior syphilis N=79 (43) 51 (65) received treatmet 28 (35) o atibiotic treatmet 22

23 Maagemet based o iitial serology ad syphilis history CIA+ / RPR- / TP-PA- N=71 Prior treated syphilis N=6 (8) 2 (33) received repeat treatmet 4 (66) o atibiotic treatmet No prior syphilis N=65 (92) 7 (11) received treatmet 58 (89) o atibiotic treatmet Repeat Serology Testig Results CIA+ / RPR- / TP-PA+ N=184 Repeat Serology N=78 Iitially treated =31 (64) 0 seroreverted to CIA- 27 (87) remaied CIA+/RPR-/TPPA+ 4 (13) serocoverted to CIA+/RPR+ Not treated iitially =47 (36) 0 seroreverted to CIA- 41 (87) remaied CIA+/RPR-/TPPA+ 6 (13) serocoverted to CIA+/RPR+ 23

24 Repeat Serology Testig Results CIA+/ RPR- / TP-PA- N=71 Repeat Serology N=31 Iitially treated N=6 =31(19) 0 seroreverted 0 to to CIA- CIA- 6 (100) 27 (87) remaied CIA+/RPR-/TPPA+ 0 serocoverted 4 (13) serocoverted to CIA+/RPR+ to CIA+/RPR+ Not treated iitally N=25 (81) 7 (28) seroreverted to CIA- 17 (68) remaied CIA+/RPR-/TPPA+ 1 (4) serocoverted to CIA+/RPR High EIA/CIA idex values may predict TP-PA positivity (=255) TPPA Negative TPPA Positive Proportio N=79 idividuals with CIA idex value >12.0; 100 of were TP-PA positive Cutoff Idex Value Park IU et al. upublished data 24

25 Kaiser Study Coclusios Amog CIA+/RPR- patiets, performace of a secod trepoemal test is useful i low prevalece settigs to guide treatmet decisios Coflictig trepoemal results (CIA+/TP-PA-) may represet false positives, especially if low CIA idex value. Repeat testig should be cosidered Amog CIA+/RPR- patiets at high risk, repeat testig should be performed to rule out early syphilis Ackowledgmets Departmet of Public Health Joa Chow, MPH, DrPH Gail Bola, MD Deise Gilso Michael Samuel DrPH Kaiser Permaete Norther Regioal Laboratory Jeffrey Schapiro, MD Je Shieh, PhD Mark Staley, MPH Sa Fracisco DPH: Kyle Berstei PhD Los Ageles DPH: Moica Muñoz, Sarah Guerry MD 25

26 CDC RECOMMENDATIONS FOR THE USE OF EIA/CIA Recommeded algorithm for reverse sequece syphilis screeig EIA or CIA EIA/CIA+ EIA/CIA- Quatitative RPR RPR+ Syphilis (past or preset) TP-PA TP-PA+ Syphilis (past or preset) RPR- TP-PA- Syphilis ulikely MMWR / February 11, 2011 / Vol. 60 / No. 5 26

27 Recommeded algorithm for reverse sequece syphilis screeig EIA or CIA EIA/CIA+ If icubatig or early primary syphilis is suspected, treat with bezathie peicilli G 2.4 millio uits IM x 1 Quatitative RPR RPR+ Syphilis (past or preset) TP-PA TP-PA+ Syphilis (past or preset) RPR- TP-PA- Syphilis ulikely MMWR / February 11, 2011 / Vol. 60 / No. 5 Recommeded algorithm for reverse sequece syphilis screeig EIA or CIA EIA/CIA+ EIA/CIA- If icubatig or primary syphilis is suspected, treat with bezathie peicilli G 2.4 millio uits IM x 1 Quatitative RPR Evaluate cliically, determie if treated for syphilis i the past, assess risk of ifectio, ad admiister therapy accordig to CDC s STD Treatmet Guidelies if ot previously treated RPR+ Syphilis (past or preset) TP-PA TP-PA+ Syphilis (past or preset) EIA/CIA- RPR- TP-PA- Syphilis ulikely MMWR / February 11, 2011 / Vol. 60 / No. 5 27

