WEB ANNEX E. SYSTEMATIC REVIEW FOR SYNDROMIC MANAGEMENT OF GENITAL ULCER DISEASE GUIDELINES FOR THE MANAGEMENT OF SYMPTOMATIC SEXUALLY TRANSMITTED INFECTIONS JUNE 2021 WEB ANNEX E. SYSTEMATIC REVIEW FOR SYNDROMIC MANAGEMENT OF GENITAL ULCER DISEASE JUNE 2021 GUIDELINES FOR THE MANAGEMENT OF SYMPTOMATIC SEXUALLY TRANSMITTED INFECTIONS Guidelines for the management of symptomatic sexually transmitted infections: Web Annex E. Systematic review for syndromic management of genital ulcer disease ISBN 978-92-4-003482-2 (electronic version) © World Health Organization 2021 Some rights reserved. This work is available under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/ licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. 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The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. This publication forms part of the WHO guideline entitled Guidelines for the management of symptomatic sexually transmitted infections. It is being made publicly available for transparency purposes and information, in accordance with the WHO handbook for guideline development, 2nd edition (2014). Design and layout by 400 Communications. iii CONTENTS 1. Introduction 1 2. Methods 2 3. Results 5 3.1 PRISMA flow chart for genital ulcer syndromes 5 3.2 Genital ulcer disease 6 3.3 Risk of bias assessment using QUADAS-2 26 4. References 40 5. Appendix A – Search Results 48 5.1 Genital ulcers syndromes 48 11. INTRODUCTION Sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), continue to present significant health, social, and economic problems in the developing world, leading to considerable morbidity, mortality, and stigma. In under-resourced settings, the lack of adequate laboratory infrastructure and/or high prohibitive costs of diagnostics means that in many settings, STI management relies on syndromic management rather than aetiological diagnosis and management. In these settings, the detection of asymptomatic STIs is largely non-existent. Therefore, synthesizing the latest evidence for the performance of syndromic STI case management would help the World Health Organization (WHO) in their guideline recommendations for syndromic STI management, last updated in 2003.[1] To evaluate if there is still a role for syndromic STI management or whether STI diagnostics are critical for STI case management, we systematically reviewed the evidence for the performance of syndromic management of STIs. Specifically, we conducted reviews on the diagnostic accuracy and aetiologies of syndromic case management of genital ulcer, anorectal infection and lower abdominal pain. Our specific objectives were to review the flowcharts used for: • people presenting with genital ulcer disease to detect herpes simplex virus (HSV) or syphilis or lymphogranuloma venereum (LGV) or chancroid, or if no flowcharts found, a minor review of test accuracy of different tests, or risk association/prevalence. • people presenting with the anorectal syndrome to detect anal STIs or if no flowcharts found, a major review of test accuracy of different tests, or risk association/prevalence. • people presenting with lower abdominal pain to detect pelvic inflammatory disease (PID) or vaginal or cervical infections, or if no flowcharts found, a major review of test accuracy of different tests, or risk association/prevalence. 22. METHODS Study inclusion • Clinical guidelines/algorithms – Flow charts for genital ulcer (for syphilis, HSV, LGV, chancroid), anorectal syndromes (for Ct/Ng/ Mg/LGV/HSV/Tp/Donovanosis), lower abdominal pain (for PID, vaginal/cervical infections), and vaginal discharge • Randomized controlled trials • Observational studies • Report on at least one of: – Comparing syndromic case management against laboratory-confirmed STIs – Risk factor analysis of signs/symptoms associated with STI diagnoses and other risk factors associated with STI syndromes Study exclusion • Contains no original data i.e. systematic reviews/Letter/editorials/Commentaries/Book chapters – But can use these to identify other relevant primary studies • Qualitative research about outcomes • Duplicated results from another study • Laboratory studies about testing STI diagnostic performance • Studies restricting study population, e.g. men with urethritis, women with cervicitis Search method Three separate searches were conducted: one for each of the syndromes under investigation. We included papers that focused on other aspects of syndromic management (i.e. acceptability, feasibility, equity, resources) in addition to the accuracy or sensitivity of the syndromic management approach. The search for each syndrome has been constructed as below. • Concept 1: syndromic management • Concept 2: syndrome under investigation • Concept 3: diagnostic accuracy and sensitivity papers • Results group 1: concept 1 AND concept 2 AND concept 3 • Results group 2: (concept 1 AND concept 2) NOT Results group 1 32. Methods A draft search strategy was compiled in the OvidSP Medline database by an experienced information specialist. The search strategy included strings of terms, synonyms and controlled vocabulary terms (where available). As the syndromic management approach was not introduced until 1996, the search was limited to papers published in 1995 or after. No other limits were added. This search strategy was refined with the project team until the results retrieved reflected the scope of the project. The agreed OvidSP Medline search was adapted for each database to incorporate database-specific syntax and controlled vocabularies. Full details of the search strings used for each database can be found in the appendix. A The following databases were searched on 12 and 13 September 2019. • Ovid SP Medline and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, 1946 to September 11, 2019 • OvidSP Embase, 1974 to 11 September 2019 • OvidSP Global Health, 1910 to week 35, 2019 • OvidSP Northern Light Life Sciences Conference Abstracts, 2010 to Week 34, 2019 • Ebsco CINAHL Plus, complete database • Ebsco Africa-Wide Information, complete database • Clarivate Analytics Web of Science Core Collection, consisting of the following databases: – Science Citation Index Expanded (SCI-EXPANDED), 1970 - present – Social Sciences Citation Index (SSCI), 1970 - present – Arts & Humanities Citation Index (A&HCI), 1975 - present – Conference Proceedings Citation Index - Science (CPCI-S), 1990 - present – Conference Proceedings Citation Index - Social Science & Humanities (CPCI-SSH), 1990 - present – Emerging Sources Citation Index (ESCI), 2015 – present • BIREME/PAHO/WHO Virtual Health Library LILACS, complete database All citations identified by our searches were imported into EndNote X9 software. Duplicates were identified and removed using the method described on the LAS blog.1 Data extraction We followed the guidelines in the Cochrane Handbook 5.1.[2] Three groups of two independent reviewers screened the title and abstracts of unduplicated papers. Discrepancies in screening were resolved by a third reviewer (JO). Each team extracted relevant data from deduplicated full publications. Risk of bias assessment was conducted using the Joanna Briggs Institute Checklist for diagnostic studies.[3] 1 Falconer, Jane, Removing duplicates from an EndNote library. Library & Archives Service Blog: London School of Hygiene & Tropical Medicine. 2018. [online blog] http://blogs.lshtm.ac.uk/library/2018/12/07/removing-duplicates-from-an-endnote-library/. 4 Web Annex E. Systematic review for syndromic management of genital ulcer disease Statistical analysis Diagnostic accuracy cannot be summarized by one measure as sensitivity and specificity are correlated. Therefore, we must choose hierarchical (multilevel) models that use a binomial data structure, i.e. we use a hierarchical logistic regression model in STATA 13.1. After pooling the studies, we report the sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratio. The inverse of the negative likelihood ratio (1/LR-) can be used to compare with the positive likelihood ratio to indicate whether the positive or negative test result has a greater impact on the odds of disease. Likelihood ratios assess the probability or likelihood that the test result obtained would be expected in a person with the condition, compared to the probability or likelihood that the same result would be seen in a person without the condition. The positive likelihood ratio LR+ sensitivity (1–speci city) = TP (TP+FN) = FP (FP+TN) ÷ expresses how many times more likely people with the condition are to receive a positive test result compared to those who do not have the condition, while the negative likelihood ratio LR– (1–sensitivity) (speci city) = FN (TP+FN) = TN (FP+TN) ÷ expresses how likely it is that people with the condition will receive a negative test result compared to those who do not have the condition. To graphically display the trade-off between sensitivity and specificity, we present the summary receiver operating characteristic (SROC) curve from the hierarchical summary receiver operating characteristic (HROC) model [4] and prediction region (i.e. for the forecast of the true sensitivity and specificity in a future study). We also plot the summary operating point and its confidence region. Forest plots for showing within-study estimates and confidence intervals for sensitivity and specificity separately. In the meta-analyses below, we have only included papers where we could calculate the numbers of true positive, false positives, true negatives and false negatives. For the other papers without this data, we have summarized their results qualitatively (i.e. without pooling). [12] McGee, Steven (1 August 2002). "Simplifying likelihood ratios". Journal of General Internal Medicine. 17 (8): 647–650. doi:10.1046/j.1525-1497.2002.10750.x. ISSN 0884-8734. PMC 1495095. PMID 12213147. [13] Henderson, Mark C.; Tierney, Lawrence M.; Smetana, Gerald W. (2012). The Patient History (2nd ed.). McGraw-Hill. p. 30. ISBN 978-0-07-162494-7. 