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Rapid tests for diagnosing syphilis: validation in an STD clinic in the Amazon Region, Brazil

Testes rpidos para diagnstico de sfilis: valida !o em clnica de DST na Regi!o Amaz"nica, Brasil

Adele Sch#artz Benza$en%& 'nri()e *al+n *arca%%& ,os.arlos *omes Sardinha%& ,o!o .atarino D)tra ,)nior%& Rosanna /eeling%%%

Fundao de Dermatologia Tropical e Venereologia Alfredo da Matta, Manaus, Brasil II Universidad Cali to !arcia, "avana, Cu#a III $orld "ealt% &rgani'ation, !eneva, ()it'erland Correspondence

ABSTRA.T Correct, earl* diagnosis and treatment of s*p%ilis are essential for its control+ Traditional diagnostic tests depend on speciali'ed e,uipment, installations, and %uman resources+ In t%e searc% for ,uic-, simple tests, a pro.ect )as conducted on t%e validation and reproduci#ilit* of four different tests, previousl* assessed #* $"& reference la#oratories+ T%e stud* also verified t%e operational c%aracteristics and acceptance #* patients and %ealt% professionals+ (amples o#tained at an (TD clinic )ere from /01 and 203 patients )it% /1 and /2 positive results according to FTA4A#s 5gold standard6 in studies 1 and 2, respectivel*+ T%e sensitivit* varied from 30 to 789, specificit* )as greater t%an 739, and ::V )as ; 7<9+ =eproduci#ilit* )as ; 7>9 and -appa inde <+70, comparing t%e results o#tained #* different %ealt% )or-ers+ T%e tests too- less t%an 2< minutes to perform, and more t%an 7<9 of patients agreed to )ait up to t)o %ours for t%e results+ T%e tests presented t%e necessar* re,uirements for use in diagnosis of s*p%ilis, t%us providing an additional option for controlling t%is disease+ (*p%ilis? (e uall* Transmitted Diseases? =eproduci#ilit* of =esults? Diagnosis

R'S012 & diagn@stico e o tratamento corretos e precoces da sAfilis so essenciais para o seu controle+ &s testes diagn@sticos tradicionais dependem de e,uipamentos, instalaBes e recursos %umanos especiali'ados+ Ca #usca de testes de e ecuo simplificada e rDpida, reali'ou4se pro.eto de validao e da reproduti#ilidade de ,uatro diferentes testes anteriormente avaliados pelos la#orat@rios de referEncia da &rgani'ao Mundial da (aFde+ Verificaram4se tam#Gm as caracterAsticas operacionais e aceita#ilidade dos pacientes e dos profissionais de saFde+ As amostras o#tidas numa clAnica de D(T constaram de /01 e 203 pacientes com /1 e /2 positivos no FTA4A#s 5padro ouro6 nos estudos 1 e 2, respectivamente+ A sensi#ilidade variou entre 30 e 789, especificidade superior a 739 e valor preditivo positivo ; 7<9+ A reproduti#ilidade foi superior a 7>9 e <,70 no Andice de -appa, comparando4se os resultados o#tidos pelos diferentes profissionais+ A e ecuo dos testes foi de menos de vinte minutos, e mais de 7<9 dos pacientes concordaram em esperar o seu resultado atG duas %oras+ &s testes apresentaram re,uisitos necessDrios para serem empregados no diagn@stico da sAfilis, dando assim mais uma opo para o controle desta infeco+

Sfilis; Doenas Sexualmente Transmissveis; Reprodutibilidade dos Testes; Diagnstico

(*p%ilis is one of t%e primar* causes of adverse events during pregnanc*, aside from #eing one of t%e most prevalent se uall* transmitted diseases 5(TD6 1+ It %as a glo#al distri#ution, #ut it affects developing countries in Africa, Asia, Hatin America, and t%e Cari##ean )it% greater intensit*+ T%e $orld "ealt% &rgani'ation 5$"&6 estimated t%at in 1777 t%ere )ere 12 million ne) cases of s*p%ilis of )%ic% more t%an >/9 of t%em reported in poor countries, )it% a tendenc* of continuous increasing in t%e last *ears 2,I,0,/,8,>+ Fetal deat%s and mor#idit* t%roug% congenital s*p%ilis can #e prevented if identified and treated ade,uatel* in t%e mot%ers infected #efore t%e #eginning of t%e t%ird trimester+ Cevert%eless, unfortunatel*, t%e ma.orit* of pregnant )omen infected #* s*p%ilis are as*mptomatic and it is onl* possi#le to identif* t%em if t%e* are included in programs of prevention and control and perform serological tests+ In t%e case of adults, t%e algorit%ms designed to manage genital ulcer s*ndrome include s*p%ilis as one of t%e most pro#a#le causes, ma-ing possi#le a proper treatment of t%is pat%olog*+ Mean)%ile, most of t%e time, patients are totall*