28 Recommeded algorithm for reverse sequece syphilis screeig EIA or CIA EIA/CIA+ If icubatig or primary syphilis is suspected, treat with bezathie peicilli G 2.4 millio uits IM x 1 Quatitative RPR Evaluate cliically, determie if treated for syphilis i the past, assess risk of ifectio, ad admiister therapy accordig to CDC s STD Treatmet Guidelies if ot previously treated RPR+ Syphilis (past or preset) TP-PA Evaluate cliically, determie if treated for syphilis i the past, assess risk of ifectio, ad admiister therapy accordig to CDC s STD Treatmet Guidelies if ot previously treated TP-PA+ Syphilis (past or preset) RPR- TP-PA- Syphilis ulikely MMWR / February 11, 2011 / Vol. 60 / No. 5 Recommeded algorithm for reverse sequece syphilis screeig EIA or CIA EIA/CIA+ EIA/CIA- If icubatig or primary syphilis is suspected, treat with bezathie peicilli G 2.4 millio uits IM x 1 Quatitative RPR Evaluate cliically, determie if treated for syphilis i the past, assess risk of ifectio, ad admiister therapy accordig to CDC s STD Treatmet Guidelies if ot previously treated RPR+ Syphilis (past or preset) TP-PA Evaluate cliically, determie if treated for syphilis i the past, assess risk of ifectio, ad admiister therapy accordig to CDC s STD Treatmet Guidelies if ot previously treated TP-PA+ Syphilis (past or preset) EIA/CIA- RPR- TP-PA- Syphilis ulikely If at risk for syphilis, repeat RPR i several weeks MMWR / February 11, 2011 / Vol. 60 / No. 5 28

29 RESEARCH NEEDS TO PROVIDE AN EVIDENCE BASIS FOR FUTURE GUIDELINES Research eeds Compare head-to-head the performace of EIAs, CIAs, TP-PA, FTA-ABS test, ad microbead immuoassay Well-defied patiet populatios whose cliical history ad syphilis risk are kow HIV-ifected persos Pregat wome Characterize discordat sera with oreactive cofirmatory trepoemal tests by immuoblottig Defie reactivities with T. pallidum atiges Study utility of immuoglobuli M trepoemal testig Diagosis of early primary syphilis Evaluatio of ifectio i asymptomatic, seropositive, utreated persos 29

30 Questio ad Aswer Sessio Questios may be submitted durig the Webiar via the chat fuctio. If you have questios about the reverse sequece syphilis screeig followig the Webiar you may submit them to Cotiuig Medical Educatio (CME) Iformatio To receive CME, a evaluatio ad request for certificate must be completed at: You must complete the evaluatio by April 30, 2011 to receive CME credit Certificates will be set out via startig April 15, Cotiuig Nursig Educatio (CNE) ad other types of Cotiuig Educatio (CE) are ot available for this program. If you have CME questios, please cotact Joh Fitch at Joh.Fitch@dhha.org 30

31 April is Natioal STD Awareess Moth Visit our web sites for updated tools, materials, ad resources to help support your local STD prevetio efforts. provider.gytow.org Educatioal ad Traiig Resources Natioal Network of STD/HIV Prevetio Traiig Ceters CDC Divisio of STD Prevetio or

32 Ackowledgmets Ro Ballard Rheta Bares Susa Blak James Bethea Hele Burside Joa Chow David Cox Joh Fitch Suzae Haecker Nia Martiez Alyso Richmod Justi Radolf Preeti Pathela Julie Schilliger Susie Zato Kim Workowski For more iformatio please cotact Ceters for Disease Cotrol ad Prevetio Prevetio 1600 Clifto Road NE, Atlata, GA Telephoe, CDC-INFO ( )/TTY: Web: The fidigs ad coclusios i this report are those of the authors ad do ot ecessarily represet the official positio of the Ceters for Disease Cotrol ad Prevetio. Natioal Ceter for HIV/AIDS, Viral Hepatitis, STD, ad TB Prevetio Divisio of STD Prevetio 32

33 High EIA/CIA idex values may predict TP-PA positivity (=674) Wog E ad Padori M, 2011STD epub ahead of prit 33