53. RESULTS 3.1 PRISMA flow chart for genital ulcer syndromes In cl ud ed El ig ib ili ty Sc re en in g Id en tifi ca tio n Records identified through database searching (n = 14,190) Records after duplicates removed (n = 9,904) Titles/Abstracts screened (n = 9,904) Full-text articles assessed for eligibility (n = 151) Records excluded for irrelevant content (n = 9,753) Studies included in analysis (n = 68) Full-text articles excluded (n = 83) 68 No information about syndrome 9 No primary data 6 paper not found 6 Web Annex E. Systematic review for syndromic management of genital ulcer disease 3.2 Genital ulcer disease • Country income level – 3/68 (4%) High income – 23/68 (34%) Upper Middle – 25/68 (37%) Lower Middle – 15/68 (22%) Low • Study population recruited from (may not add up to 100% because of multiple recruitment sites) – 33/68 (49%) Sexual health clinics – 22/68 (32%) Community setting (incl. bar, discos, CBOs) – 14/68 (21%) Hospital • Year of study – 54/68 (79%) 2009 and before – 9/68 (13%) 2010-2014 – 5/68 (7%) 2015 and after 73. Results Fo r d et ec tio n of a ny S TI s, fo ur s tu di es p ro vi de d fo ur e st im at es fo r p oo lin g: tw o st ud ie s ev al ua tin g th e ac cu ra cy o f G U D to d et ec t a ny S TI s, a nd tw o st ud ie s ev al ua tin g th e ac cu ra cy o f c lin ic al d ia gn os is o f a ny S TI s fo r a p op ul at io n w ith G U D. T he re w er e to o fe w s tu di es to c on du ct a m et a- an al ys is . De te ct io n of a ny S TI s fo r g en ita l u lc er s yn dr om e (s ha de d ro ws re pr es en ts s tu di es te st in g pr es en ce o f u lc er to de te ct a ny S TI s) St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a po si ti ve ca se de fin ed Pa th og en s D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Da s[ 5] 20 13 In di a Lo w m id dl e 29 7 ST I a nd gy na ec ol og y ou tp at ie nt s 22 % m al e 12 % G U D Pr es en ce o f ul ce r HS V, C G, CM V, T P VD RL , T PH A, Sm ea r, HS V- Ab 14 21 5 27 41 Li u[ 6] 20 03 Ch in a U pp er m id dl e 55 Se xu al h ea lth cl in ic 10 0% m al e 14 % G U D Pr es en ce o f ul ce r HS V, T P, HD PC R, R PR , TP PA 13 0 40 2 Sa nc he z[ 7] 19 95 -6 Do m in ic an Re pu bl ic U pp er m id dl e 81 G en er al pr ac tic e 10 0% m al e 10 0% G U D Sy m pt om s + ex am in at io n HS V, T P, HD M -P CR 13 12 28 28 Sa nc he z[ 7] 19 95 -6 Pe ru U pp er m id dl e 63 G en er al pr ac tic e 10 0% m al e 10 0% G U D Sy m pt om s + ex am in at io n HS V, T P, HD M -P CR 2 7 29 25 8 Web Annex E. Systematic review for syndromic management of genital ulcer disease For detecting herpes from a clinical diagnosis of herpes, 15 studies provided 20 estimates for pooling. The pooled sensitivity for detecting herpes using a syndromic management approach is 40.4% (95% CI: 23.0-60.6), and pooled specificity is 88.0% (95% CI: 75.3-94.6). The diagnostic odds ratio is 4.95 (95% CI: 3.37-7.28). The positive likelihood ratio is 3.35 (95% CI: 2.27-4.97), and the negative likelihood ratio is 0.68 (95% CI: 0.53-0.86). The inverse negative likelihood ratio is 1.48 (95% CI: 1.16-1.88). For a cohort of 1000 individuals: Prevalence Sensitivity Specificity PPV NPV Number of cases Missed cases False Positive (Overtreated) 0.05 0.404 0.88 0.151 0.966 50 30 114 0.1 0.404 0.88 0.272 0.930 100 60 108 0.15 0.404 0.88 0.373 0.893 150 89 102 0.2 0.404 0.88 0.457 0.855 200 119 96 0.25 0.404 0.88 0.529 0.816 250 149 90 0.3 0.404 0.88 0.591 0.775 300 179 84 0.35 0.404 0.88 0.644 0.733 350 209 78 0.4 0.404 0.88 0.692 0.689 400 238 72 0.45 0.404 0.88 0.734 0.643 450 268 66 0.5 0.404 0.88 0.771 0.596 500 298 60 0.55 0.404 0.88 0.804 0.547 550 328 54 0.6 0.404 0.88 0.835 0.496 600 358 48 0.65 0.404 0.88 0.862 0.443 650 387 42 0.7 0.404 0.88 0.887 0.388 700 417 36 0.75 0.404 0.88 0.910 0.330 750 447 30 0.8 0.404 0.88 0.931 0.270 800 477 24 0.85 0.404 0.88 0.950 0.207 850 507 18 0.9 0.404 0.88 0.968 0.141 900 536 12 0.95 0.404 0.88 0.985 0.072 950 566 6 1 0.404 0.88 1.000 0.000 1000 596 0 93. Results Se ns iti vi ty Specificity Study estimate 1 0 .8 .6 .4 .2 0 .2 .4 .6 .8 1 Summary point HSROC curve 95% confidence region 95% prediction region 10 Web Annex E. Systematic review for syndromic management of genital ulcer disease Co m pa rin g th e ac cu ra cy o f c lin ic al d ia gn os is o f h er pe s wi th th e ae tio lo gi ca l d ia gn os is o f h er pe s St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Be he ts [8 ] 19 97 M ad ag as ca r Lo w 19 6 Se xu al h ea lth cl in ic 71 % m al e Cl in ic al d ia gn os is * M -P CR 0 19 2 17 5 Be he ts [9 ] 19 96 Ja m ai ca U pp er m id dl e 30 4 Se xu al H ea lth cl in ic 83 % m al e Cl in ic al d ia gn os is * M -P CR 85 73 24 12 2 Be yr er [1 0] 19 95 -6 Th ai la nd U pp er m id dl e 38 Se xu al h ea lth cl in ic 79 % fe m al e se x w or ke rs Cl in ic al d ia gn os is * M -P CR 21 11 3 3 Bh av sa r [1 1] 20 11 -1 2 In di a Lo w m id dl e 96 Ho sp ita l 79 % m al e Cl in ic al d ia gn os is * Tz an ck s m ea r Ig M fo r H SV -2 33 0 38 25 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Hi st or y an d ex am in at io n Cy to pa th ic ef fe ct o n Ve ro ce lls 4 85 4 30 2 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Hi st or y an d ex am in at io n + s yp hi lis s er ol og y or da rk fie ld m ic ro sc op y Cy to pa th ic ef fe ct o n Ve ro ce lls 4 85 4 30 2 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Cl in ic al d ia gn os is * Cy to pa th ic ef fe ct o n Ve ro ce lls 43 46 87 21 9 Di Ca rlo [1 3] 19 90 - 19 92 U SA Hi gh 22 0 Se xu al h ea lth cl in ic 10 0% m en Cl in ic al d ia gn os is * Cu ltu re 20 37 10 15 3 Hi na [1 4] 20 15 -1 6 In di a Lo w m id dl e 96 Se xu al h ea lth cl in ic 75 % m al es Cl in ic al d ia gn os is * Tz an ck s m ea rs , HS V2 -Ig M 33 2 36 25 Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R 7 10 1 74 Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R 5 19 3 65 113. Results St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R 0 24 0 68 Pr ab ha ka r [1 6] 20 08 -9 In di a Lo w m id dl e 18 1 Se xu al h ea lth cl in ic 10 0% m al e Cl in ic al d ia gn os is * M -P CR 59 31 37 54 Ri sb ud [1 7] 19 94 In di a Lo w m id dl e 30 2 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M -P CR 48 47 32 17 5 Sa nc he z[ 7] 19 95 -6 Do m in ic an Re pu bl ic U pp er m id dl e 81 G en er al pr ac tic e 10 0% m al e Cl in ic al d ia gn os is * M -P CR 19 16 10 36 Sa nc he z[ 7] 19 95 -6 Pe ru U pp er m id dl e 63 G en er al pr ac tic e 10 0% m al e Cl in ic al d ia gn os is * M -P CR 15 12 17 19 W an g[ 18 ] 19 98 -9 9 Ch in a U pp er m id dl e 96 Se xu al h ea lth cl in ic 52 % m al es Cl in ic al d ia gn os is * M -P CR 25 8 36 27 W an g[ 19 ] 20 00 -1 Ch in a U pp er m id dl e 22 7 Se xu al h ea lth cl in ic 90 % m al e Cl in ic al d ia gn os is * M -P CR 49 22 78 78 Fa st [2 0] 19 80 Ke ny a Lo w m id dl e 70 “S pe ci al tr ea tm en t cl in ic ” 10 0% m al e Cl in ic al d ia gn os is * Cu ltu re 3 3 1 63 Da ng or [2 1] U nc le ar So ut h Af ric a U pp er m id dl e 21 0 Ho sp ita l 10 0% m al e Cl in ic al d ia gn os is * Cu ltu re 5 2 21 18 2 *“ D ia gn os tic te st ” is c lin ic ia n’ s di ag no si s of h er pe s (r at he r t ha n th e pr es en ce o f u lc er ) – C lin ic al d ia gn os is is b as ed o n ph ys ic al e xa m in at io n an d hi st or y 12 Web Annex E. Systematic review for syndromic management of genital ulcer disease For detecting herpes from the presence of a genital ulcer, seven studies provided ten estimates for pooling. The pooled sensitivity for detecting herpes using a syndromic management approach is 42.2% (95% CI: 10.9-81.3), and pooled specificity is 91.0% (95% CI: 65.9-98.1). The diagnostic odds ratio is 7.38 (95% CI: 1.29-42.09). The positive likelihood ratio is 4.69 (95% CI: 1.22-18.01), and the negative likelihood ratio is 0.64 (95% CI: 0.32-1.27). The inverse negative likelihood ratio is 1.57 (95% CI: 0.79-3.15). For a cohort of 1000 individuals: Prevalence Sensitivity Specificity PPV NPV Number of cases Missed cases False Positive (Overtreated) 0.05 0.422 0.91 0.198 0.968 50 29 86 0.1 0.422 0.91 0.343 0.934 100 58 81 0.15 0.422 0.91 0.453 0.899 150 87 77 0.2 0.422 0.91 0.540 0.863 200 116 72 0.25 0.422 0.91 0.610 0.825 250 145 68 0.3 0.422 0.91 0.668 0.786 300 173 63 0.35 0.422 0.91 0.716 0.745 350 202 59 0.4 0.422 0.91 0.758 0.703 400 231 54 0.45 0.422 0.91 0.793 0.658 450 260 50 0.5 0.422 0.91 0.824 0.612 500 289 45 0.55 0.422 0.91 0.851 0.563 550 318 41 0.6 0.422 0.91 0.876 0.512 600 347 36 0.65 0.422 0.91 0.897 0.459 650 376 32 0.7 0.422 0.91 0.916 0.403 700 405 27 0.75 0.422 0.91 0.934 0.344 750 434 23 0.8 0.422 0.91 0.949 0.282 800 462 18 0.85 0.422 0.91 0.964 0.217 850 491 14 0.9 0.422 0.91 0.977 0.149 900 520 9 0.95 0.422 0.91 0.989 0.077 950 549 4 1 0.422 0.91 1.000 0.000 1000 578 0 133. Results Se ns iti vi ty Specificity Study estimate 1 0 .8 .6 .4 .2 0 .2 .4 .6 .8 1 Summary point HSROC curve 95% confidence region 95% prediction region 14 Web Annex E. Systematic review for syndromic management of genital ulcer disease Co m pa rin g th e ac cu ra cy o f t he p re se nc e of G UD w ith th e ae tio lo gi ca l d ia gn os is o f h er pe s St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re r ec ru it ed Su b- po pu la ti on H ow is a po si ti ve ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Ch ou dh ry [2 2] 20 07 -8 In di a Lo w m id dl e 30 0 Se xu al h ea lth c lin ic 64 % m al e 16 % M SM Cl in ic al di ag no si s* G ra m s ta in , HS V- Ig M 57 12 3 22 8 Cl ar k[ 23 ] 20 03 -5 Pe ru U pp er m id dl e 32 85 Co m m un ity s et tin g 73 % h et er os ex ua l m en 16 % M SM Cl in ic al di ag no si s* HS V2 -A b 78 77 0 16 2 22 75 Li u[ 6] 20 03 Ch in a U pp er m id dl e 55 Se xu al h ea lth c lin ic 67 % m al e 7. 