as*mptomatic and, not #eing diagnosed correctl*, are not treated, and %ave important complications related to gestation and c%ild#irt%, facilitating t%e se ual transmission of "IV 3,7+ Man* developed countries %ave esta#lis%ed trac-ing activities in t%eir s*p%ilis control programs+ T%e* %ave #een using tests called nontreponemal tests, li-e t%e Venereal Disease =esearc% Ha#orator* 5VD=H6 and t%e =apid :lasma =eagent test 5=:=6+ Aside from #eing eas* to carr* out, t%eir lo) cost, and t%eir relativel* rapid results, t%e* cannot #e applied in all t%e countr*Js primar* %ealt% care units in virtue of t%e fact t%e* re,uire refrigeration or ot%er la#orator* facilities li-e electricit*, or a centrifuge, for e ample+ Toget%er )it% t%ese factors, )%en t%ese tests are emplo*ed, principall* on pregnant )omen, up to 239 percent of positive results are #iologicall* false reactions and+ even in ideal conditions re,uire additional tests of greater specificit* 5treponemal tests, suc% as t%e fluorescent treponemal anti#od* a#sorption test4FTA4A#s, t%e micro%emagglutination test and %emoagglutination test for Treponema pallidum anti#odies4 T:"A, etc+6 1,1<+ In Bra'il, t%ere %as #een an investment in t%e scale4up of t%e primar* %ealt% care net)or- #* means of t%e implementation of t%e Famil* "ealt% :rogram 5F":6 and t%e )or- of communit* %ealt% agents, and an ample net)or- of diagnostic la#oratories %as #een installed+ Kven so, t%e distri#ution of t%ese services is une,ual, and reflects t%e different realities of regions and su#regions+ For t%ese reason, t%e (pecial :rogramme for =esearc% and Training in Tropical Disease 5TD=6L(e uall* Transmitted Diseases Diagnostics Initiative 5(DI6 of t%e $"& stimulates t%e searc% for ne) tests for diagnosing s*p%ilis t%at compl* )it% t%e necessar* re,uisitesM rapid results 5less t%an 1/ minutes6, ease of use #* professionals )%o )or- directl* )it% t%e patients, not re,uiring t%e resources of traditional la#oratories, #eing sta#le at room temperature, possessing good sensitivit* and specificit*, and lo) cost+ T%us t%e* can #e used on large scale in primar* %ealt% care facilities in developing countries to ade,uatel* identif* and treat t%e greatest num#er of infected people+ More t%an t)ent* commerciall* availa#le rapid tests e ist + T%e (DI program first selected si of t%e most promising ones for evaluation of t%eir performance, utili'ing serum #an-s in eig%t countries 5t%e United (tates, =ussia, C%ina, (ri Han-a, Tan'ania, !am#ia, (out% Africa, and "aiti6+ In t%is researc% >37 samples )ere used, and sensitivit* values of 3/4739, and a specificit* of 7I4739 )ere o#tained, )%en t%e* )ere compared )it% test of %emogglutination and agglutination in particles against T. pallidum 5T:"A and T::A6 as a gold standard 1/+

After)ards, in t%e *ear 2<<I, four different sites in Asia 5C%ina6, Africa 5(out% Africa6, and America 5"aiti and Bra'il6 )ere selected to reali'e and validate t%eir operational c%aracteristics and acceptance #* t%e patients and %ealt% professionals t%at )or- )it% t%e care of patients living )it% (TD+ For t%is stage, four rapid tests )ere selected, fundamentall* #ased on t%eir common c%aracteristics, of using )%ole #lood samples, serum or plasma, and not re,uiring refrigeration+ T%e validation of t%e four rapid tests at a speciali'ed clinic in t%e cit* of Manaus, Ama'onas (tate, Bra'il, is discussed in t%is article+ T%e o#.ective of t%is stud* )as to evaluate t%e operational c%aracteristics 5validation and reproduci#ilit*6 of four diagnostic tests proposed, under t%e denomination of Nrapid tests for s*p%ilisN+ Also evaluated )ere t%e feasi#ilit* and accepta#ilit* of t%eir use #* %ealt% professionals )%o )or- directl* in caring for cases of suspected s*p%ilis or ot%er (TD, as )ell as for t%e possi#ilit* of t%is clientele to get t%e results of t%e test #efore terminating t%e consultation+

