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1 대한요로생식기감염학회지 : 제3권제1호 2008년 4월 Korean J UTII Vol.3, No.1, April 2008 종설 성매개감염의혁신적인진단법 가톨릭대학교의과대학비뇨기과학교실 이승주 [Abstract] Innovative Diagnostics for Sexually Transmitted Infections Seung-Ju Lee From the Department of Urology, College of Medicine, The Catholic University, Seoul, Korea Diagnostics for sexually transmitted infections (STIs) with easy non-invasive sample collection are important to increase testing and hence to reduce the spread of this infection. From this point of view, molecular technologies and rapid point-of-care tests are innovations which have gradually shifted the paradigm in the diagnosis of STIs from biological to molecular amplification and from laboratory to near-patient testing. These powerful diagnostic tools have improved and will continue to have a significant impact on our ability to design strategies and programs for the control and prevention of STIs. (Korean J UTII 2008;3:38-49) Key Words: Sexually transmitted infection, Diagnosis, Nucleic acid amplification technics, Point-of-care system 서 과거 venereal disease (VD) 라고불리던성병은 1990 년대에들어서 sexually transmitted disease (STD) 즉, 성전파성질환이라불리게되었다. 이를계기로 venereal 이라고하는신화적인용어에서성접촉에의한질환이라는보다의학적인용어로바뀌게되었고, 원인이되는세균, 바이러스그리고기생충도대부분밝혀지게되었다. 하지만최근에는다시 sexually transmitted 론 교신저자 : 이승주, 가톨릭대학교의과대학비뇨기과학교실경기도수원시팔달구지동 93-6 성빈센트병원 Tel: lee.seungju@gmail.com 43 infection (STI) 즉, 성매개감염이라는용어가널리사용되기시작하였다. STD의 disease는명백한증상과징후를가지는질환만을의미하지만, STIs는증상과징후를가지고있지않은무증상감염도포함한다. 이는질환과감염을구별한것인데, 실제로클라미디아, 임균, 헤르페스, 인유두종바이러스와같은 STIs의흔한원인이되는세균과바이러스들은많은부분이질환이아닌감염상태로존재하는것이사실이다. 따라서 STI가 STD에비해보다포괄적이며, 전파와감염이라는공중보건학적의미가강조된용어라할수있다. 이러한용어와개념의변화에는진단기술의혁신적인발달이크게기여했다고볼수있는데, 그중두가지가바로분자생물학적진단법의발달과

2 44 대한요로생식기감염학회지 : 제 3 권제 1 호 2008 년 4 월 Past Model First symptoms Symptombased Treatment diagnosis Recover and visit Costly and ineffective Missed diagnosis No screening Current and Future Proposed Model Behavioral predisposition Stratified population Screening and prevention Diagnosis Treatment and monitoring Followup Earlier diagnosis Effective Control & Prevention Cost-effective healthcare Better patient outcomes Fig. 1. The proposed healthcare model for sexually transmitted infections. rapid 또는 point-of-care (POC) test라고불리는신속검사의발달이다. 분자생물학적진단기술은현재 STIs 진단의패러다임을과거생물학적진단에서분자생물학적수준으로변화시키고있다. 1 배양검사에의존하던생물학적진단과비교해볼때, 분자생물학적비배양검사는비교적높은민감도와특이도를나타내고, 검체의운반이편리하며, 자동화된설비를갖출수있어검사처리시간이빠르다는특징이있다. 또한인유두종바이러스나클라미디아처럼실험실적배양이힘든미생물들을쉽게검출할수있게되었다. 이러한진단법의혁신은 STIs의진단, 관리, 예방을위한전략수립에도큰영향을보이고있으며, 앞으로도많은변화를가져올것이다. 분자생물학적진단법이가져온가장큰장점은 STIs 를증상과징후가없는감염상태에서조기진단할수있게되었다는것이다. 조기진단은결국 STIs 또는 STDs로인한후유증을감소시키고타인으로의전파도줄일수있게된다. 최근인간의모든질환을다루는접근방식이과거증상에따라진단하고치료하던개념에서점차선별검사를통해조기진단하여치료또는예방하는개념으로변하고있듯이 STIs도이러한진단법의혁신을통해조기진단함으로써 STIs를효과적으로관리, 예방할수있게된것이다. 