5% G U D Pr es en ce o f ul ce r PC R 15 0 38 2 M ur al id ha r [2 4] 20 13 In di a Lo w m id dl e 12 08 Se xu al h ea lth c lin ic 10 0% he te ro se xu al s 25 .4 % G U D Cl in ic al di ag no si s* G ie m sa s ta in , PC R, H SV 2- Ig M 76 6 5 11 21 O ’F ar re ll [2 5] 20 07 So ut h Af ric a U pp er m id dl e 64 2 Se xu al h ea lth c lin ic 50 % m al es 7% G U D Sy m pt om s + ris k fa ct or s HS V2 -A b 14 0 34 7 22 13 3 O tie no [2 6] 20 07 -9 Ke ny a Lo w m id dl e 78 6 En ro lle d in g en er al po pu la tio n st ud y 10 0% fe m al es liv in g w ith H IV Cl in ic al di ag no si s* HS V2 -Ig G 0 14 14 79 6 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 6 Ho sp ita l 10 0% m al es li vi ng w ith H IV Se lf- re po rt ed sy m pt om s HS V- 2 se ro lo gy 61 26 2 5 38 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 6 Ho sp ita l FS W Se lf- re po rt ed sy m pt om s HS V- 2 se ro lo gy 55 7 23 4 69 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 6 Ho sp ita l M SM Se lf- re po rt ed sy m pt om s HS V- 2 se ro lo gy 20 64 7 23 4 69 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 6 Ho sp ita l Se lf- re po rt ed sy m pt om s HS V- 2 se ro lo gy 37 29 9 22 34 5 *C lin ic al d ia gn os is is b as ed o n ph ys ic al e xa m in at io n an d hi st or y 153. Results To detect syphilis using a clinical diagnosis of syphilis among individuals with GUD, 15 studies provided 22 estimates for pooling. The pooled sensitivity for detecting syphilis is 64.4% (95% CI: 44.8-80.2), and pooled specificity is 83.7% (95% CI: 67.0-92.9). The diagnostic odds ratio is 9.32 (95% CI: 4.35-20.00). The positive likelihood ratio is 3.96 (95% CI: 2.08-7.54), and the negative likelihood ratio is 0.42 (95% CI: 0.27-0.66). The inverse of the negative likelihood ratio is 2.35 (95% CI: 1.52-3.65). For a cohort of 1000 individuals: Prevalence Sensitivity Specificity PPV NPV Number of cases Missed cases False Positive (Overtreated) 0.05 0.644 0.837 0.172 0.978 50 18 155 0.1 0.644 0.837 0.305 0.955 100 36 147 0.15 0.644 0.837 0.411 0.930 150 53 139 0.2 0.644 0.837 0.497 0.904 200 71 130 0.25 0.644 0.837 0.568 0.876 250 89 122 0.3 0.644 0.837 0.629 0.846 300 107 114 0.35 0.644 0.837 0.680 0.814 350 125 106 0.4 0.644 0.837 0.725 0.779 400 142 98 0.45 0.644 0.837 0.764 0.742 450 160 90 0.5 0.644 0.837 0.798 0.702 500 178 82 0.55 0.644 0.837 0.828 0.658 550 196 73 0.6 0.644 0.837 0.856 0.611 600 214 65 0.65 0.644 0.837 0.880 0.559 650 231 57 0.7 0.644 0.837 0.902 0.502 700 249 49 0.75 0.644 0.837 0.922 0.439 750 267 41 0.8 0.644 0.837 0.940 0.370 800 285 33 0.85 0.644 0.837 0.957 0.293 850 303 24 0.9 0.644 0.837 0.973 0.207 900 320 16 0.95 0.644 0.837 0.987 0.110 950 338 8 1 0.644 0.837 1.000 0.000 1000 356 0 16 Web Annex E. Systematic review for syndromic management of genital ulcer disease Se ns iti vi ty Specificity Study estimate 1 0 .8 .6 .4 .2 0 .2 .4 .6 .8 1 Summary point HSROC curve 95% confidence region 95% prediction region 173. Results Co m pa rin g th e ac cu ra cy o f c lin ic al d ia gn os is o f h er pe s wi th th e ae tio lo gi ca l d ia gn os is o f h er pe s St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Be he ts [8 ] 19 97 M ad ag as ca r Lo w 19 6 Se xu al h ea lth cl in ic 71 % m al e Cl in ic al d ia gn os is * M -P CR 52 4 11 2 28 Be he ts [9 ] 19 96 Ja m ai ca U pp er m id dl e 30 4 Se xu al H ea lth cl in ic 83 % m al e Cl in ic al d ia gn os is * M -P CR 21 10 24 24 9 Be yr er [1 0] 19 95 -6 Th ai la nd U pp er m id dl e 38 Se xu al h ea lth cl in ic 79 % fe m al e se x w or ke rs Cl in ic al d ia gn os is * M -P CR 0 1 1 36 Bh av sa r [1 1] 20 11 -1 2 In di a Lo w m id dl e 96 Ho sp ita l 79 % m al e Cl in ic al d ia gn os is * VD RL , T PH A 19 24 1 52 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Hi st or y an d ex am in at io n RP R, T PH A, Da rk fie ld m ic ro sc op y 10 8 2 27 9 6 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Hi st or y an d ex am in at io n + s yp hi lis s er ol og y or da rk fie ld m ic ro sc op y RP R, T PH A, Da rk fie ld m ic ro sc op y 10 7 3 9 27 6 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Cl in ic al d ia gn os is * RP R, T PH A, Da rk fie ld m ic ro sc op y 20 90 31 25 4 Di Ca rlo [1 3] 19 90 - 19 92 U SA Hi gh 22 0 Se xu al h ea lth cl in ic 10 0% m en Cl in ic al d ia gn os is * Da rk fie ld m ic ro sc op y 14 31 3 17 2 Ha ns on [2 8] 19 96 Za m bi a Lo w m id dl e 95 Ho sp ita l 10 0% m al e Cl in ic al d ia gn os is * Da rk fie ld m ic ro sc op y, RP R, T PH A 24 17 14 40 Ha ns on [2 8] 19 96 Za m bi a Lo w m id dl e 13 1 Ho sp ita l 10 0% fe m al e Cl in ic al d ia gn os is * Da rk fie ld m ic ro sc op y, RP R, T PH A 14 22 12 83 18 Web Annex E. Systematic review for syndromic management of genital ulcer disease St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R, R PR , FT A- Ab s 5 18 1 68 Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R, R PR , FT A- Ab s 30 4 52 6 Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R, R PR , FT A- Ab s 33 1 52 6 N di ny a- Ac ho la [2 9] 19 90 -9 1 Ke ny a Lo w m id dl e 17 2 Pr im ar y ca re 47 % m al es Cl in ic al d ia gn os is * RP R 6 18 19 12 9 Pr ab ha ka r [1 6] 20 08 -9 In di a Lo w m id dl e 18 1 Se xu al h ea lth cl in ic 10 0% m al e Cl in ic al d ia gn os is * M -P CR 26 18 72 78 Sa nc he z[ 7] 19 95 -6 Do m in ic an Re pu bl ic U pp er m id dl e 81 G en er al pr ac tic e 10 0% m al e Cl in ic al d ia gn os is * M -P CR 2 2 11 66 Sa nc he z[ 7] 19 95 -6 Do m in ic an Re pu bl ic U pp er m id dl e 63 G en er al pr ac tic e 10 0% m al e Cl in ic al d ia gn os is * M -P CR 2 4 8 49 W an g[ 18 ] 19 98 -9 9 Ch in a U pp er m id dl e 96 Se xu al h ea lth cl in ic 10 0% ha d “S TI sy m pt om s” Cl in ic al d ia gn os is * M -P CR , R PR , TP PA 18 5 12 61 W an g[ 19 ] 20 00 -1 Ch in a U pp er m id dl e 22 7 Se xu al h ea lth cl in ic 90 % m al e Sy m pt om s + E xa m in at io n + R is k fa ct or s M -P CR , Da rk fie ld m ic ro sc op y, RP R, T PP A 94 12 6 11 5 Fa st [2 0] 19 80 Ke ny a Lo w m id dl e 70 “S pe ci al tr ea tm en t cl in ic ” 10 0% m al e Cl in ic al d ia gn os is * RP R, D ar kfi el d m ic ro sc op y 6 4 4 56 Da ng or [2 1] U nc le ar So ut h Af ric a U pp er m id dl e 21 0 Ho sp ita l 10 0% m al e Cl in ic al d ia gn os is * RP R, F TA -A BS , da rk fie ld m ic ro sc op y 22 3 25 16 0 *C lin ic al d ia gn os is is b as ed o n ph ys ic al e xa m in at io n an d hi st or y 193. Results For detection of syphilis from the presence of GUD, 12 studies provided 15 estimates for pooling. The pooled sensitivity for detecting syphilis is 20.0% (95% CI: 7.0-45.3), and pooled specificity is 92.6% (95% CI: 81.6-97.2). The diagnostic odds ratio is 3.12 (95% CI: 1.24-7.88). The positive likelihood ratio is 2.70 (95% CI: 1.23-5.91), and the negative likelihood ratio is 0.86 (95% CI: 0.71- 1.05). The inverse of the negative likelihood ratio is 1.16 (95% CI: 0.95-1.41). For a cohort of 1000 individuals: Prevalence Sensitivity Specificity PPV NPV Number of cases Missed cases False Positive (Overtreated) 0.05 0.2 0.926 0.125 0.957 50 40 70 0.1 0.2 0.926 0.231 0.912 100 80 67 0.15 0.2 0.926 0.323 0.868 150 120 63 0.2 0.2 0.926 0.403 0.822 200 160 59 0.25 0.2 0.926 0.474 0.776 250 200 56 0.3 0.2 0.926 0.537 0.730 300 240 52 0.35 0.2 0.926 0.593 0.683 350 280 48 0.4 0.2 0.926 0.643 0.635 400 320 44 0.45 0.2 0.926 0.689 0.586 450 360 41 0.5 0.2 0.926 0.730 0.537 500 400 37 0.55 0.2 0.926 0.768 0.486 550 440 33 0.6 0.2 0.926 0.802 0.436 600 480 30 0.65 0.2 0.926 0.834 0.384 650 520 26 0.7 0.2 0.926 0.863 0.332 700 560 22 0.75 0.2 0.926 0.890 0.278 750 600 19 0.8 0.2 0.926 0.915 0.224 800 640 15 0.85 0.2 0.926 0.939 0.170 850 680 11 0.9 0.2 0.926 0.961 0.114 900 720 7 0.95 0.2 0.926 0.981 0.057 950 760 4 1 0.2 0.926 1.000 0.000 1000 800 0 20 Web Annex E. Systematic review for syndromic management of genital ulcer disease Di ag no si s of s yp hi lis fr om th e pr es en ce o f G UD St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a po si ti ve ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Ch ou dh ry [2 2] 20 07 -8 In di a Lo w m id dl e 30 0 Se xu al h ea lth cl in ic 64 % m al e 16 % M SM Cl in ic al di ag no si s* VD RL , T PH A 11 3 4 28 2 Cl ar k[ 23 ] 20 03 -5 Pe ru U pp er m id dl e 32 85 Co m m un ity se tt in g 73 % h et er os ex ua l m en 16 % M SM Sy m pt om / Ex am in at io n + R PR RP R, T PP A 6 91 23 4 29 54 Da ly [3 0] 19 89 -9 1 Ke ny a Lo w m id dl e 43 67 Fa m ily pl an ni ng cl in ic 10 0% fe m al es Cl in ic al di ag no si s* RP R 4 79 76 42 08 De sa i[3 1] 20 00 In di a Lo w m id dl e 11 8 Se xu al h ea lth cl in ic 10 0% F SW Sy m pt om s + Ex am in at io n RP R, T PH A 4 23 3 88 Li u[ 6] 20 03 Ch in a U pp er m id dl e 55 Se xu al h ea lth cl in ic 10 0% m al e 14 % G U D Pr es en ce o f ul ce r PC R, R PR , T PP A 13 0 40 2 M ur al id ha r [2 4] 20 13 In di a Lo w m id dl e 90 Se xu al h ea lth cl in ic 67 % m al e 7. 5% G U D Cl in ic al di ag no si s* Da rk fie ld m ic ro sc op y, P CR , VD RL , T PH A, FT A- Ab s 4 3 2 81 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 6 Ho sp ita l 10 0% fe m al es liv in g w ith H IV Se lf- re po rt ed sy m pt om s RP R, T PP A 0 2 4 36 0 213. Results St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a po si ti ve ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 5 Ho sp ita l 10 0% m al es li vi ng w ith H IV Se lf- re po rt ed sy m pt om s RP R, T PP A 5 58 15 28 7 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 76 8 Ho sp ita l FS W Se lf- re po rt ed sy m pt om s RP R, T PP A 1 16 24 72 7 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 70 3 Ho sp ita l M SM Se lf- re po rt ed sy m pt om s RP R, T PP A 2 31 65 60 5 Sh ah es m ae ili [3 2] 20 15 Ira n (Is la m ic Re pu bl ic o f) U pp er m id dl e 13 37 Co m m un ity 10 0% F SW 3% G U D Se lf- re po rt ed sy m pt om s Ra pi d te st s – SD Bi ol in e HI V/ Sy ph ili s Du o + A le re Sy ph ili s RP R, E IA 0 5 40 12 92 Ts ai [3 3] 20 08 Ta iw an , Ch in a Hi gh 13 8 Se xu al h ea lth cl in ic 10 0% m al es 29 % G U D Cl in ic al di ag no si s* RP R, T PH A 26 7 86 19 O ’F ar re ll[ 25 ] 20 07 So ut h Af ric a U pp er m id dl e 64 5 Se xu al h ea lth cl in ic 10 0% he te ro se xu al s 25 .4 % G U D Sy m pt om s + ris k fa ct or s RP R, T PP A 17 29 14 7 45 2 O tie no [2 6] 20 07 -9 Ke ny a Lo w m id dl e 82 4 En ro lle d in g en er al po pu la tio n st ud y 50 % m al es 7% G U D Cl in ic al di ag no si s* RP R, T PP A 0 14 14 79 6 Yu [3 4] 20 02 -4 Ta iw an , Ch in a Hi gh 30 7 Se xu al h ea lth cl in ic 10 0% m al e 11 % G U D Cl in ic al di ag no si s M -P CR , R PR , T PH A 8 13 17 26 9 *C lin ic al d ia gn os is is b as ed o n ph ys ic al e xa m in at io n an d hi st or y 22 Web Annex E. Systematic review for syndromic management of genital ulcer disease For detection of chancroid, 13 studies provided 18 estimates for pooling. The pooled sensitivity for detecting chancroid using a syndromic management approach is 78.2% (95% CI: 63.5-88.0), and pooled specificity is 56.5% (95% CI: 37.1-74.2). The diagnostic odds ratio is 4.66 (95% CI: 2.84-7.64). The positive likelihood ratio is 1.80 (95% CI: 1.28-2.52), and the negative likelihood ratio is 0.39 (95% CI: 0.27-0.55). The inverse negative likelihood ratio is 2.59 (95% CI: 1.81-3.71). For a cohort of 1000 individuals: Prevalence Sensitivity Specificity PPV NPV Number of cases Missed cases False Positive (Overtreated) 0.05 0.782 0.565 0.086 0.980 50 11 413 0.1 0.782 0.565 0.166 0.959 100 22 392 0.15 0.782 0.565 