1aterial and methods

.omparative validation research of fo)r rapid treponemic tests for the diagnosis of syphilis $%ole #lood samples from patients )%o presented t%emselves in a consecutive manner at a clinic speciali'ed in (TD in Manaus )ere used, and serum samples from t%e same patients in t%e la#orator*+ T%e FTA4A#s test )as used as a Ngold standardN+ T%e tests validated )ereM 516 (*p%ic%ec-4$B 5Oualpro Diagnostics, India6? 526 (D Bioline (*p%ilis I+< 5(tandard Diagnostics, (out% Porea6? 5I6 Determine (*p%ilis T: 5A##ott Ha#oratories, U+(+A+6? 506 VisiTect (*p%ilis 5&mega Diagnostics, (cotland6+ All t%ese producing companies donated t%e ,uantities necessar* for t%e validation tests to t%e $"&+ During t%e researc% all t%e patients )ere treated #ased on t%e results of routine clinical e ams 5VD=H and FTA4A#s6+ T%e validation stage activities )ere carried out at four different sitesM Asia 5C%ina6, Africa 5(out% Africa6, and America 5"aiti and Bra'il6+ T%e follo)ing p%ases )ere carried out at a speciali'ed clinic in ManausM Q T%e investigation )as divided into t)o stages, #ecause t%e tests )ere delivered at different times+ In t%e first part t%e (*p%ic%ec-4 $B and t%e (D Biolina (*p%ilis tests )ere validated 5stud* period 16+ After)ards t%e tests of VisiTect (*p%ilis and Determine (*p%ilis T: )ere completed 5stud* period 26+

Q T%e participating patients )ere recruited from among t%ose )%o presented t%emselves at t%e speciali'ed (TD clinic in a voluntar* and consecutive manner, starting on Marc% 1, 2<<I, #eing randoml* selected for stud* 1, and starting in on Ranuar* 1/, 2<<0 for stud* 2+ Q All patients signed an Informed Consent Form stating t%at t%eir participation in t%e researc% )as voluntar*+ Q Criteria for inclusion )ere men and )omen over 13 *ears old )it% no previous %istor* of s*p%ilis, )%ile criteria for e clusion )ere t%ose under 13 *ears old andLor )it% previous %istor* of s*p%ilis or positive serolog* for s*p%ilis+ Q T)o teams )ere prepared for t%e e ecution of t%e e amsM 5a6 professionals )%o )or- directl* providing %ealt% care in clinics 5nurses and paramedics6, and 5#6 #ioc%emists and regular field la#orator* tec%nicians+ Q From eac% participant in t%e studies 1<ml of venous #lood )as dra)n, in vacutainer tu#es+ From t%is total 1ml )as immediatel* used for evaluating t%e rapid tests in t%e clinic, )%ile t%e rest )as sent to t%e la#orator* for centrifuging and t%e e ecution of t%e same rapid tests #* t%e la#orator* team, in t%e same )a* t%at is done )%en carr*ing out routine tests 5VD=H, serum anti4"IV etc+6 and t%e gold standard e am 5FTA4A#s6+ An ali,uot of 2ml )as stored in a free'er at 4><SC for future tests and ,ualit* control to #e carried out #* t%e reference la#oratories of (DIL$"& in all samples t%at tested positive, and 1<9 of t%ose t%at tested negative+ Q Identification, epidemiological data, as )ell as test results from eac% patient )ere recorded on a form and dou#le entered into a data#ase using t%e Kpi Info 8+0 soft)are 5CDC? Centers for Disease Control and :revention, Atlanta, U+(+A+6+ Q T%e sample si'e )as determined t%roug% multicentric protocols, according to eac% site c%aracteristics, and %ad to incorporate a num#er of patients large enoug% to reac% fift* positive patients using t%e gold standard test 5FTA4A#s6+ In t%is stud* pro.ect, t%e sample )as /01 people for stud* 1, and 203 for stud* 2+ A possi#le e planation for t%e difference in sample si'e )as t%e fact t%at t%e period )%en stud* 2 )as #eing carried out coincided )it% an increment of se )or-ers see-ing treatment+ Q T%e samples of studies 1 and 2 )ere anal*'ed to verif* if t%e* )ere a#le to minimi'e t%e random error+ It is -no)n t%at t%e appropriate sample si'e for evaluating a specific test is determined #* t%e formula as follo)s 18M C T U2 Vp 514:6WLD2 and t%is applied to t%e s*p%ilis prevalence o#tained in t%e patient group 57+09 and 21+196 %as enoug% po)er to arrive at a