이는비용적인측면에서도훨씬경제적이고, 환자에게도더좋은치료 결과를보일수있을것으로예상된다 (Fig. 1). 신속검사의개발은과거병의원의검사실내에서만이루어지던 STIs 검사를검사실밖으로가지고나가게됨으로써검사를위해병의원을찾아오는데걸리던시간의지연을줄일수있게하였다. 2 환자로하여금시간, 장소, 방법에구애받지않고검사를받을수있게하여조기진단이가능하게되었고, 그로인해후유증감소와타인에게로의전파를감소시켜건강증진에기여할수있었다. 아직여러가지문제점들이남아있음에도불구하고분자생물학적검사법과신속검사법의발달은 STIs 진단의혁신을가져왔음을부인할수없는상황이다. 이에본저자는현재개발되어사용되고있는분자생물학적 STIs 진단법과신속검사법들을소개하고각각의장점과문제점들을알아보기로한다. 본론 1. 핵산검사 (Necleic acid tests) 현재다양한핵산검사방법들이 STIs의진단을위해사용되고있으며, 이들은각각다른민감도, 특이도, 그리고재현성을가지고있다. 핵산검사는일반적으로효소면역측정법 (enzyme immunoassay, EIA) 등과

3 이승주 : 성매개감염의혁신적인진단법 45 EIA No. of organisms per sample Amplified nucleic acid (PCR or LCR) Non-amplified nucleic acid Fig. 2. Sensitivity ranges of various diagnostic technologies for sexually transmitted infections. Abbreviations: PCR=polymerase chain reaction, LCR=ligase chain reaction, EIA=enzyme immunoassay. Table 1. Examples of FDA-approved nucleic acid tests for sexually transmitted infections Target organisms Technology Instrument Kit Company Chlamydia trachomatis (CT) detection PCR LCR TMA HC COBAS AMPLICOR LCx APTIMA -Combo 2 HC 2 Roche Abbott Gen-Probe Digene Neisseria gonorrhoeae (GC) detection PCR LCR HC COBAS AMPLICOR LCx HC 2 Roche Abbott Digene CT/GC screening/detection HPA SDA ProbeTec TM ET Gen-Probe Becton-Dickinson HPV screening HC HC 2 Digene HIV confirmatory test TMA APTIMA HIV-1 RNA Qualitative Assay Gen-Probe Gardnerella, Trichomonas, and Candida Hybridization Affirm TM VPIII Becton-Dickinson Abbreviations: PCR=polymerase chain reaction, LCR=ligase chain reaction, TMA=transcription mediated amplification, HC=hybrid capture, HPA=hybridization protection assay, SDA=strand displacement amplification, FDA=food drug association 같은비핵산검사에비해민감도가더높다. 핵산검사는핵산의증폭여부에따라핵산증폭검사 (nucleic acid amplification test; NAATs) 와핵산비증폭검사 (Non-amplified nucleic acid test) 로나눈다. NAATs는이론적으로 1개의핵산만으로도그핵산을증폭하여 검사가가능하지만, 핵산비증폭검사는검사를위해적어도 10,000개이상의핵산이필요하다 (Fig. 2). 3 핵산검사의기본과정은세가지단계로나누어지는데, 검체준비, 부합화 / 증폭, 그리고검출의과정이다. 3 핵산검사의다양한종류는이세가지단계에

4 46 대한요로생식기감염학회지 : 제 3 권제 1 호 2008 년 4 월 서각각어떠한기술을사용하느냐에따라달려있다. 검체준비과정에서는표준화된방법을통해미생물로부터핵산을분리할지라도검체의종류나상태, 검체수집과정에따라핵산분리의효율이달라질수있다. 어떤검체안에는억제물질이존재할수있으며, 이는핵산의분리나증폭을억제하여검사의민감도나특이도를변화시킬수있다. 따라서이러한억제물질을최소화할수있는검체수집이나준비과정이검사의정확도를높일수있는방법이된다. 부합화 / 증폭과정에서는표적이되는핵산이얼마나정확하게증폭되느냐에따라검사의민감도가좌우된다. 검출단계에서는표지자의종류및효율, 그리고검출방법에따라민감도와특이도가달라진다. 대부분의 NAATs는효소가부착된핵산탐색자를사용하여증폭된핵산을검출하는데, 이효소를다시고민감도를가진화학형광물질을통해밝혀내는것이다. 핵산검사는이미 10년이상실험실에서사용되어왔고, 최근여러장비들이개발되면서임상적목적의사용이증가하고있다. 미국식품의약청의승인을받은 STIs 진단을위한핵산검사법은 Table 1과같다. 1) 핵산증폭검사 (NAATs) 의특징 NAATs는핵산비증폭검사에비해민감도의측면에서더우수한검사이다. 일반적인비증폭검사에서는검출할수없는낮은농도에존재하는특정표적유전자를효소를통해증폭해냄으로써민감도를크게높일수있다. 상업적으로개발된 NAATs는주로 Chlamydia trachomatis, Neisseria gonorrhoeae, human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV) 등과같은세균과바이러스의정성검사에사용된다. 