0.241 0.936 150 33 370 0.2 0.782 0.565 0.310 0.912 200 44 348 0.25 0.782 0.565 0.375 0.886 250 55 326 0.3 0.782 0.565 0.435 0.858 300 65 305 0.35 0.782 0.565 0.492 0.828 350 76 283 0.4 0.782 0.565 0.545 0.795 400 87 261 0.45 0.782 0.565 0.595 0.760 450 98 239 0.5 0.782 0.565 0.643 0.722 500 109 218 0.55 0.782 0.565 0.687 0.680 550 120 196 0.6 0.782 0.565 0.729 0.633 600 131 174 0.65 0.782 0.565 0.770 0.583 650 142 152 0.7 0.782 0.565 0.807 0.526 700 153 131 0.75 0.782 0.565 0.844 0.463 750 164 109 0.8 0.782 0.565 0.878 0.393 800 174 87 0.85 0.782 0.565 0.911 0.314 850 185 65 0.9 0.782 0.565 0.942 0.224 900 196 43 0.95 0.782 0.565 0.972 0.120 950 207 22 1 0.782 0.565 1.000 0.000 1000 218 0 233. Results Se ns iti vi ty Specificity Study estimate 1 0 .8 .6 .4 .2 0 .2 .4 .6 .8 1 Summary point HSROC curve 95% confidence region 95% prediction region 24 Web Annex E. Systematic review for syndromic management of genital ulcer disease De te ct io n of c ha nc ro id u si ng a c lin ic al d ia gn os is o f c ha nc ro id in a p op ul at io n wi th G UD St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Be he ts [8 ] 19 97 M ad ag as ca r Lo w 19 6 Se xu al h ea lth cl in ic 71 % m al e 10 0% G U D Cl in ic al d ia gn os is * M -P CR 34 30 63 69 Be he ts [9 ] 19 96 Ja m ai ca U pp er m id dl e 30 4 Se xu al H ea lth cl in ic 83 % m al e 10 0% G U D Cl in ic al d ia gn os is * M -P CR 54 18 57 17 5 Be he ts [1 0] 19 95 -6 Th ai la nd U pp er m id dl e 38 Se xu al h ea lth cl in ic 79 % fe m al e se x w or ke rs 10 0% G U D Cl in ic al d ia gn os is * M -P CR 0 0 6 32 Bh av sa r[1 1] 20 11 - 12 In di a Lo w m id dl e 96 Ho sp ita l 79 % m al e 10 0% G U D Cl in ic al d ia gn os is * G ra m s ta in 2 1 1 92 Bo ga er ts [1 2] 19 90 - 92 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e 10 0% G U D Hi st or y an d ex am in at io n Cu ltu re 11 5 0 27 2 8 Bo ga er ts [1 2] 19 90 - 92 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e 10 0% G U D Hi st or y an d ex am in at io n + sy ph ili s se ro lo gy or d ar kfi el d m ic ro sc op y Cu ltu re 83 32 18 8 92 Bo ga er ts [1 2] 19 90 - 92 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e 10 0% G U D Cl in ic al d ia gn os is * Cu ltu re 74 41 67 21 3 Di Ca rlo [1 3] 19 90 - 19 92 U SA Hi gh 22 0 Se xu al h ea lth cl in ic 10 0% m en 10 0% G U D Cl in ic al d ia gn os is * Cu ltu re 40 78 6 96 Ht un [1 5] 19 93 - 94 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic 10 0% G U D Cl in ic al d ia gn os is * M PC R 54 2 22 14 Ht un [1 5] 19 93 - 94 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic 10 0% G U D Cl in ic al d ia gn os is * M PC R 51 4 31 6 Ht un [1 5] 19 93 - 94 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic 10 0% G U D Cl in ic al d ia gn os is * M PC R 53 3 32 4 253. Results St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve N di ny a- Ac ho la [2 9] 19 90 - 91 Ke ny a Lo w m id dl e 15 6 Pr im ar y ca re 47 % m al es 10 0% G U D Cl in ic al d ia gn os is * Cu ltu re 51 5 76 24 Pr ab ha ka r [1 6] 20 08 -9 In di a Lo w m id dl e 18 1 Se xu al h ea lth cl in ic 10 0% m al e 10 0% G U D Cl in ic al d ia gn os is * M -P CR 59 31 37 54 Ri sb ud [1 7] 19 94 In di a Lo w m id dl e 30 2 Se xu al h ea lth cl in ic 10 0% G U D Cl in ic al d ia gn os is * M -P CR 53 31 76 14 2 Sa nc he z[ 7] 19 95 -6 Do m in ic an Re pu bl ic U pp er m id dl e 81 G en er al pr ac tic e 10 0% m al e 10 0% G U D Cl in ic al d ia gn os is * M -P CR 11 10 17 43 Sa nc he z[ 7] 19 95 -6 Pe ru U pp er m id dl e 63 G en er al pr ac tic e 10 0% m al e 10 0% G U D Cl in ic al d ia gn os is * M -P CR 0 3 21 39 Fa st [2 0] 19 80 Ke ny a Lo w m id dl e 70 “S pe ci al tr ea tm en t cl in ic ” 10 0% m al e 10 0% G U D Cl in ic al d ia gn os is * Cu ltu re 42 6 8 14 Da ng or [2 1] U nc le ar So ut h Af ric a U pp er m id dl e 21 0 Ho sp ita l 10 0% G U D Cl in ic al d ia gn os is * 11 7 30 14 49 Fo r d et ec tio n of c ha nc ro id u sin g G U D, tw o st ud ie s pr ov id ed tw o es tim at es fo r p oo lin g. W e w er e un ab le to c on du ct a m et a- an al ys is du e to to o fe w s tu di es . St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Li u[ 6] 20 03 Ch in a U pp er m id dl e 55 Se xu al h ea lth cl in ic 10 0% m al e 14 % G U D Pr es en ce o f u lc er PC R 0 0 53 2 M ur al id ha r [2 4] 20 13 In di a Lo w m id dl e 90 Se xu al h ea lth cl in ic 67 % m al e 7. 5% G U D Cl in ic al d ia gn os is * G ra m s ta in , cu ltu re , P CR 0 1 10 79 *C lin ic al d ia gn os is is b as ed o n ph ys ic al e xa m in at io n an d hi st or y 26 Web Annex E. Systematic review for syndromic management of genital ulcer disease 3.3 Risk of bias assessment using QUADAS-2 Study Patient selection Index Test Reference standard Flow and Timing Behets[8] Low Low Low Low Behets[9] Low Low Low Low Beyrer[10] Low Low Low Low Bhavsar[11] Low Low Low High1 Low Bogaerts[12] Low Low Low High2 Low DiCarlo[13] Low Low Low High3 Low Hina[14] Low Low High Low Htun[15] Low Low Low Low Prabhakar[16] Low Low Low Low Risbud[17] Low Low Low Low Sanchez[7] Low Low Low Low Wang[18] Low Low Unclear Low Wang[19] Low Low Low Low Fast[20] Low Low Low High4 Low Dangor[21] Low Low Low High4 Low Hanson[28] Low Low Low High5 Low Ndinya-Achola[29] Low Low High Low Das[5] Low Low Unclear Low Liu[6] Low Low Unclear Low Choudhry[22] Low Low Low High5 Low Clark[23] Low Low Low Low Muralidhar[24] Low Low Low Low O'Farrell[25] Low Low Low Low Otieno[26] Low Low Low High6 Low Shah[27] Low Low Low High6 Low Daly[30] Low Low Low High7 Low Desai[31] Low Low Low Low Shahesmaeili[32] Low Low Low Low Tsai[33] Low Low Low Low Yu[34] Low Low Low Low 1 High risk for NG, HD, CG, HSV, Low risk for TP 2 High risk for NG, HD, HSV, Low risk for TP 3 High risk for HD, HSV, Low risk for TP 4 High risk for CT, HD, HSV, Low risk for TP 5 High risk for CT, NG, HD, CG, HSV, Low risk for TP 6 High risk for HSV, Low risk for CT, NG, TP 7 High risk for NG, Low risk for TP Recommendations from WHO as depicted by Vickerman contrasting 1994 and 2003 algorithms.[59] 273. Results Quite rare to have an explicit evaluation of WHO algorithms[12] 28 Web Annex E. Systematic review for syndromic management of genital ulcer disease 293. Results Chinese algorithm[19] 30 Web Annex E. Systematic review for syndromic management of genital ulcer disease Cote d’Ivoire[61] 313. Results GUD algorithm used in Botswana[56] 32 Web Annex E. Systematic review for syndromic management of genital ulcer disease Chinese algorithm[18] 333. Results Brazil algorithm[85] 34 Web Annex E. Systematic review for syndromic management of genital ulcer disease India’s algorithm[16] 353. Results Rwanda (1998 publication)[86] 36 Web Annex E. Systematic review for syndromic management of genital ulcer disease Aetiology of GUD 155 patients attending outpatient department in hospital, Swaziland (1979)[87] • 65 HD • 25 TP • 18 LGV • 17 HSV • 5 Mixed • 0 none 19 primary health centre, Ethiopia, (2001)[68] • 2 TP 100 patients from STI clinic in Kenya (1980)[20] • 6 mixed • 48 HD • 6 HSV • 10 TP • 0 LGV • 36 no infections 307 people from STI clinic in Taiwan, China (2002-2004)[34] • 21 TP 210 people from STI clinic in Rwanda (1986)[98] • 37 TP • 32 HSV • 24 HD • 13 LGV • 29 Mixed • 75 none 227 people from STI clinic in China (2000-2001) [19] • 78 TP • 43 HSV • 28 TP + HSV • 76 no diagnosis • 0 HD 96 people from STI clinic in China (1998-1999) [18] • 23 TP • 33 HSV • 40 – no pathogen • 0 HD 76 people presenting at medical centre in Mozambique (2005)[99] • 47 HSV • 3 LGV • 3 HD • 0 CG (donovanosis) • 0 TP • 23 no diagnosis • 2 mixed infection (HSV and LGV) 42 women from the health centre and hospital dispensary in Rwanda (1994)[86] • 34 TP 38 men from the health centre and hospital dispensary in Rwanda (1994)[86] • 37 TP 81 men from STI clinics in the Dominican Republic(1995-6)[7] • 5% TP • 26% HD • 43% HSV 63 men from STI clinics in Peru (1995-6)[7] • 10% TP • 5% HD • 43% HSV 194 patients from STI clinics in India (2008-9) [16] • 76 HSV • 27 TP • 17 Mixed • 1 HD 373. Results 202 patients from general outpatients clinic in Uganda (1999-2001)[38] • 80 HSV-2 • 7 TP • 5 HD • 15 multiple 100 patients from rural Uganda (xx)[36] • 61 HSV-2 • 5 TP • 3 HSV-1 • 1 HD • 1 multiple 398 patients from STI clinic in Malawi (2004- 2006)[100] • 67% HSV2 (serology) • 15% TP • 15% HD • 6% LGV • 6% mixed • 20% no aetiology 59 patients attending primary care in the Central African Republic (1993)[58] • 16 HD • 20 TP • 19 HSV • 10 (2 organisms or more) 298 from STI clinic in the USA (1992-1994)[101] • 102 HSV • 75 TP • 65 HD • 62 negative • 7 mixed 240 patients in South Africa in hospital in South Africa (?published 1990)[21] • 29 no diagnosis • 37 – mixed • 147 HD • 7 HSV • 52 TP • 8 LGV • 1 CG 90 patients attending STI clinic in India (2010- 11)[24] • 6 TP • 66 HSV • 0 HD • 0 LGV • 0 Donovanosis 105 patients attending STI clinic Lesotho (1993- 4)[102] • 56% HD • 23% syphilis • 26% HSV 587 people attending STI clinic in South Africa (2000-2001)[83] • 48% HSV • 14% TP • 11% CT-LGV • 10% HD • 1% CG 156 people attending STI clinic in Brazil (1995) [85] • 31% TP 70 people attending “clinics” in Zimbabwe (2015)[79] • 17 HSV • 8 TP • 1 CT-LGV • 0 HD 778 people attending STI clinic in Malawi (1992-3)[78] • 129/758 TP • 204/778 HD 100 people attending STI clinic in Lesotho (1993-4)[15] • 56 HD • 26 HSV • 23 TP • 7 CT 38 Web Annex E. Systematic review for syndromic management of genital ulcer disease 137 people attending STD clinic in Malawi (1998-1999)[52] • 47 HSV • 41 HD • 5 TP 136 people attending STD clinic in Malawi (unclear, published 2003)[103] • 3% TP • 30% HD • 35% HSV 304 people from Jamaica[9] • 158 HSV • 72 HD • 31 TP 446 men from a sexual health clinic in the USA (1990-1992)[13] • 45 TP • 118 HD • 57 HSV 98 patients from urban STD clinic in Uganda (date unclear, before 1995)[104] • 48 HSV • 11/89 TP 61 attendees of public STD clinic with GUD in Madagascar (1992-93)[105] • 56% syphilis • 29% LGV • 20% chancroid • 2% HSV 196 attendees of STD clinic with GUD Madagascar (1997)[8] • 61 HD (chancroid) • 51 TP • 15 HSV • 3 TP and HSV • 2 HD and TP • 1 HD and HSV 778 people of STD clinic in Malawi (1992-93)[71] • 204 HD • 137 TP 100 people from STI clinic in South Africa (1988-9)[106] • 40 TP • 18 HSV • 16 CG • 14 • HD • 6 LGV • 18 none • 13 multiple 201 people from STI clinic in India (2008-9)[107] • 49 HSV • 20 TP • 3 CG • 30 HD • 1 LGV 100 men from STI clinic in South Africa (1989) [108] • 29 TP • 12 HD • 9 CG • 9 HSV • 3 LGV • 14 Mixed • 24 none 104 patients, STI clinic, Gambia (before 1987) [88] • 54 HD • 23 TP • 7 LGV • 6 HSV • 28 no • 15 mixed 516 people from STI clinics in the USA (1994) [109] • 16 HD • 51 TP • 320 HSV • 13 Mixed • 116 none 393. 