ma imum accepta#le error of I9 and /9 in eac% of t%e samples, respectivel*+ Q For validation of t%e tests, sensitivit*, specificit*, positive predictive value 5::V6, and negative predictive value 5C:V6 )ere calculated )it% t%eir respective confidence interval of 7/9 57/9CI6+ To evaluate t%e reproduci#ilit* of eac% test, glo#al agreement rates and -appa indices )ere emplo*ed+ To investigate t%e e istence of statisticall* significant differences #et)een t%e validation results for eac% test, c%i4s,uare tests for proportional differences )ere carried out 5)it% Xates correction6+ Q To get opinions a#out t%e operational ,ualities of eac% test an opinion ,uestionnaire )as created and filled out #* t%e 1I professionals responsi#le for t%e e ecution of rapid test evaluations+

T%e validation of t%e tests )as carried out in t)o different time stages in distinct samples of patients, eac% of t%em used to evaluate a pair of tests+ T%e comparison of t%e validation results, t%erefore, cannot #e e tended to t%e four tests toget%er and onl* can #e referred to #* separate pairs, denominated studies 1 and 2+ T%e same professionals )or-ed on all four tests,minimi'ing statistical #ias+ In t%e first stud* to validate t%e tests (*p%ic%ec-4$B and (D Bioline (*p%ilis, a total of /01 consecutive patients )ere studied during t%e period from Marc% 1 t%roug% Rune 10, 2<<I until /1 cases %ad tested positive for FTA4A#s+ In t%e second stud* to validate t%e tests VisiTect (*p%ilis and Determine (*p%ilis T: a total of 203 consecutive patients )ere studied from Ranuar* 1/ t%roug% Rune 2/, 2<<0 until /2 cases %ad tested positive for FTA4 A#s+ T%e principal c%aracteristics of t%e patients in t%e t)o samples studied are presented in Ta#les 1 and 2+

T%e epidemiological varia#les of t%e patients included in t%e samples under anal*sis and t%e la#orator* results of t%e t)o studies )ere recorded on registration forms and in t%e la#orator* ledgers+ T%e reproduci#ilit* of t%e tests, )%en done #* t%e pro.ect teams 5patient care team and la#orator* team6 )ere evaluated t%roug% t%e percentage of agreement and t%e -appa coefficient+ For t%e purpose of t%is stud* )%en t%ese indicators %ad values of more t%an <+3< t%e reproduci#ilit* )as considered good and )%en t%e* )ere greater t%an 7<9 and <+7<, as e cellent+ Ta#le 2 s%o)s t%e prevalences of s*p%ilis according to t%e principal reasons for patient consultation+ In t%e t)o groups studied, suspicion of latent s*p%ilis and patients directed to t%e service under suspicion of secondar* s*p%ilis presented t%e %ig%est prevalence valuesM 88+89 and 88+89, >8+79 and 82+/9, respectivel*+ Altoget%er, all t%e groups included %ad %ig% or moderatel* s*p%ilis prevalence rates, 7+09 in t%e first period and 219 in t%e second, as )as to #e e pected at a (TD speciali'ed clinic+ T%e performance of t%e four tests, relative to t%eir principal validation indicators are s%o)n in Ta#le I+ "o)ever, as )as e plained earlier, t%ese results can onl* #e anal*'ed independentl* in relation to t%e t)o pairs t%at )ere anal*'ed eac% time 5stud* 1 and stud* 26+

In #ot% t%e studies, t%e four rapid tests )ere compared )it% t%e FTA4A#s and t%e VD=H 5routinel* emplo*ed in %ealt% service6+ T%e tests carried out #* t%e professionals )or-ing in t%e clinic )ere compared to t%ose carried out in t%e la#orator* #* professionals more e perienced in t%is t*pe of )or- 5Ta#le I6+ T%e validation of sensitivit* compared to FTA4A#s s%o)ed t%at in stud* 1 (D Bioline (*p%ilis 533+29 and 7<96 %ad slig%tl* %ig%er values t%an (*p%ic%ec-4$B 530+I9 and 7<96 )%et%er t%e* )ere performed #* t%e clinical professionals or #* t%e la#orator* professionals+ "o)ever t%e 7/CI9 intervals of #ot% tests overlap and, t%erefore, it cannot #e stated t%at t%e sensitivit* of one test is %ig%er t%an t%e sensitivit* of t%e second one+ T%e specificit* of t%e t)o rapid tests )as similar and, in general, )it% ver* %ig% values, %ig%er t%an 739 and t%e V:: s%o)ed a slig%tl* #etter performance of (*p%ic%ec-4$B, #ut #ot% )it% a ver* similar 7/9CI+ T%e anal*sis of reproduci#ilit* or relia#ilit* )as carried out t%roug% a comparison of t%e results o#tained for eac% test )%en it )as e ecuted #* clinic professionals and )%en it )as e ecuted