그러나최근에는 HIV, HBV, HCV와같은바이러스의부하가병의진단, 예후, 치료감시에중요한영향을미치는것으로밝혀지면서정량검사의중요성이강조되는경우도있다. 4 현재상업적으로개발된 NAATs를증폭과정의온도변화여부와표적유전자, 그리고사용되는효소에따라표 2 에열거하였다. 현재 STIs 예방및관리의주요표적미생물은가장 흔한세균성 STIs인 N. gonorrhoeae와 C. trachomatis이다. NAATs는특히이두가지세균에대한조기진단에큰기여를하였고, 선별검사와감시사업을쉽게하여 STIs 예방과관리를혁신하였다. 5 NAATs의가장큰특징은바로분자생물학적방법의훌륭한민감도에있다. 임상검체에서아주미세한양의표적핵산만있어도검출하여증폭이가능하다. 이러한높은민감도는소변검체만으로도자궁경부와요도의감염을진단할수있게하였고, 또한여성이본인스스로질의도말을통해얻은검체로도진단이가능할수있게하였다 (Table 3). 6 검체의운반을위한요구조건도배양검사등에비해훨씬완화되어검체수집장소에서의일시적인보관이가능하다. 이러한장점들은공중보건학적 STIs 선별검사프로그램에혁신적인변화를가져오게되었는데, 학교나군대와같은큰집단에서의현장검사가가능해졌고, 7,8 자가검체수집과우편배송을통한새로운선별검사방법이도입된것이다. 9 최근우리나라에서시행된 STIs의집단유병률조사들도바로이러한 NAATs의장점을활용한것이다. 10,11 검체에따른 NAATs의민감도와특이도를기존의다른진단방법들과비교하여표 4에나타내었다. 2) 클라미디아와임균감염의진단을위한핵산증폭검사 (NAATs) C. trachomatis의진단에있어서 NAATs는이미남자와여자에있어서모두표준진단법으로인정되었으며, N. gonorrhoeae의진단에서도검체의운반과배양조건이나쁜상황에서 NAATs가추천되고있다. 12 핵산중에서 DNA를증폭하는 polymerase chain reaction (PCR) 방법과 strand displacement amplification (SDA) 방법이외에최근 C. trachomatis 와 N. gonorrhoeae의 RNA를증폭하여민감도와특이도를높인 transcription mediated amplification (TMA) 방법도상업적인장비로사용되고있다. 이들은모두환자와무증상감염자의소변뿐만아니라요도및자궁경부도말검체를통한검사방법으로미국식품의약청의승인을받았다. 각각의검사방법은증폭되는핵산의형태와표적

5 이승주 : 성매개감염의혁신적인진단법 47 Table 2. Nucleic acid amplification technologies Technology Company Isothermal Target Enzymes PCR LCR SDA TMA NASBA Roche Abbott Becton-Dickinson Gen Probe Organon Teknika No No Yes Yes Yes DNA DNA DNA RNA RNA DNA polymerase DNA ligase DNA polymerase and restriction endonuclease Reverse transcriptase and RNA polymerase Reverse transcriptase, RNase H, RNA polymerase Abbreviations: PCR=polymerase chain reaction, LCR=ligase chain reaction, SDA=strand displacement amplification, TMA=transcription mediated amplification, NASBA=nucleic acid sequence based amplification Table 3. Specimens that have been used successfully for the detection of C. trachomatis with nucleic acid amplification test (NAATs) Men Urethral swabs* First-catch urine* Women Cervical swabs* Urethral swabs* First-catch urine* Vaginal swabs Vulvar swabs Tampons *: types of specimens that have been extensively evaluated for use in NAATs 핵산에따라구별되며, 증폭과정도각각다른특징을가지고있다. 각검사방법의비교는표 5에정리하였다. 3) 핵산증폭검사 (NAATs) 의문제점 NAATs의첫번째문제점은위양성문제이다. NAATs는민감도는아주높지만특이도는그렇지않다. NAATs의특이도가 99% 이상으로보고되는경우도있지만배양검사나직접균을동정해내는경우처럼 100% 완전하지는않다. 따라서유병률이낮은인구집단을검사할때위양성의확률이높아지는위험이있다. 13 예를들면, 특이도 99.5% 인검사가있을때 0.5% (1-특이도) 는위양성이된다. 어떤집단에서검사결과양성률이 1.0% 일때는그반이위양성이되는것이므로, 이때양성예측률은 50% 밖에되지않는다. 비록검사가양성이라도진짜그 STIs에걸려있을비율은 10명중에 5명밖에되지않는것이다. 특이도를높이기위해서는다른방법으로재검사를하던지, 아니면검체를한번더받아다시검사하여결과를판정해야한다. 14 결국 최종진단은의사의판단이지검사결과가아닌것이다. 위양성과같은지나친결과해석이결국비용증가를초래하게되는것이다. NAATs의두번째문제점은위음성문제이다. PCR과 SDA 같은 NAATs는검체내에존재하는각종억제물질로인해위음성의결과가초래될수있다. 이러한억제물질은남성요도검체나여성자궁내검체에비해소변검체를사용할때더많이나타난다. 소변내억제물질로는혈색소, 당, 아질산염, β-hcg, 그리고결정체등이알려져있으며, 이물질들로인한증폭억제효과를줄이기위한방법으로는희석, 열처리, 얼림녹임등이사용될수있다. 15 최근상업적 NAATs 장비들은억제물질제거제또는그러한제거제가포함되어있는검체용기들을사용하고있다. 또한각각의검사키트에내부대조검체를삽입함으로써억제여부를관찰할수있게하였다. NAATs검사중 TMA는다른 NAATs와는달리고유의표적획득단계를가지고있어증폭억제를막을수있다는장점이있으며, 그결과위음성을막아민감도가향상될수있다. 기존의배양검사와의비교