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J Clin Microbiol. 1996;34(1):49-54. 102. Morse SA, Trees DL, Htun Y, Radebe F, Orle KA, Dangor Y, et al. Comparison of clinical diagnosis and standard laboratory and molecular methods for the diagnosis of genital ulcer disease in lesotho: Association with human immunodeficiency virus infection. Journal of Infectious Diseases. 1997;175(3):583-9. 103. Hoyo C, Hoffman I, Moser BK, Hobbs M. Syndromic criteria to improve GUD diagnosis. American Journal of Epidemiology. 2003;157(11):S47-S. 474. References 104. Kamya MR, Nsubuga P, Grant RM, Hellman N. The high prevalence of genital herpes among patients with genital ulcer disease in Uganda. Sex Transm Dis. 1995;22(6):351-4. 105. Harms G, Matull R, Randrianasolo D, Andriamiadana J, Rasamindrakotroka A, Kirsch T, et al. Pattern of sexually transmitted diseases in a Malagasy population. Sex Transm Dis. 1994;21(6):315-20. 106. O'Farrell N, Hoosen AA, Coetzee KD, van den Ende J. Genital ulcer disease in women in Durban, South Africa. Genitourin Med. 1991;67(4):322-6. 107. Vora R, Anjaneyan G, Doctor C, Gupta R. Clinico-epidemiological study of sexually transmitted infections in males at a rural-based tertiary care center. Indian J Sex Transm Dis AIDS. 2011;32(2):86-9. 108. O'Farrell N, Hoosen AA, Coetzee KD, van den Ende J. Genital ulcer disease in men in Durban, South Africa. Genitourin Med. 1991;67(4):327-30. 109. Mertz KJ, Trees D, Levine WC, Lewis JS, Litchfield B, Pettus KS, et al. Etiology of genital ulcers and prevalence of human immunodeficiency virus coinfection in 10 US cities. The Genital Ulcer Disease Surveillance Group. J Infect Dis. 1998;178(6):1795-8. 110. Gomes CM, Giraldo PC, Gomes Fde A, Amaral R, Passos MR, Goncalves AK. Genital ulcers in women: clinical, microbiologic and histopathologic characteristics. Braz J Infect Dis. 2007;11(2):254-60. 111. Lewis DA, Muller E, Steele L, Sternberg M, Radebe F, Lyall M, et al. Prevalence and associations of genital ulcer and urethral pathogens in men presenting with genital ulcer syndrome to primary health care clinics in South Africa. Sex Transm Dis. 2012;39(11):880-5. 112. Becker M, Stephen J, Moses S, Washington R, Maclean I, Cheang M, et al. Etiology and determinants of sexually transmitted infections in Karnataka state, south India. Sex Transm Dis. 2010;37(3):159-64. 113. Mertz KJ, Weiss JB, Webb RM, Levine WC, Lewis JS, Orle KA, et al. An investigation of genital ulcers in Jackson, Mississippi, with use of a multiplex polymerase chain reaction assay: high prevalence of chancroid and human immunodeficiency virus infection. J Infect Dis. 1998;178(4):1060-6. 114. Bruisten SM, Cairo I, Fennema H, Pijl A, Buimer M, Peerbooms PG, et al. Diagnosing genital ulcer disease in a clinic for sexually transmitted diseases in Amsterdam, The Netherlands. J Clin Microbiol. 2001;39(2):601-5. 48 5. APPENDIX A – SEARCH RESULTS 5.1 Genital ulcers syndromes The search retrieved a total of 14,190- results. 4286 (30%) were identified as duplicates. The number of results pre-and post-deduplication is listed in the table below. Database name Diagnostic accuracy: Total number of results Diagnostic accuracy: Number of results once duplicates removed Other papers: Total number of results Other papers: Number of results once duplicates removed Ovid SP Medline and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1753 1748 941 940 OvidSP Embase 4687 3564 2590 2063 OvidSP Global Health 1159 428 398 202 OvidSP Northern Light Life Sciences Conference Abstracts 60 30 74 39 Ebsco CINAHL Plus 526 120 470 209 Ebsco Africa-Wide Information 287 26 63 13 Clarivate Analytics Web of Science Core Collection 893 346 216 108 BIREME/PAHO/WHO Virtual Health Library LILACS 44 41 29 27 Total 9409 6303 4781 3601 For more information, contact: World Health Organization Department of Global HIV, Hepatitis and STI Programme 20, avenue Appia 1211 Geneva 27 Switzerland Email: hiv-aids@who.int www.who.int/hiv
WEB ANNEX E. SYSTEMATIC REVIEW FOR SYNDROMIC MANAGEMENT OF GENITAL ULCER DISEASE GUIDELINES FOR THE MANAGEMENT OF SYMPTOMATIC SEXUALLY TRANSMITTED INFECTIONS JUNE 2021 WEB ANNEX E. SYSTEMATIC REVIEW FOR SYNDROMIC MANAGEMENT OF GENITAL ULCER DISEASE JUNE 2021 GUIDELINES FOR THE MANAGEMENT OF SYMPTOMATIC SEXUALLY TRANSMITTED INFECTIONS Guidelines for the management of symptomatic sexually transmitted infections: Web Annex E. Systematic review for syndromic management of genital ulcer disease ISBN 978-92-4-003482-2 (electronic version) © World Health Organization 2021 Some rights reserved. This work is available under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/ licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization (http://www.wipo.int/amc/en/ mediation/rules/). Suggested citation. Guidelines for the management of symptomatic sexually transmitted infections: Web Annex E. Systematic review for syndromic management of genital ulcer disease. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/ about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. This publication forms part of the WHO guideline entitled Guidelines for the management of symptomatic sexually transmitted infections. It is being made publicly available for transparency purposes and information, in accordance with the WHO handbook for guideline development, 2nd edition (2014). Design and layout by 400 Communications. iii CONTENTS 1. Introduction 1 2. Methods 2 3. Results 5 3.1 PRISMA flow chart for genital ulcer syndromes 5 3.2 Genital ulcer disease 6 3.3 Risk of bias assessment using QUADAS-2 26 4. References 40 5. Appendix A – Search Results 48 5.1 Genital ulcers syndromes 48 11. INTRODUCTION Sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), continue to present significant health, social, and economic problems in the developing world, leading to considerable morbidity, mortality, and stigma. In under-resourced settings, the lack of adequate laboratory infrastructure and/or high prohibitive costs of diagnostics means that in many settings, STI management relies on syndromic management rather than aetiological diagnosis and management. In these settings, the detection of asymptomatic STIs is largely non-existent. Therefore, synthesizing the latest evidence for the performance of syndromic STI case management would help the World Health Organization (WHO) in their guideline recommendations for syndromic STI management, last updated in 2003.[1] To evaluate if there is still a role for syndromic STI management or whether STI diagnostics are critical for STI case management, we systematically reviewed the evidence for the performance of syndromic management of STIs. Specifically, we conducted reviews on the diagnostic accuracy and aetiologies of syndromic case management of genital ulcer, anorectal infection and lower abdominal pain. Our specific objectives were to review the flowcharts used for: • people presenting with genital ulcer disease to detect herpes simplex virus (HSV) or syphilis or lymphogranuloma venereum (LGV) or chancroid, or if no flowcharts found, a minor review of test accuracy of different tests, or risk association/prevalence. • people presenting with the anorectal syndrome to detect anal STIs or if no flowcharts found, a major review of test accuracy of different tests, or risk association/prevalence. • people presenting with lower abdominal pain to detect pelvic inflammatory disease (PID) or vaginal or cervical infections, or if no flowcharts found, a major review of test accuracy of different tests, or risk association/prevalence. 22. METHODS Study inclusion • Clinical guidelines/algorithms – Flow charts for genital ulcer (for syphilis, HSV, LGV, chancroid), anorectal syndromes (for Ct/Ng/ Mg/LGV/HSV/Tp/Donovanosis), lower abdominal pain (for PID, vaginal/cervical infections), and vaginal discharge • Randomized controlled trials • Observational studies • Report on at least one of: – Comparing syndromic case management against laboratory-confirmed STIs – Risk factor analysis of signs/symptoms associated with STI diagnoses and other risk factors associated with STI syndromes Study exclusion • Contains no original data i.e. systematic reviews/Letter/editorials/Commentaries/Book chapters – But can use these to identify other relevant primary studies • Qualitative research about outcomes • Duplicated results from another study • Laboratory studies about testing STI diagnostic performance • Studies restricting study population, e.g. men with urethritis, women with cervicitis Search method Three separate searches were conducted: one for each of the syndromes under investigation. We included papers that focused on other aspects of syndromic management (i.e. acceptability, feasibility, equity, resources) in addition to the accuracy or sensitivity of the syndromic management approach. The search for each syndrome has been constructed as below. • Concept 1: syndromic management • Concept 2: syndrome under investigation • Concept 3: diagnostic accuracy and sensitivity papers • Results group 1: concept 1 AND concept 2 AND concept 3 • Results group 2: (concept 1 AND concept 2) NOT Results group 1 32. Methods A draft search strategy was compiled in the OvidSP Medline database by an experienced information specialist. The search strategy included strings of terms, synonyms and controlled vocabulary terms (where available). As the syndromic management approach was not introduced until 1996, the search was limited to papers published in 1995 or after. No other limits were added. This search strategy was refined with the project team until the results retrieved reflected the scope of the project. The agreed OvidSP Medline search was adapted for each database to incorporate database-specific syntax and controlled vocabularies. Full details of the search strings used for each database can be found in the appendix. A The following databases were searched on 12 and 13 September 2019. • Ovid SP Medline and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, 1946 to September 11, 2019 • OvidSP Embase, 1974 to 11 September 2019 • OvidSP Global Health, 1910 to week 35, 2019 • OvidSP Northern Light Life Sciences Conference Abstracts, 2010 to Week 34, 2019 • Ebsco CINAHL Plus, complete database • Ebsco Africa-Wide Information, complete database • Clarivate Analytics Web of Science Core Collection, consisting of the following databases: – Science Citation Index Expanded (SCI-EXPANDED), 1970 - present – Social Sciences Citation Index (SSCI), 1970 - present – Arts & Humanities Citation Index (A&HCI), 1975 - present – Conference Proceedings Citation Index - Science (CPCI-S), 1990 - present – Conference Proceedings Citation Index - Social Science & Humanities (CPCI-SSH), 1990 - present – Emerging Sources Citation Index (ESCI), 2015 – present • BIREME/PAHO/WHO Virtual Health Library LILACS, complete database All citations identified by our searches were imported into EndNote X9 software. Duplicates were identified and removed using the method described on the LAS blog.1 Data extraction We followed the guidelines in the Cochrane Handbook 5.1.