#* t%e la#orator* team, emplo*ing for t%is t%e overall agreement indicators, or t%e percentage of agreement or t%e -appa inde + T%e reproduci#ilit* ac%ieved #* t%e (D Bioline (*p%ilis and (*p%ic%ec-4$B proved e cellent )%en e ecuted #* #ot% teams, )it% agreement values of 779 and -appa inde ; <+7/9 for #ot% tests 5Ta#le 06+

In stud* 2, t%e VisiTect (*p%ilis test s%o)ed sensitivit* values of 78+29 and 78+29, specificities of 73+/9 and 73+/9, and V:: of 70+I9 and 70+I9, respectivel*, )%en carried out #* t%e %ealt% care or t%e la#orator* team+ In #ot% cases results )ere %ig%er to t%ose o#tained )it% Determine (*p%ilis T: t%at %ad sensitivities of 33+/9 and 33+/9, specificities of 7>+79 and 7>+79, and V::s of 729 and 729 )%en carried out #* #ot% teams+ T%e 7/9CI for t%e sensitivit* value of VisiTect (*p%ilis )%en carried out #* t%e la#orator* team )as found to #e #et)een 3/+> and 77+I, surpassing t%at of Determine (*p%ilis T: )it% #et)een >/+7 and 7/+2, respectivel*+ A c%i4s,uare test for proportion differences p T <+<<2, confirmed t%at t%e VisiTect (*p%ilis )as more sensitive t%an t%e Determine (*p%ilis T:+ T%e reproduci#ilit* in t%e second stud* )as e cellent 51+<6 for #ot% tests, )it% similar results )%en carried out #* #ot% t%e %ealt% care and la#orator* teams+ T%e possi#ilit* of patients #eing a#le to )ait for e am results at t%e clinic )as %ig%M 72+19 in t%e first stud*, 7>9 in t%e second, and, in total, for #ot% studies, of 7I+>9 5>I7L>376+ $%en as-ed %o) long t%e* )ere )illing to )ait, 1<<9 of t%e participant in #ot% studies agreed to )ait up to I< minutes, /7+19 in up to

an %our, and II9 up to t)o %ours, %o)ever as t%e average )ait for test results )as 1/ minutes 5#et)een 1< and 2< minutes6, it )as confirmed t%at more t%an 7<9 of t%e participants in #ot% studies )ere )illing to )ait for t%eir results 5Ta#le /6+

T%e results of t%e opinion ,uestionnaire applied to t%ose professionals performing t%e tests s%o)ed t%at instruction compre%ension, managea#ilit*, and results interpretation )ere rated 1<<9 eas*, or ver* eas*, for all four tests+ T%e speed of o#taining results )it% different e ecutors )as al)a*s less t%an 1/ minutes, for (D Bioline (*p%ilis 51<<96, (*p%ic%ec-4$B 5>/96, VisiTect (*p%ilis 53796, and Determine (*p%ilis T: 5>396+

$%en compared )it% FTA4A#s, t%e four rapid tests s%o)ed sensi#ilit*, specificit* and V:: performance superior to t%at o#tained using VD=H, )%ic% is t%e tec%ni,ue most used in t%e routine trac-ing of s*p%ilis in Bra'il, nevert%eless t%e specificit* of t%e four tests )as ver* similar to t%at of VD=H+ In general it can #e said t%at t%e sensitivit*, specificit*, and V:: of t%e four tests, )%en dealing )it% patients )%o %ad %ig% s*p%ilis prevalence rates, )as satisfactor*, as )ell as its reproduci#ilit* )%en comparing t%e results o#tained #* t%e %ealt% care team )it% t%ose of t%e la#orator* team, giving evidence t%at all four tests are easil* e ecuted+