6 48 대한요로생식기감염학회지 : 제 3 권제 1 호 2008 년 4 월 Table 4. Performance of diagnostic tests for the detection of C. trachomatis and N. gonorrhoeae in urogenital specimens Diagnostic test, specimen type C. trachomatis (%) N. gonorrhoeae (%) Sensitivity Specificity Sensitivity Specificity Culture Gram stain, symptomatic men NA a NA Gram stain, asymptomatic men NA NA Gram stain, women NA NA Direct fluorescent antibody >99 NA NA Enzyme immunoassay NA NA Probe hybridization PCR, cervical PCR, female urine PCR, male urine SDA, cervical SDA, female urine SDA, male urine SDA, male urethra NP b NP TMA, cervical TMA, female urine TMA, male urine TMA, male urethra a: test not applicable, b: data not provided Abbreviations: PCR=polymerase chain reaction, SDA=strand displacement amplification, TMA=transcription mediated amplification 를통한 NAATs의장단점을표 6에정리하였다. NAATs의세번째문제점은검사의남용이다. 소변을검체로사용함으로써검체수집이아주쉬워지게되었다. 이점은일반인에대한검사나공중보건을위한특정집단에서의선별검사프로그램을진행하는데큰장점이되었지만, 반면에적응증이되지않는불필요한경우까지검사를남용하게될수있다. 예를들면, STIs가아닌세균성질염또는비위험군인모든무증상여성에적용되는선별검사등이다. 물론확실치않은질염의경우임질이나클라미디아감염을감별진단하기위해서는 NAATs가필요할수있겠지만질염진단의표준방법은아닌것이다. NAATs의네번째문제점은검사비가비싸다는것이다. 최근 STIs를위한 NAATs검사는두가지균주이상을동시에검사하는다중검사 (multiplex test) 를선호한다. 비록여러균주에대한동시검사가편리하고이상적이기는하지만과연다중검사가임상적으로적응증이되느냐하는문제와그에따른비용증가는결코간과할수만은없다. 2. 신속검사 (Rapid or Point-of-Care tests) 최근신속검사의발달은특별한장비없이 STIs 검사결과를 30분이내에알아볼수있게하였다

7 이승주 : 성매개감염의혁신적인진단법 49 Table 5. Comparison of commercially available nucleic acid amplification test (NAATs) for the diagnosis of C. trachomatis and N. gonorrhoeae infections Type of nucleic acid amplified Nucleic-acid targets Differences in method of amplification PCR (Roche COBAS AMPLICOR) SDA (BD ProbeTec TM ET) TMA (Gen-Probe APTIMA -Combo 2) DNA DNA Ribosomal RNA (rrna) CT: omp1 gene on cryptic plasmid GC: Cytosine methyl transferase gene (M:Ngo P11) or pilin gene Primer binds to DNA gene sequence, which is subsequently amplified. Oligonucleotide probe binds to the DNA copies (amplicons), which are ultimately detected using a spectrophotometer. CT: omp1 gene on cryptic plasmid GC: pilin gene Uses isothermal technique, which reduces non-specific binding of primers. Primer binds to double helix and displaces one of the strands prior to amplification. Amplified gene sequences are ultimately detected by fluorescent probes. Advantages First NAATs available Isothermal technique is thought to allow more efficient amplification and therefore improve sensitivity Disadvantages Lower specificity due to cross-reactivity with genes in non-gonococcal