[2] Three groups of two independent reviewers screened the title and abstracts of unduplicated papers. Discrepancies in screening were resolved by a third reviewer (JO). Each team extracted relevant data from deduplicated full publications. Risk of bias assessment was conducted using the Joanna Briggs Institute Checklist for diagnostic studies.[3] 1 Falconer, Jane, Removing duplicates from an EndNote library. Library & Archives Service Blog: London School of Hygiene & Tropical Medicine. 2018. [online blog] http://blogs.lshtm.ac.uk/library/2018/12/07/removing-duplicates-from-an-endnote-library/. 4 Web Annex E. Systematic review for syndromic management of genital ulcer disease Statistical analysis Diagnostic accuracy cannot be summarized by one measure as sensitivity and specificity are correlated. Therefore, we must choose hierarchical (multilevel) models that use a binomial data structure, i.e. we use a hierarchical logistic regression model in STATA 13.1. After pooling the studies, we report the sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratio. The inverse of the negative likelihood ratio (1/LR-) can be used to compare with the positive likelihood ratio to indicate whether the positive or negative test result has a greater impact on the odds of disease. Likelihood ratios assess the probability or likelihood that the test result obtained would be expected in a person with the condition, compared to the probability or likelihood that the same result would be seen in a person without the condition. The positive likelihood ratio LR+ sensitivity (1–speci city) = TP (TP+FN) = FP (FP+TN) ÷ expresses how many times more likely people with the condition are to receive a positive test result compared to those who do not have the condition, while the negative likelihood ratio LR– (1–sensitivity) (speci city) = FN (TP+FN) = TN (FP+TN) ÷ expresses how likely it is that people with the condition will receive a negative test result compared to those who do not have the condition. To graphically display the trade-off between sensitivity and specificity, we present the summary receiver operating characteristic (SROC) curve from the hierarchical summary receiver operating characteristic (HROC) model [4] and prediction region (i.e. for the forecast of the true sensitivity and specificity in a future study). We also plot the summary operating point and its confidence region. Forest plots for showing within-study estimates and confidence intervals for sensitivity and specificity separately. In the meta-analyses below, we have only included papers where we could calculate the numbers of true positive, false positives, true negatives and false negatives. For the other papers without this data, we have summarized their results qualitatively (i.e. without pooling). [12] McGee, Steven (1 August 2002). "Simplifying likelihood ratios". Journal of General Internal Medicine. 17 (8): 647–650. doi:10.1046/j.1525-1497.2002.10750.x. ISSN 0884-8734. PMC 1495095. PMID 12213147. [13] Henderson, Mark C.; Tierney, Lawrence M.; Smetana, Gerald W. (2012). The Patient History (2nd ed.). McGraw-Hill. p. 30. ISBN 978-0-07-162494-7. 53. RESULTS 3.1 PRISMA flow chart for genital ulcer syndromes In cl ud ed El ig ib ili ty Sc re en in g Id en tifi ca tio n Records identified through database searching (n = 14,190) Records after duplicates removed (n = 9,904) Titles/Abstracts screened (n = 9,904) Full-text articles assessed for eligibility (n = 151) Records excluded for irrelevant content (n = 9,753) Studies included in analysis (n = 68) Full-text articles excluded (n = 83) 68 No information about syndrome 9 No primary data 6 paper not found 6 Web Annex E. Systematic review for syndromic management of genital ulcer disease 3.2 Genital ulcer disease • Country income level – 3/68 (4%) High income – 23/68 (34%) Upper Middle – 25/68 (37%) Lower Middle – 15/68 (22%) Low • Study population recruited from (may not add up to 100% because of multiple recruitment sites) – 33/68 (49%) Sexual health clinics – 22/68 (32%) Community setting (incl. bar, discos, CBOs) – 14/68 (21%) Hospital • Year of study – 54/68 (79%) 2009 and before – 9/68 (13%) 2010-2014 – 5/68 (7%) 2015 and after 73. Results Fo r d et ec tio n of a ny S TI s, fo ur s tu di es p ro vi de d fo ur e st im at es fo r p oo lin g: tw o st ud ie s ev al ua tin g th e ac cu ra cy o f G U D to d et ec t a ny S TI s, a nd tw o st ud ie s ev al ua tin g th e ac cu ra cy o f c lin ic al d ia gn os is o f a ny S TI s fo r a p op ul at io n w ith G U D. T he re w er e to o fe w s tu di es to c on du ct a m et a- an al ys is . De te ct io n of a ny S TI s fo r g en ita l u lc er s yn dr om e (s ha de d ro ws re pr es en ts s tu di es te st in g pr es en ce o f u lc er to de te ct a ny S TI s) St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a po si ti ve ca se de fin ed Pa th og en s D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Da s[ 5] 20 13 In di a Lo w m id dl e 29 7 ST I a nd gy na ec ol og y ou tp at ie nt s 22 % m al e 12 % G U D Pr es en ce o f ul ce r HS V, C G, CM V, T P VD RL , T PH A, Sm ea r, HS V- Ab 14 21 5 27 41 Li u[ 6] 20 03 Ch in a U pp er m id dl e 55 Se xu al h ea lth cl in ic 10 0% m al e 14 % G U D Pr es en ce o f ul ce r HS V, T P, HD PC R, R PR , TP PA 13 0 40 2 Sa nc he z[ 7] 19 95 -6 Do m in ic an Re pu bl ic U pp er m id dl e 81 G en er al pr ac tic e 10 0% m al e 10 0% G U D Sy m pt om s + ex am in at io n HS V, T P, HD M -P CR 13 12 28 28 Sa nc he z[ 7] 19 95 -6 Pe ru U pp er m id dl e 63 G en er al pr ac tic e 10 0% m al e 10 0% G U D Sy m pt om s + ex am in at io n HS V, T P, HD M -P CR 2 7 29 25 8 Web Annex E. Systematic review for syndromic management of genital ulcer disease For detecting herpes from a clinical diagnosis of herpes, 15 studies provided 20 estimates for pooling. The pooled sensitivity for detecting herpes using a syndromic management approach is 40.4% (95% CI: 23.0-60.6), and pooled specificity is 88.0% (95% CI: 75.3-94.6). The diagnostic odds ratio is 4.95 (95% CI: 3.37-7.28). The positive likelihood ratio is 3.35 (95% CI: 2.27-4.97), and the negative likelihood ratio is 0.68 (95% CI: 0.53-0.86). The inverse negative likelihood ratio is 1.48 (95% CI: 1.16-1.88). For a cohort of 1000 individuals: Prevalence Sensitivity Specificity PPV NPV Number of cases Missed cases False Positive (Overtreated) 0.05 0.404 0.88 0.151 0.966 50 30 114 0.1 0.404 0.88 0.272 0.930 100 60 108 0.15 0.404 0.88 0.373 0.893 150 89 102 0.2 0.404 0.88 0.457 0.855 200 119 96 0.25 0.404 0.88 0.529 0.816 250 149 90 0.3 0.404 0.88 0.591 0.775 300 179 84 0.35 0.404 0.88 0.644 0.733 350 209 78 0.4 0.404 0.88 0.692 0.689 400 238 72 0.45 0.404 0.88 0.734 0.643 450 268 66 0.5 0.404 0.88 0.771 0.596 500 298 60 0.55 0.404 0.88 0.804 0.547 550 328 54 0.6 0.404 0.88 0.835 0.496 600 358 48 0.65 0.404 0.88 0.862 0.443 650 387 42 0.7 0.404 0.88 0.887 0.388 700 417 36 0.75 0.404 0.88 0.910 0.330 750 447 30 0.8 0.404 0.88 0.931 0.270 800 477 24 0.85 0.404 0.88 0.950 0.207 850 507 18 0.9 0.404 0.88 0.968 0.141 900 536 12 0.95 0.404 0.88 0.985 0.072 950 566 6 1 0.404 0.88 1.000 0.000 1000 596 0 93. Results Se ns iti vi ty Specificity Study estimate 1 0 .8 .6 .4 .2 0 .2 .4 .6 .8 1 Summary point HSROC curve 95% confidence region 95% prediction region 10 Web Annex E. Systematic review for syndromic management of genital ulcer disease Co m pa rin g th e ac cu ra cy o f c lin ic al d ia gn os is o f h er pe s wi th th e ae tio lo gi ca l d ia gn os is o f h er pe s St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Be he ts [8 ] 19 97 M ad ag as ca r Lo w 19 6 Se xu al h ea lth cl in ic 71 % m al e Cl in ic al d ia gn os is * M -P CR 0 19 2 17 5 Be he ts [9 ] 19 96 Ja m ai ca U pp er m id dl e 30 4 Se xu al H ea lth cl in ic 83 % m al e Cl in ic al d ia gn os is * M -P CR 85 73 24 12 2 Be yr er [1 0] 19 95 -6 Th ai la nd U pp er m id dl e 38 Se xu al h ea lth cl in ic 79 % fe m al e se x w or ke rs Cl in ic al d ia gn os is * M -P CR 21 11 3 3 Bh av sa r [1 1] 20 11 -1 2 In di a Lo w m id dl e 96 Ho sp ita l 79 % m al e Cl in ic al d ia gn os is * Tz an ck s m ea r Ig M fo r H SV -2 33 0 38 25 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Hi st or y an d ex am in at io n Cy to pa th ic ef fe ct o n Ve ro ce lls 4 85 4 30 2 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Hi st or y an d ex am in at io n + s yp hi lis s er ol og y or da rk fie ld m ic ro sc op y Cy to pa th ic ef fe ct o n Ve ro ce lls 4 85 4 30 2 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Cl in ic al d ia gn os is * Cy to pa th ic ef fe ct o n Ve ro ce lls 43 46 87 21 9 Di Ca rlo [1 3] 19 90 - 19 92 U SA Hi gh 22 0 Se xu al h ea lth cl in ic 10 0% m en Cl in ic al d ia gn os is * Cu ltu re 20 37 10 15 3 Hi na [1 4] 20 15 -1 6 In di a Lo w m id dl e 96 Se xu al h ea lth cl in ic 75 % m al es Cl in ic al d ia gn os is * Tz an ck s m ea rs , HS V2 -Ig M 33 2 36 25 Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R 7 10 1 74 Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R 5 19 3 65 113. Results St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R 0 24 0 68 Pr ab ha ka r [1 6] 20 08 -9 In di a Lo w m id dl e 18 1 Se xu al h ea lth cl in ic 10 0% m al e Cl in ic al d ia gn os is * M -P CR 59 31 37 54 Ri sb ud [1 7] 19 94 In di a Lo w m id dl e 30 2 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M -P CR 48 47 32 17 5 Sa nc he z[ 7] 19 95 -6 Do m in ic an Re pu bl ic U pp er m id dl e 81 G en er al pr ac tic