In stud* 1, t%e (D Bioline (*p%ilis presented a sensitivit* 57<+296 %ig%er to t%at of (*p%ic%ec-4$B 533+296+ T%is difference, %o)ever, )as not statisticall* significant, suggesting t%at t%e performance of #ot% of t%em, )%en dealing )it% %ig% prevalence s*p%ilis cases, )as similar+ T%e reproduci#ilit*, measured #* emplo*ing indicators of overall agreement and )it% t%e -appa inde , )as also ver* similar for #ot% teams, demonstrating t%at it is possi#le to use t%em, independent of t%e team of professionals carr*ing t%em out+ In stud* 2, t%e VisiTect (*p%ilis test 578+296 %ad greater sensitivit*, statisticall* significant 5p T <+<<26, )%en compared )it% t%at of Determine (*p%ilis T: 533+/96+ T%e specificit* values 573+/9 and 7>+/9, respectivel*6 )ere %ig%, and similar, in #ot% of t%e tests+ T%e reproduci#ilit* )as e cellent 5of 1<<96 possi#l* in virtue of t%e fact t%at t%e professionals %ad #ecome more e perienced and trained )it% t%e ne) tec%nolog* after stud* 1+ Despite t%e fact t%at VisiTect (*p%ilis, of t%e four tests studied, s%o)ed t%e greatest sensitivit*, it is not possi#le to #e certain t%at it is #etter t%an (D Bioline (*p%ilis and (*p%ic%ec-4 $B as t%e samples emplo*ed for validation )ere not t%e same+ $%en comparing t%e results of t%ese tests found #* t%e la#orator* professionals )it% t%ose of t%e first (DI 11 stud*, t%e follo)ing performances for eac% of t%e four tests researc%ed )ere o#served+ SD Bioline Syphilis In Manaus, t%e sensitivit* of 57<+296 )as #elo) t%e )eig%ted mean for t%e eig%t (DI reference la#oratories 57/96+ &nl* one of t%em, from 5C%ina6, )as slig%tl* lo)er 53796+ Its specificit* in t%e Bra'ilian site )as found to #e 577+096, %ig%er t%an t%e mean of t%e (DI studies 570+796, and onl* t%e studies carried out in :ort4au4:rince 5"aiti6 and Colom#o 5(ri Han-a6 o#tained 1<<9+ Syphichec$34B T%e point sensitivit* found in Manaus 533+296 )as %ig%er t%an t%e )eig%ted results of t%e eig%t studies 530+/96, and onl* one of t%em, t%e !am#ian stud*, )it% 789, )as %ig%er+ T%e specificit* 577+896 )as also slig%tl* superior to t%at pondered in t%e eig%t studies 57>+>96, alt%oug% four of t%em %ad %ig%er values t%an t%ose ac%ieved in t%e Bra'ilian cit*+ 5isiTect Syphilis

T%e mean point value o#tained in Manaus 578+296 )as muc% %ig%er t%an t%e mean of t%e (DI studies 53/96, and )as also %ig%er t%an t%ose o#tained in t%e eig%t studies? on t%e ot%er %and, t%e specificities )ere ver* similar 573+/9 and 7396+ Determine Syphilis T/ In Manaus, t%e value o#tained 533+/96 )as lo)er t%an t%e mean of t%e (DI stud* 57>+296, onl* #eing similar to t%at o#tained in Birming%am 5U+P6+ T%e specificit* )as %ig%er in t%e Bra'ilian cit* 57>+796, compared to t%e (DI mean 570+1796+ T%e Determine (*p%ilis T: )as also recentl* evaluated in a .oint stud* carried out #* t%e CDC, t%e :an American "ealt% &rgani'ationL$"&, and t%e Instituto Kvandro C%agas e Instituto &s)lado Cru' VKvandro C%agas Institute and &s)aldo Cru' InstituteW in Bra'il 1>, #eing interpreted #* t%ree different o#servers+ T%e sensitivit* in relation to t%e gold standard emplo*ed 5T:"A6 varied #et)een 7/+89 and 739, )%ic% )ere %ig%er t%an t%ose encountered in Manaus+ T%e specificit*, on t%e ot%er %and, varied #et)een 7/+>9 and 7>+I9, a similar gradient to t%e one made evident #* t%e present researc%+ Anot%er stud* of Determine (*p%ilis T:, carried out in (o :aulo, Bra'il 5Instituto Adolfo Hut'LAdolfo Hut' Institute6, found a sensitivit* of 7I+89, a specificit* of 72+/9, and a V:: of 7/+29 )%en compared to FTA4A#s and t%e T:"A 13+ A more pronounced difference )as o#served #et)een t%e results of different validations carried out in reference to t%e VisiTect (*p%ilis test )%ic% s%o)ed a %ig%er sensitivit* in Manaus )%en compared to t%e results o#tained in t%e eig%t (DI la#oratories+ T%e prevalence of positive cases in t%e sample su#mitted in t%e first (DI stud* )as %ig%er 5around /<96 t%an t%at of t%e one studied in Manaus 52<+196, )%ic% ma* e plain t%e different findings+ It )ill #e necessar*, %o)ever, to collect additional information a#out its performance in populations )it% lo) prevalence 5I9 or less6, to confirm t%at t%is e planation is satisfactor*+ In t%e peer4revie)ed international #i#liograp%*, onl* studies a#out Determine (*p%ilis T: )ere found, and it seems to #e, of t%e four tests studied, t%e #est -no)n and studied+ T%e studies carried out #* more t%an do'en different o#servers demonstrate a sensitivit* t%at oscillates #et)een 339 5Birming%am and Manaus6 and 1<<9 5Mosco) V=ussiaW, Colom#o, and !am#ia6 and t%at, com#ined )it% a %ig% specificit*, var*ing from 339 5!am#ia6 to 1<<9 5Mosco)6, and e cellent reproduci#ilit* 5Manaus and =io de Raneiro6, defines it as an e cellent test+ Mean)%ile, in t%e Manaus stud*, )%en compared )it% t%e