species (N. meningiditis) Lower sensitivity as there are only a few copies of target DNA per cell Amplification inhibitors cause false negatives Difficulties with reproducibility and quality control Lower specificity due to cross-reactivity with genes of related species (particularly for Neisseria spp.) Amplification inhibitors cause false negatives CT: 23S subunit of rrna GC: 16S subunit of rrna Only available NAATs, which amplifies RNA. Has a novel target capture step where the primer-bound nucleic acid target binds to a magnet prior to amplification, allowing substrate inhibitors to be cleansed from the sample. Amplified target is detected using two distinct light-producing labels. Best reproducibility profile of the available NAATs Minimal problems with false positives due to crossreactivity with genes from similar organisms (particularly Neisseria spp.) Target capture step essentially eliminates inhibitors, thereby improving sensitivity At least 2000 copies of r-rna are present in each bacterium (in contrast to only a few copies of the DNA targets), leading to production of billions of copies of target RNA, thereby improving sensitivity Abbreviations: PCR=polymerase chain reaction, SDA=strand displacement amplification, TMA=transcription mediated amplification

8 50 대한요로생식기감염학회지 : 제 3 권제 1 호 2008 년 4 월 Table 6. Comparison of bacterial culture and nucleic acid amplification test (NAATs) for the diagnosis of C. trachomatis and N. gonorrhoeae infections Advantages Disadvantages Culture Nearly perfect specificity Ability to retain the isolate to perform antimicrobial susceptibility testing and isolate subtyping Technique is labor-intensive, difficult to standardize and expensive Long turn-around time (24 to 72 hours) Relatively poor sensitivity (particularly for CT, as it is an obligate intracellular bacterium) Decreased sensitivity if organism viability is compromised or if specimen transport, storage conditions are inadequate Decreased sensitivity in the setting of a low bacterial load NAATs Do not require viable organisms for detection A single NAATs can detect CT and GC simultaneously High sensitivity, as nucleic acid can be amplified from a single organism Rapid processing (result is available often in 4 to 5 hours) Can be performed on non-invasively performed specimens (urine, self-collected vaginal swabs, self-collected rectal swabs) Specificity may be decreased due to sample contamination if strict qualitycontrol measures are not implemented Decreased specificity due to crossreactivity with genes from related species (particularly for GC) Decreased sensitivity due to amplification inhibitors seen with specific NAATs (e.g., PCR, SDA) DNA-based NAATs have decreased sensitivity due to low numbers of target DNA in each bacterium Certain NAATs have difficulties with reproducibility (e.g., SDA) 비록 NAATs가정확도면에서여러가지장점을가지고있고높은유병률을가진집단에서는비용대비효과가크다고할수있지만, 검사비가비싸고검사를위해서는숙련된기술을필요로한다. 