e 10 0% m al e Cl in ic al d ia gn os is * M -P CR 19 16 10 36 Sa nc he z[ 7] 19 95 -6 Pe ru U pp er m id dl e 63 G en er al pr ac tic e 10 0% m al e Cl in ic al d ia gn os is * M -P CR 15 12 17 19 W an g[ 18 ] 19 98 -9 9 Ch in a U pp er m id dl e 96 Se xu al h ea lth cl in ic 52 % m al es Cl in ic al d ia gn os is * M -P CR 25 8 36 27 W an g[ 19 ] 20 00 -1 Ch in a U pp er m id dl e 22 7 Se xu al h ea lth cl in ic 90 % m al e Cl in ic al d ia gn os is * M -P CR 49 22 78 78 Fa st [2 0] 19 80 Ke ny a Lo w m id dl e 70 “S pe ci al tr ea tm en t cl in ic ” 10 0% m al e Cl in ic al d ia gn os is * Cu ltu re 3 3 1 63 Da ng or [2 1] U nc le ar So ut h Af ric a U pp er m id dl e 21 0 Ho sp ita l 10 0% m al e Cl in ic al d ia gn os is * Cu ltu re 5 2 21 18 2 *“ D ia gn os tic te st ” is c lin ic ia n’ s di ag no si s of h er pe s (r at he r t ha n th e pr es en ce o f u lc er ) – C lin ic al d ia gn os is is b as ed o n ph ys ic al e xa m in at io n an d hi st or y 12 Web Annex E. Systematic review for syndromic management of genital ulcer disease For detecting herpes from the presence of a genital ulcer, seven studies provided ten estimates for pooling. The pooled sensitivity for detecting herpes using a syndromic management approach is 42.2% (95% CI: 10.9-81.3), and pooled specificity is 91.0% (95% CI: 65.9-98.1). The diagnostic odds ratio is 7.38 (95% CI: 1.29-42.09). The positive likelihood ratio is 4.69 (95% CI: 1.22-18.01), and the negative likelihood ratio is 0.64 (95% CI: 0.32-1.27). The inverse negative likelihood ratio is 1.57 (95% CI: 0.79-3.15). For a cohort of 1000 individuals: Prevalence Sensitivity Specificity PPV NPV Number of cases Missed cases False Positive (Overtreated) 0.05 0.422 0.91 0.198 0.968 50 29 86 0.1 0.422 0.91 0.343 0.934 100 58 81 0.15 0.422 0.91 0.453 0.899 150 87 77 0.2 0.422 0.91 0.540 0.863 200 116 72 0.25 0.422 0.91 0.610 0.825 250 145 68 0.3 0.422 0.91 0.668 0.786 300 173 63 0.35 0.422 0.91 0.716 0.745 350 202 59 0.4 0.422 0.91 0.758 0.703 400 231 54 0.45 0.422 0.91 0.793 0.658 450 260 50 0.5 0.422 0.91 0.824 0.612 500 289 45 0.55 0.422 0.91 0.851 0.563 550 318 41 0.6 0.422 0.91 0.876 0.512 600 347 36 0.65 0.422 0.91 0.897 0.459 650 376 32 0.7 0.422 0.91 0.916 0.403 700 405 27 0.75 0.422 0.91 0.934 0.344 750 434 23 0.8 0.422 0.91 0.949 0.282 800 462 18 0.85 0.422 0.91 0.964 0.217 850 491 14 0.9 0.422 0.91 0.977 0.149 900 520 9 0.95 0.422 0.91 0.989 0.077 950 549 4 1 0.422 0.91 1.000 0.000 1000 578 0 133. Results Se ns iti vi ty Specificity Study estimate 1 0 .8 .6 .4 .2 0 .2 .4 .6 .8 1 Summary point HSROC curve 95% confidence region 95% prediction region 14 Web Annex E. Systematic review for syndromic management of genital ulcer disease Co m pa rin g th e ac cu ra cy o f t he p re se nc e of G UD w ith th e ae tio lo gi ca l d ia gn os is o f h er pe s St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re r ec ru it ed Su b- po pu la ti on H ow is a po si ti ve ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Ch ou dh ry [2 2] 20 07 -8 In di a Lo w m id dl e 30 0 Se xu al h ea lth c lin ic 64 % m al e 16 % M SM Cl in ic al di ag no si s* G ra m s ta in , HS V- Ig M 57 12 3 22 8 Cl ar k[ 23 ] 20 03 -5 Pe ru U pp er m id dl e 32 85 Co m m un ity s et tin g 73 % h et er os ex ua l m en 16 % M SM Cl in ic al di ag no si s* HS V2 -A b 78 77 0 16 2 22 75 Li u[ 6] 20 03 Ch in a U pp er m id dl e 55 Se xu al h ea lth c lin ic 67 % m al e 7. 5% G U D Pr es en ce o f ul ce r PC R 15 0 38 2 M ur al id ha r [2 4] 20 13 In di a Lo w m id dl e 12 08 Se xu al h ea lth c lin ic 10 0% he te ro se xu al s 25 .4 % G U D Cl in ic al di ag no si s* G ie m sa s ta in , PC R, H SV 2- Ig M 76 6 5 11 21 O ’F ar re ll [2 5] 20 07 So ut h Af ric a U pp er m id dl e 64 2 Se xu al h ea lth c lin ic 50 % m al es 7% G U D Sy m pt om s + ris k fa ct or s HS V2 -A b 14 0 34 7 22 13 3 O tie no [2 6] 20 07 -9 Ke ny a Lo w m id dl e 78 6 En ro lle d in g en er al po pu la tio n st ud y 10 0% fe m al es liv in g w ith H IV Cl in ic al di ag no si s* HS V2 -Ig G 0 14 14 79 6 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 6 Ho sp ita l 10 0% m al es li vi ng w ith H IV Se lf- re po rt ed sy m pt om s HS V- 2 se ro lo gy 61 26 2 5 38 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 6 Ho sp ita l FS W Se lf- re po rt ed sy m pt om s HS V- 2 se ro lo gy 55 7 23 4 69 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 6 Ho sp ita l M SM Se lf- re po rt ed sy m pt om s HS V- 2 se ro lo gy 20 64 7 23 4 69 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 6 Ho sp ita l Se lf- re po rt ed sy m pt om s HS V- 2 se ro lo gy 37 29 9 22 34 5 *C lin ic al d ia gn os is is b as ed o n ph ys ic al e xa m in at io n an d hi st or y 153. Results To detect syphilis using a clinical diagnosis of syphilis among individuals with GUD, 15 studies provided 22 estimates for pooling. The pooled sensitivity for detecting syphilis is 64.4% (95% CI: 44.8-80.2), and pooled specificity is 83.7% (95% CI: 67.0-92.9). The diagnostic odds ratio is 9.32 (95% CI: 4.35-20.00). The positive likelihood ratio is 3.96 (95% CI: 2.08-7.54), and the negative likelihood ratio is 0.42 (95% CI: 0.27-0.66). The inverse of the negative likelihood ratio is 2.35 (95% CI: 1.52-3.65). For a cohort of 1000 individuals: Prevalence Sensitivity Specificity PPV NPV Number of cases Missed cases False Positive (Overtreated) 0.05 0.644 0.837 0.172 0.978 50 18 155 0.1 0.644 0.837 0.305 0.955 100 36 147 0.15 0.644 0.837 0.411 0.930 150 53 139 0.2 0.644 0.837 0.497 0.904 200 71 130 0.25 0.644 0.837 0.568 0.876 250 89 122 0.3 0.644 0.837 0.629 0.846 300 107 114 0.35 0.644 0.837 0.680 0.814 350 125 106 0.4 0.644 0.837 0.725 0.779 400 142 98 0.45 0.644 0.837 0.764 0.742 450 160 90 0.5 0.644 0.837 0.798 0.702 500 178 82 0.55 0.644 0.837 0.828 0.658 550 196 73 0.6 0.644 0.837 0.856 0.611 600 214 65 0.65 0.644 0.837 0.880 0.559 650 231 57 0.7 0.644 0.837 0.902 0.502 700 249 49 0.75 0.644 0.837 0.922 0.439 750 267 41 0.8 0.644 0.837 0.940 0.370 800 285 33 0.85 0.644 0.837 0.957 0.293 850 303 24 0.9 0.644 0.837 0.973 0.207 900 320 16 0.95 0.644 0.837 0.987 0.110 950 338 8 1 0.644 0.837 1.000 0.000 1000 356 0 16 Web Annex E. Systematic review for syndromic management of genital ulcer disease Se ns iti vi ty Specificity Study estimate 1 0 .8 .6 .4 .2 0 .2 .4 .6 .8 1 Summary point HSROC curve 95% confidence region 95% prediction region 173. Results Co m pa rin g th e ac cu ra cy o f c lin ic al d ia gn os is o f h er pe s wi th th e ae tio lo gi ca l d ia gn os is o f h er pe s St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Be he ts [8 ] 19 97 M ad ag as ca r Lo w 19 6 Se xu al h ea lth cl in ic 71 % m al e Cl in ic al d ia gn os is * M -P CR 52 4 11 2 28 Be he ts [9 ] 19 96 Ja m ai ca U pp er m id dl e 30 4 Se xu al H ea lth cl in ic 83 % m al e Cl in ic al d ia gn os is * M -P CR 21 10 24 24 9 Be yr er [1 0] 19 95 -6 Th ai la nd U pp er m id dl e 38 Se xu al h ea lth cl in ic 79 % fe m al e se x w or ke rs Cl in ic al d ia gn os is * M -P CR 0 1 1 36 Bh av sa r [1 1] 20 11 -1 2 In di a Lo w m id dl e 96 Ho sp ita l 79 % m al e Cl in ic al d ia gn os is * VD RL , T PH A 19 24 1 52 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Hi st or y an d ex am in at io n RP R, T PH A, Da rk fie ld m ic ro sc op y 10 8 2 27 9 6 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Hi st or y an d ex am in at io n + s yp hi lis s er ol og y or da rk fie ld m ic ro sc op y RP R, T PH A, Da rk fie ld m ic ro sc op y 10 7 3 9 27 6 Bo ga er ts [1 2] 19 90 -9 2 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e Cl in ic al d ia gn os is * RP R, T PH A, Da rk fie ld m ic ro sc op y 20 90 31 25 4 Di Ca rlo [1 3] 19 90 - 19 92 U SA Hi gh 22 0 Se xu al h ea lth cl in ic 10 0% m en Cl in ic al d ia gn os is * Da rk fie ld m ic ro sc op y 14 31 3 17 2 Ha ns on [2 8] 19 96 Za m bi a Lo w m id dl e 95 Ho sp ita l 10 0% m al e Cl in ic al d ia gn os is * Da rk fie ld m ic ro sc op y, RP R, T PH A 24 17 14 40 Ha ns on [2 8] 19 96 Za m bi a Lo w m id dl e 13 1 Ho sp ita l 10 0% fe m al e Cl in ic al d ia gn os is * Da rk fie ld m ic ro sc op y, RP R, T PH A 14 22 12 83 18 Web Annex E. Systematic review for syndromic management of genital ulcer disease St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R, R PR , FT A- Ab s 5 18 1 68 Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R, R PR , FT A- Ab s 30 4 52 6 Ht un [1 5] 19 93 -9 4 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic Cl in ic al d ia gn os is * M PC R, R PR , FT A- Ab s 33 1 52 6 N di ny a- Ac ho la [2 9] 19 90 -9 1 Ke ny a Lo w m id dl e 17 2 Pr im ar y ca re 47 % m al es Cl in ic al d ia gn os is * RP R 6 18 19 12 9 Pr ab ha ka r [1 6] 20 08 -9 In di a Lo w m id dl e 18 1 Se xu al h ea lth cl in ic 10 0% m al e Cl in ic al d ia gn os is * M -P CR 26 18 72 78 Sa nc he z[ 7] 19 95 -6 Do m in ic an Re pu bl ic U pp er m id dl e 81 G en er al pr ac tic e 10 0% m al e Cl in ic al d ia gn os is * M -P CR 2 2 11 66 Sa nc he z[ 7] 19 95 -6 Do m in ic an Re pu bl ic U pp er m id dl e 63 G en er al pr ac tic e 10 0% m al e Cl in ic al d ia gn os is * M -P CR 2 4 8 49 W an g[ 18 ] 19 98 -9 9 Ch in a U pp er m id dl e 96 Se xu al h ea lth cl in ic 10 0% ha d “S TI sy m pt om s” Cl in ic al d ia gn os is * M -P CR , R PR , TP PA 18 5 12 61 W an g[ 19 ] 20 00 -1 Ch in a U pp er m id dl e 22 7 Se xu al h ea lth cl in ic 90 % m al e Sy m pt om s + E xa m in at io n + R is k fa ct or s M -P CR , Da rk fie ld m ic ro sc op y, RP R, T PP A 94 12 6 11 5 Fa st [2 0] 19 80 Ke ny a Lo w m id dl e 70 “S pe ci al tr ea tm en t cl in ic ” 10 0% m al e Cl in ic al d ia gn os is * RP R, D ar kfi el d m ic ro sc op y 6 4 4 56 Da ng or [2 1] U nc le ar So ut h Af ric a U pp er m id dl e 21 0 Ho sp ita l 10 0% m al e Cl in ic al d ia gn os is * RP R, F TA -A BS , da rk fie ld m ic ro sc op y 22 3 25 16 0 *C lin ic al d ia gn os is is b as ed o n ph ys ic al e xa m in at io n an d hi st or y 193. Results For detection of syphilis from the presence of GUD, 12 studies provided 15 estimates for pooling. The pooled sensitivity for detecting syphilis is 20.0% (95% CI: 7.0-45.3), and pooled specificity is 92.6% (95% CI: 81.6-97.2). The diagnostic odds ratio is 3.12 (95% CI: 1.24-7.88). The positive likelihood ratio is 2.70 (95% CI: 1.23-5.91), and the negative likelihood ratio is 0.86 (95% CI: 0.71- 1.05). The inverse of the negative likelihood ratio is 1.16 (95% CI: 0.95-1.41). For a cohort of 