VisiTect (*p%ilis test, t%is last one %ad a stisticall* significant %ig%er sensivit*, possi#l* due to variations of temperature and %umidit* )%ic% are ver* %ig% in t%e Bra'ilian cit*, possi#l* causing alterations in t%e strip of Determine (*p%ilis T: 5t%e onl* one of t%e four tests )%ic% uses suc% strips6+ T%is %*pot%esis s%ould #e verified in t%e future+ Anot%er element t%at s%ould al)a*s #e remem#ered is t%at a positive result of an* one of t%ese rapid tests 5as also occurs )it% ot%er treponemic tests6 does not necessaril* mean a recent or active infection+ T%is is a negative factor for t%eir use as a trac-ing test in areas of %ig% prevalence )%ere t%ere are man* people t%at %ave alread* %ad s*p%ilis and %ave #een treated and cured of it and )ill still test positive )it% rapid tests+ T%is implies t%e additional use of t%e tests currentl* used, VD=H or =:=, )it% titration, to avoid unnecessar* treatment+ Finall*, it )as s%o)n t%at more t%an 7<9 of t%e participants in #ot% studies )ere )illing to )ait up to I< minutes, a large enoug% time to get results in all four of t%e tests+ T%e %ealt% professionals responsi#le for t%eir e ecution considered t%at all of t%e four tests )ere relativel* eas* to e ecute and interpret+

To sum up, t%e tests validated presented ,uite %ig% sensitivit*, specificit* and ::V+ Kasil* manipulated #* %ealt% professionals, t%e* %ad %ig% accepta#ilit* among #ot% t%e patients and t%e %ealt% professionals t%at participated in t%e studies+ T%e stud* demonstrated t%at it is possi#le to guarantee treatment to people on t%eir first contact )it% t%e %ealt% s*stem+ T%ese results lead t%e aut%ors to #elieve in t%e necessit* of t%e incorporation of t%ese rapid tests as one more tool in t%e fig%t against s*p%ilis, emp%asi'ing t%eir utili'ation in %ard4to4reac% populations+

A+ (+ Ben'a-en participated in t%e ela#oration of t%e pro.ect, t%e e ecution coordination of it, and t%e )riting and editing of t%e article+ K+ !+ !arcia contri#uted to t%e epidemiological data anal*sis+ R+ C+ !+ (ardin%a and R+ C+ Dutra Runior participated in t%e e ecution of t%e pro.ect and t%e )riting and editing of t%e article+ =+ :eeling colla#orated on t%e final discussion of t%e article+

To t%e emplo*ees of t%e !erEncia de D(T da Fundao de Dermatologia Tropical e Venereologia Alfredo da Matta? for t%e support of t%e United Cations C%ildrenJs FundLUnited Cations

Development :rogrammeL$orld Ban-L$orld "ealt% &rgani'ation (pecial :rogramme for =esearc% and Training in Tropical Diseases, and for t%e suggestions :rof+ Dr+ Adauto AraF.o and Dra+ Hui'a "arunari Matida+