또한많은 STIs 환자들이검사결과를확인하기위하여병원을재방문하는것을어려워하고있어정확도가좀떨어지더라도현장에서즉시결과를확인할수있는신속검사가실험실로보내지는좀더민감한검사보다선호될수있는한이유이다. 이러한신속검사는즉각적인치료를가능하게하여골반염증또는불임과같은장기적인후유증을예방하고남에게로의 STIs 전파를막을수있게한다. 또한 STIs 에대한상담과배우자에대한통보를시간지체없이그자리에서시작할수있게할수있다. 비록 Table 7. The ideal rapid test: ASSURED criteria A = Affordable S = Sensitive S = Specific U = User-friendly (simple to perform in a few steps with minimal training) R = Robust and rapid (results available in less than 30 min) E = Equipment-free D = Deliverable to those who need them 신속검사가실험실검사에비해그민감도가낮지만실제로실험실검사를받고도결과확인과치료를위한재방문을하지못한환자들이많다는사실을고려하면오히려 STIs 관리에더유리하다는보고들

9 이승주 : 성매개감염의혁신적인진단법 51 도있다. 19,20 신속검사의비교적낮은민감도때문에이검사가과연언제유용한지에대한논란이있을수있으며, 어떤검사를선택하느냐는결국각각의 STIs 관리프로그램또는공중보건프로그램에따라결정해야할문제이다. 21 많은 STIs 신속검사가상업적으로판매되고있지 만, 이들검사에대한평가는아직잘이루어지지못하고있다. 다만세계보건기구산하의 Sexullay Transmitted Diseases Diagnostic Initiative (SDI) 에서 ASSURED criteria라는일정기준을정해놓고일부신속검사에대한평가를시행하여발표하고있다 (Table 7). 이기준에의하면이상적신속검사는적 Table 8. Rapid tests for the diagnosis of sexually transmitted infections and vaginosis Condition Type Target Specimens Chlamydia trachomatis infection Neisseria gonorrhoeae infection ICS or optical immunoassays Antigen Urethral, cervical swabs Gram stain Morphology Urethral, cervical swabs ICS or optical immunoassays Antigen Urethral, cervical swabs Trichomonas Wet mount Motile Vaginal secretions Vaginalis infection Bacterial vaginosis Syphilis Herpes simplex virus type 2 ICS Gram stain Trichomonad antigen Gram-negative rods Vaginal swab Vaginal swab Sensitivity (%) Specificity (%) Comments Performance compared with NAATs or culture; some kits can be used with concentrated urine from men >90, M 45 65, F >95, M 90 95, F Performance compared with culture; requires microscope and technical expertise Performance compared with culture; some kits can be used with concentrated urine from men Performance compared with culture; requires microscope Performance compared with culture and wet mount NA* NA* Requires microscope; scoring standardised (Nugent score) Wet mount Clue cells Vaginal fluid Performance compared with Nugent score; requires microscope Card test ph and proline aminopeptidase Vaginal Swab ICS Sialidase Vaginal swab Non-treponemal-s pecific tests Treponemalspecific tests Dark field microscopy Performance compared with Nugent score; 40 59% sensitivity, 92 95% specificity against ph and amine test Performance compared with Gram stain Antibody Serum Reagent requires refrigeration; requires centrifuge to separate serum and rotator Antibody Motile spirochaete Serum, plasma or whole blood Lesion material Do not distinguish between current and past infection < Requires microscope; low sensitivity owing to prior application of antiseptic or antibiotic treatment ICS Antibody Serum Performance compared with culture for sensitivity and immunoblot for specificity ICS; immunochromatographic strip, M; male, F; female *: Performance uncertain in the absence of consensus reference standard

10 52 대한요로생식기감염학회지 : 제 3 권제 1 호 2008 년 4 월 당한가격에, 적절한민감도와특이도를갖추고, 사용하기편하면서, 신속하고다른설비없이검사가가능하며, 원하는검사자까지쉽게전달할수있어야한다는것이다. 표 8에현재사용가능한신속검사들을그특징과함께나열하였다. 1) C. trachomatis and N. gonorrhoeae를위한신속검사임균진단을위한신속검사는과거로부터많이사용되어오던요도도말검체를이용한그람염색법을비롯하여임균의항원을검출하는면역분석법들이있다. 21 C. trachomatis 검출을위한신속검사역시항원검출의방법으로개발되어왔고, 높은친화력의항체를고정시킨 nitrocellulose strip을통해항원을검출한다. 환자의검체속에있는세균의항원은 strip의항체와결합하게되고이는색깔을가진선으로나타난다. 플라스틱용기에포장되면신속검사키트로사용할수있으며, 다른검사장비없이 30분이내에결과를확인할수있게된다. 대부분의제조회사들이높은민감도와특이도를주장하고있지만그들이말하는정확도가대조시험을통해검증된바없으며, SDI는 NAATs와비교하여민감도는 50 70%, 특이도는 91 98% 정도라고발표하고있다. 만약질도말검체를사용할경우민감도는 40% 이하로감소한다. 22,23 수있는가정용검사키트가개발되어흥미를끌고있다. 마지막석달을맞이한임산부가사용할경우조산의위험도를알아볼수있다는장점을가지고있으며, 장갑형태로되어있는검사키트의끝부분에 ph 지시계가삽입되어있어 1주일에 2번정도질내 ph 변화를측정하도록설명되어있다. 3) 매독을위한신속검사매독의검사는전통적으로 VDRL이나 RPR과같은 non-treponemal 검사와 TPHA와같은 treponemal 검사를동시에실시하여확진하여왔다. 최근전혈을이용하고, 실온에서보관이가능하며다른장비가필요없는간단한신속검사들이소개되어판매되고있다. 28 이중몇몇신속검사키트들은 SDI에의해평가되었는데, 표준적인 treponemal 검사에비해민감도와특이도가각각 85 98% 와 92 98% 로나타났다. 29 이들신속검사는 treponemal 특이항체를검사하는것으로 treponemal 특이항체가치료후에도지속되는성질때문에현성감염과과거감염을구별하지못하는단점이있다. 여러후진국에서는아직도임산부의매독이출생전후기신생아사망의주요원인이되고있는실정에서이러한매독신속검사의보급은이들국가에서선천성매독을예방할수있는중요한수단이될수있을것이다. 30 2) 질분비물을가진환자를위한신속검사원래질염의진단은숙련된병리기사의현미경소견만으로도간단하고신속하게시행할수있다. T. vaginalis를위한습식표본검사와질분비물의산성도, 그리고 amines 검출을위한 Whiff 검사와 clue cell의관찰이세균성질염진단의표준으로여겨져왔다. 또한그람염색도말검사에서의 lactobacilli의비율을측정하여 Amsel criteria나 Nugent score에적용시켜진단할수있다. 24,25 최근에는 T. vaginalis의항원을측정할수있는카드형태또는 immunochromatographic strips 형태로된신속검사가개발되었다. 26,27 이러한신속검사키트는그사용은편리하지만아직정확도의평가가부족한상태이다. 이외에도질의산성도를측정할 4) 생식기헤르페스를위한신속검사생식기헤르페스를일으키는 Herpes simplex virus 제2형의항체에대한신속검사가상품화되어있다. 31 하지만대부분의국가에서아직헤르페스감염에대한관리정책을가지고있지않고, 완치할수있는치료방법도없는상태에서이러한신속검사가질병관리의측면에서유용한지는확실치않다. 결론세계보건기구는완치가능한세균성 STIs가매년 3억 4천만건이상발생한다고추정하고있으며, 이중클라미디아는 9천 2백만건, 임균은 6천 2백만

11 이승주 : 성매개감염의혁신적인진단법 53 건, 매독은 1천 2백만건, 트리코모나스증은 1억 7 천 4백만건이다. 문제는이들의 90% 이상이 STIs 검사를제공받을수없거나검사가극히제한된상태에있다는것이다. STIs의관리나예방을위해서는진단검사가중요하다. 대부분의 STIs 감염자들은증상이없는무증상상태이거나증상이아주경하기때문에검사와치료를받지못할때만성골반통, 골반염증, 자궁외임신, 자궁암등의심각한후유증을야기할수있다. 이러한관점에서볼때, 최근 STIs 진단의혁신으로소개되고있는 NAATs와신속검사는감염자들에게조기진단과치료를가능하게하는중요한수단이될것이다. 하지만 NAATs는그우수한민감도에도불구하고몇가지문제점들을가지고있고, 신속검사의대부분도아직그정확도와효과가검증되지않은부분이많아오히려오진을유발하여그로인한비용증가를초래할위험을가지고있다. 