1+ :eeling =$, "tun Xe+ Diagnostic tools for preventing and management maternal and congenital s*p%ilisM and overvie)+ Bull $orld "ealt% &rgan 2<<0? 32M0I7408+ V Hin-s W 2+ $orld "ealt% &rgani'ation+ (e uall* transmitted infections increasingM 2/< million ne) infections annuall*+ !enevaM $orld "ealt% &rgani'ation? 177<+ 5$"& Features, 1/26+ V Hin-s W I+ De (c%r*ver A, Me%eus A+ Kpidemiolog* of se uall* transmitted diseasesM t%e glo#al picture+ Bull $orld "ealt% &rgan 177<? 83M8I74/0+ V Hin-s W 0+ $orld "ealt% &rgani'ation+ !lo#al prevalence and incidence of selected cura#le se uall* transmitted diseasesM overvie) and estimates+ !enevaM $orld "ealt% &rgani'ation? 177/+ V Hin-s W /+ !er#ase AC, =o)le* RT, Mertens TK+ !lo#al epidemiolog* of se uall* transmitted diseases+ Hancet 1773? I/1 (uppl IM24 0+ V Hin-s W 8+ $orld "ealt% &rgani'ation+ !lo#al prevalence and incidence of selected cura#le se uall* transmitted infectionsM overvie) and estimates+ !enevaM $orld "ealt% &rgani'ation? 2<<1+ V Hin-s W >+ !er#ase AC, =o)le* RT, "e*mann D", Ber-le* (F, :iot :+ !lo#al prevalence and incidence estimates of selected cura#le (TDs+ (e Transm Infect 1773? >0 (uppl 1M(1248+ V Hin-s W 3+ !ross-urt% ", Mos%a F, Todd R, M)i.aru#i K, Plo--e A, (en-oro P, et al+ Impact of improved treatment of se uall* transmitted diseases on "IV infection in rural Tan'aniaM randomi'ed controlled trial+ Hancet 177/? I08M/I<48+ V Hin-s W 7+ &rrot% PP, Porenromp KH, $%ite =!, C%angaluc%a R, de Vlas (R, !ra* =", et al+ Comparison of (TD prevalence in t%e M)an'a, =a-ai and Masa-a trial populationsM t%e role of selection #ias and diagnostic errors+ (e Transm Infect 2<<I? >7M734 1</+ V Hin-s W 1<+ Ma#e* D, :eeling =$, Ustiano)s-i A, :er-ins MD+ Diagnostics for t%e developing )orld+ Cat =ev Micro#iol 2<<0? 2M2I14 0<+ V Hin-s W

11+ T%e (e uall* Transmitted Diseases Diagnostics InitiativeL(pecial :rogramme for =esearc% and Training in Tropical Diseases+ Ha#orator*4#ased evaluation of rapid s*p%ilis diagnostics+ =esults from 3 (DI (ites+ !enevaM T%e (e uall* Transmitted Diseases Diagnostics InitiativeL(pecial :rogramme for =esearc% and Training in Tropical Diseases? 2<<I+ 5Diagnostics Kvaluation (eries, 16+ V Hin-s W 12+ Fears MB, :ope V+ (*p%ilis fast late agglutination test, a rapid confirmator* test+ Clin Diagn Ha# Immunol 2<<1? 3M3014 2+ V Hin-s W 1I+ Uara-olu :, Buc%anan I, Tam M, (mit% P, "oo- Ird K$+ :reliminar* evaluation of an immunoc%romatograp%ic strip test for specific Treponema pallidum anti#odies+ R Clin Micro#iol 2<<2? 0<MI<804/+ V Hin-s W 10+ $est B, $alraven !, Morison H, Brou)ers R, Baile* =+ :erformance of t%e rapid plasma reagin and t%e rapid s*p%ilis screening tests in t%e diagnosis of s*p%ilis in field condition in rural Africa+ (e Transm Infect 2<<2? >3M2324/+ V Hin-s W 1/+ Ma#e* D, :eeling =+ =apid diagnostic tests for se uall* transmitted infections+ Internacional :lanned :arent%ood Federation Medical Bulletin 2<<2? I8M14I+ V Hin-s W 18+ :ereira M!+ Avaliao de testes diagn@sticos+ InM Andrade AH((, Uic-er F, organi'adores+ MGtodos de investigao epidemiol@gica em doenas transmissAveis+ v+ 1+ BrasAliaM &rgani'ao :an4Americana da (aFdeLFundao Cacional de (aFde? 177>+ p+ 74I<+ V Hin-s W 1>+ Dia' T, Almeida M!B, Inger#ourg !, Maia (C, (ou'a =V, Mar-o)it' HK+ Kvaluation of t%e Determine =apid (*p%ilis T: assa* using sera+ Clin Diagn Ha# Immunol 2<<0? 11M734 1<1+ V Hin-s W 13+ (ato C(, Melo C(, Uer#ini HCM(, (ilveira K:=, Fagundes HR, Ueda M+ Assessment of t%e rapid test #ased on an immunoc%romatograp%* tec%ni,ue for detecting anti4Treponema pallidum anti#odies+ =ev Inst Med Trop (o :aulo 2<<I? 0/MI174 22+ V Hin-s W

.orrespondence A+ (+ Ben'a-en Fundao de Dermatologia Tropical e Venereologia Alfredo da Matta

=ua Coda.Ds 20, Manaus, AM 87<8/41I<, Brasil a#en'a-enYfuam+am+gov+#r (u#mitted on 1/LMa*L2<<8 Approved on 17L(epL2<<8