따라서 STIs 검사를이용할때는이러한점들을고려하여최선의방법을선택하여야할것이다. REFERENCES 1. Cook RL, Hutchison SL, Østergaard L, Braithwaite RS, Ness RB. Systematic review: noninvasive testisng for Chlamydia trachomatis and Neisseria gonorrhoeae. Ann Intern Med 2005;142: Peeling RW, Holmes KK, Mabey D, Ronald A. Rapid tests for sexually transmitted infections (STIs): the way forward. Sex Transm Infect 2006;82 (Suppl 5):v Morse SA, Ballard RC, Holmes KK, Moreland AA. Atlas of sexually transmitted diseases and AIDS. 3rd ed. Edinburgh: Mosby; 2003; Candotti D, Temple J, Owusu-Ofori S, Allain JP. Multiplex real-time quantitative RT-PCR assay for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus type 1. J Virol Methods 2004; 118: Klausner JD, McFarland W, Bolan G, Hernandez MT, Molitor F, Lemp GF, et al. Knock-knock: population-based survey of risk behavior, health care access and Chlamydia trachomatis infection among low-income women in the San Francisco Bay Area. J Infect Dis 2001;183: Schachter J, McCormack WM, Chernesky MA, Martin DH, Van Der Pol B, Rice PA, et al. Vaginal swabs are appropriate specimens for diagnosis of genital tract infection with Chlamydia trachomatis. J Clin Microbiol 2003;41: Kent C, Branzuela A, Fischer-Ponce L, Bascom T, Klausner JD. Chlamydia and gonorrhea screening in San Francisco high schools. Sex Transm Dis 2002; 29: Gaydos CA, Howell MR, Pare B, Clark KL, Ellis DA, Hendrix RM, et al. Chlamydia trachomatis infections in female military recruits. N Engl J Med 1998;339: Bloomfield PJ, Kent C, Campbell D, Hanbrook L, Klausner JD. Community-based chlamydia and gonorrhea screening through the United States mail, San Francisco. Sex Transm Dis 2002;29: Lee SJ, Cho YH, Kim CS, Shim BS, Cho IR, Chung JI, et al. Screening for Chlamydia and gonorrhea by strand displacement amplification in homeless adolescents attending youth shelters in Korea. J Korean Med Sc 2004;19: Lee SJ, Cho YH, Ha US, Kim SW, Yoon MS, Bae K. Sexual behavior survey and screening for chlamydia and gonorrhea in university students in South Korea. Int J Urol 2005;12: Fredlund H, Falk L, Jurstrand M, Unemo M. Molecular genetic methods for diagnosis and characterisation of Chlamydia trachomatis and Neisseria gonorrhoeae: impact on epidemiological surveillance and interventions. APMIS 2004;112: Katz AR, Effler PV, Ohye RG, Brouillet B, Lee MVC, Whiticar PM. False-positive gonorrhea test results with a nucleic acid amplification test: the impact of low prevalence on positive predictive value. Clin Infect Dis 2004;38: Zenilman JM, Miller WC, Gaydos C, Rogers SM, Turner CF. LCR testing for gonorrhoea and chlamydia in population surveys and other screenings of low prevalence populations: coping with decreased positive predictive value. Sex Transm Infect 2003;79: Verkooyen RP, Luijendijk A, Huisman WM, Goessens WH, Kluytmans JA, van Rijsoort-Vos JH, et al.

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