1000 individuals: Prevalence Sensitivity Specificity PPV NPV Number of cases Missed cases False Positive (Overtreated) 0.05 0.2 0.926 0.125 0.957 50 40 70 0.1 0.2 0.926 0.231 0.912 100 80 67 0.15 0.2 0.926 0.323 0.868 150 120 63 0.2 0.2 0.926 0.403 0.822 200 160 59 0.25 0.2 0.926 0.474 0.776 250 200 56 0.3 0.2 0.926 0.537 0.730 300 240 52 0.35 0.2 0.926 0.593 0.683 350 280 48 0.4 0.2 0.926 0.643 0.635 400 320 44 0.45 0.2 0.926 0.689 0.586 450 360 41 0.5 0.2 0.926 0.730 0.537 500 400 37 0.55 0.2 0.926 0.768 0.486 550 440 33 0.6 0.2 0.926 0.802 0.436 600 480 30 0.65 0.2 0.926 0.834 0.384 650 520 26 0.7 0.2 0.926 0.863 0.332 700 560 22 0.75 0.2 0.926 0.890 0.278 750 600 19 0.8 0.2 0.926 0.915 0.224 800 640 15 0.85 0.2 0.926 0.939 0.170 850 680 11 0.9 0.2 0.926 0.961 0.114 900 720 7 0.95 0.2 0.926 0.981 0.057 950 760 4 1 0.2 0.926 1.000 0.000 1000 800 0 20 Web Annex E. Systematic review for syndromic management of genital ulcer disease Di ag no si s of s yp hi lis fr om th e pr es en ce o f G UD St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a po si ti ve ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Ch ou dh ry [2 2] 20 07 -8 In di a Lo w m id dl e 30 0 Se xu al h ea lth cl in ic 64 % m al e 16 % M SM Cl in ic al di ag no si s* VD RL , T PH A 11 3 4 28 2 Cl ar k[ 23 ] 20 03 -5 Pe ru U pp er m id dl e 32 85 Co m m un ity se tt in g 73 % h et er os ex ua l m en 16 % M SM Sy m pt om / Ex am in at io n + R PR RP R, T PP A 6 91 23 4 29 54 Da ly [3 0] 19 89 -9 1 Ke ny a Lo w m id dl e 43 67 Fa m ily pl an ni ng cl in ic 10 0% fe m al es Cl in ic al di ag no si s* RP R 4 79 76 42 08 De sa i[3 1] 20 00 In di a Lo w m id dl e 11 8 Se xu al h ea lth cl in ic 10 0% F SW Sy m pt om s + Ex am in at io n RP R, T PH A 4 23 3 88 Li u[ 6] 20 03 Ch in a U pp er m id dl e 55 Se xu al h ea lth cl in ic 10 0% m al e 14 % G U D Pr es en ce o f ul ce r PC R, R PR , T PP A 13 0 40 2 M ur al id ha r [2 4] 20 13 In di a Lo w m id dl e 90 Se xu al h ea lth cl in ic 67 % m al e 7. 5% G U D Cl in ic al di ag no si s* Da rk fie ld m ic ro sc op y, P CR , VD RL , T PH A, FT A- Ab s 4 3 2 81 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 6 Ho sp ita l 10 0% fe m al es liv in g w ith H IV Se lf- re po rt ed sy m pt om s RP R, T PP A 0 2 4 36 0 213. Results St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a po si ti ve ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 36 5 Ho sp ita l 10 0% m al es li vi ng w ith H IV Se lf- re po rt ed sy m pt om s RP R, T PP A 5 58 15 28 7 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 76 8 Ho sp ita l FS W Se lf- re po rt ed sy m pt om s RP R, T PP A 1 16 24 72 7 Sh ah [2 7] 20 08 El S al va do r Lo w m id dl e 70 3 Ho sp ita l M SM Se lf- re po rt ed sy m pt om s RP R, T PP A 2 31 65 60 5 Sh ah es m ae ili [3 2] 20 15 Ira n (Is la m ic Re pu bl ic o f) U pp er m id dl e 13 37 Co m m un ity 10 0% F SW 3% G U D Se lf- re po rt ed sy m pt om s Ra pi d te st s – SD Bi ol in e HI V/ Sy ph ili s Du o + A le re Sy ph ili s RP R, E IA 0 5 40 12 92 Ts ai [3 3] 20 08 Ta iw an , Ch in a Hi gh 13 8 Se xu al h ea lth cl in ic 10 0% m al es 29 % G U D Cl in ic al di ag no si s* RP R, T PH A 26 7 86 19 O ’F ar re ll[ 25 ] 20 07 So ut h Af ric a U pp er m id dl e 64 5 Se xu al h ea lth cl in ic 10 0% he te ro se xu al s 25 .4 % G U D Sy m pt om s + ris k fa ct or s RP R, T PP A 17 29 14 7 45 2 O tie no [2 6] 20 07 -9 Ke ny a Lo w m id dl e 82 4 En ro lle d in g en er al po pu la tio n st ud y 50 % m al es 7% G U D Cl in ic al di ag no si s* RP R, T PP A 0 14 14 79 6 Yu [3 4] 20 02 -4 Ta iw an , Ch in a Hi gh 30 7 Se xu al h ea lth cl in ic 10 0% m al e 11 % G U D Cl in ic al di ag no si s M -P CR , R PR , T PH A 8 13 17 26 9 *C lin ic al d ia gn os is is b as ed o n ph ys ic al e xa m in at io n an d hi st or y 22 Web Annex E. Systematic review for syndromic management of genital ulcer disease For detection of chancroid, 13 studies provided 18 estimates for pooling. The pooled sensitivity for detecting chancroid using a syndromic management approach is 78.2% (95% CI: 63.5-88.0), and pooled specificity is 56.5% (95% CI: 37.1-74.2). The diagnostic odds ratio is 4.66 (95% CI: 2.84-7.64). The positive likelihood ratio is 1.80 (95% CI: 1.28-2.52), and the negative likelihood ratio is 0.39 (95% CI: 0.27-0.55). The inverse negative likelihood ratio is 2.59 (95% CI: 1.81-3.71). For a cohort of 1000 individuals: Prevalence Sensitivity Specificity PPV NPV Number of cases Missed cases False Positive (Overtreated) 0.05 0.782 0.565 0.086 0.980 50 11 413 0.1 0.782 0.565 0.166 0.959 100 22 392 0.15 0.782 0.565 0.241 0.936 150 33 370 0.2 0.782 0.565 0.310 0.912 200 44 348 0.25 0.782 0.565 0.375 0.886 250 55 326 0.3 0.782 0.565 0.435 0.858 300 65 305 0.35 0.782 0.565 0.492 0.828 350 76 283 0.4 0.782 0.565 0.545 0.795 400 87 261 0.45 0.782 0.565 0.595 0.760 450 98 239 0.5 0.782 0.565 0.643 0.722 500 109 218 0.55 0.782 0.565 0.687 0.680 550 120 196 0.6 0.782 0.565 0.729 0.633 600 131 174 0.65 0.782 0.565 0.770 0.583 650 142 152 0.7 0.782 0.565 0.807 0.526 700 153 131 0.75 0.782 0.565 0.844 0.463 750 164 109 0.8 0.782 0.565 0.878 0.393 800 174 87 0.85 0.782 0.565 0.911 0.314 850 185 65 0.9 0.782 0.565 0.942 0.224 900 196 43 0.95 0.782 0.565 0.972 0.120 950 207 22 1 0.782 0.565 1.000 0.000 1000 218 0 233. Results Se ns iti vi ty Specificity Study estimate 1 0 .8 .6 .4 .2 0 .2 .4 .6 .8 1 Summary point HSROC curve 95% confidence region 95% prediction region 24 Web Annex E. Systematic review for syndromic management of genital ulcer disease De te ct io n of c ha nc ro id u si ng a c lin ic al d ia gn os is o f c ha nc ro id in a p op ul at io n wi th G UD St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Be he ts [8 ] 19 97 M ad ag as ca r Lo w 19 6 Se xu al h ea lth cl in ic 71 % m al e 10 0% G U D Cl in ic al d ia gn os is * M -P CR 34 30 63 69 Be he ts [9 ] 19 96 Ja m ai ca U pp er m id dl e 30 4 Se xu al H ea lth cl in ic 83 % m al e 10 0% G U D Cl in ic al d ia gn os is * M -P CR 54 18 57 17 5 Be he ts [1 0] 19 95 -6 Th ai la nd U pp er m id dl e 38 Se xu al h ea lth cl in ic 79 % fe m al e se x w or ke rs 10 0% G U D Cl in ic al d ia gn os is * M -P CR 0 0 6 32 Bh av sa r[1 1] 20 11 - 12 In di a Lo w m id dl e 96 Ho sp ita l 79 % m al e 10 0% G U D Cl in ic al d ia gn os is * G ra m s ta in 2 1 1 92 Bo ga er ts [1 2] 19 90 - 92 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e 10 0% G U D Hi st or y an d ex am in at io n Cu ltu re 11 5 0 27 2 8 Bo ga er ts [1 2] 19 90 - 92 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e 10 0% G U D Hi st or y an d ex am in at io n + sy ph ili s se ro lo gy or d ar kfi el d m ic ro sc op y Cu ltu re 83 32 18 8 92 Bo ga er ts [1 2] 19 90 - 92 Rw an da Lo w 39 5 G en er al pr ac tic e 63 % m al e 10 0% G U D Cl in ic al d ia gn os is * Cu ltu re 74 41 67 21 3 Di Ca rlo [1 3] 19 90 - 19 92 U SA Hi gh 22 0 Se xu al h ea lth cl in ic 10 0% m en 10 0% G U D Cl in ic al d ia gn os is * Cu ltu re 40 78 6 96 Ht un [1 5] 19 93 - 94 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic 10 0% G U D Cl in ic al d ia gn os is * M PC R 54 2 22 14 Ht un [1 5] 19 93 - 94 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic 10 0% G U D Cl in ic al d ia gn os is * M PC R 51 4 31 6 Ht un [1 5] 19 93 - 94 Le so th o Lo w m id dl e 92 Se xu al h ea lth cl in ic 10 0% G U D Cl in ic al d ia gn os is * M PC R 53 3 32 4 253. Results St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve N di ny a- Ac ho la [2 9] 19 90 - 91 Ke ny a Lo w m id dl e 15 6 Pr im ar y ca re 47 % m al es 10 0% G U D Cl in ic al d ia gn os is * Cu ltu re 51 5 76 24 Pr ab ha ka r [1 6] 20 08 -9 In di a Lo w m id dl e 18 1 Se xu al h ea lth cl in ic 10 0% m al e 10 0% G U D Cl in ic al d ia gn os is * M -P CR 59 31 37 54 Ri sb ud [1 7] 19 94 In di a Lo w m id dl e 30 2 Se xu al h ea lth cl in ic 10 0% G U D Cl in ic al d ia gn os is * M -P CR 53 31 76 14 2 Sa nc he z[ 7] 19 95 -6 Do m in ic an Re pu bl ic U pp er m id dl e 81 G en er al pr ac tic e 10 0% m al e 10 0% G U D Cl in ic al d ia gn os is * M -P CR 11 10 17 43 Sa nc he z[ 7] 19 95 -6 Pe ru U pp er m id dl e 63 G en er al pr ac tic e 10 0% m al e 10 0% G U D Cl in ic al d ia gn os is * M -P CR 0 3 21 39 Fa st [2 0] 19 80 Ke ny a Lo w m id dl e 70 “S pe ci al tr ea tm en t cl in ic ” 10 0% m al e 10 0% G U D Cl in ic al d ia gn os is * Cu ltu re 42 6 8 14 Da ng or [2 1] U nc le ar So ut h Af ric a U pp er m id dl e 21 0 Ho sp ita l 10 0% G U D Cl in ic al d ia gn os is * 11 7 30 14 49 Fo r d et ec tio n of c ha nc ro id u sin g G U D, tw o st ud ie s pr ov id ed tw o es tim at es fo r p oo lin g. W e w er e un ab le to c on du ct a m et a- an al ys is du e to to o fe w s tu di es . St ud y Ye ar o f st ud y Co un tr y Co un tr y in co m e le ve l Sa m pl e si ze W he re re cr ui te d Su b- po pu la ti on H ow is a p os it iv e ca se d efi ne d D ia gn os ti cs Tr ue po si ti ve Fa ls e ne ga ti ve Fa ls e po si ti ve Tr ue ne ga ti ve Li u[ 6] 20 03 Ch in a U pp er m id dl e 55 Se xu al h ea lth cl in ic 10 0% m al e 14 % G U D Pr es en ce o f u lc er PC R 0 0 53 2 M ur al id ha r [2 4] 20 13 In di a Lo w m id dl e 90 Se xu al h ea lth cl in ic 67 % m al e 7. 5% G U D Cl in ic al d ia gn os is * G ra m s ta in , cu ltu re , P CR 0 1 10 79 *C lin ic al d ia gn os is is b as ed o n ph ys ic al e xa m in at io n an d hi st or y 26 Web Annex E. Systematic review for syndromic management of genital ulcer disease 3.3 Risk of bias assessment using QUADAS-2 Study Patient selection Index Test Reference standard Flow and Timing Behets[8] Low Low Low Low Behets[9] Low Low Low Low Beyrer[10] Low Low Low Low Bhavsar[11] Low Low Low High1 Low Bogaerts[12] Low Low Low High2 Low DiCarlo[13] Low Low Low High3 Low Hina[14] Low Low High Low Htun[15] Low Low Low Low Prabhakar[16] Low Low Low Low Risbud[17] Low Low Low Low Sanchez[7] Low Low Low Low Wang[18] Low Low Unclear Low Wang[19] Low Low Low Low Fast[20] Low Low Low High4 Low Dangor[21] Low Low Low High4 Low Hanson[28] Low Low Low High5 Low Ndinya-Achola[29] Low Low High Low Das[5] Low Low Unclear Low Liu[6] Low Low Unclear Low Choudhry[22] Low Low Low High5 Low Clark[23] Low Low Low Low Muralidhar[24] Low Low Low Low O'Farrell[25] Low Low Low Low Otieno[26] Low Low Low High6 Low Shah[27] Low Low Low High6 Low Daly[30] Low Low Low High7 Low Desai[31] Low Low Low Low Shahesmaeili[32] Low Low Low Low Tsai[33] Low Low Low Low Yu[34] Low Low Low Low 1 High risk for NG, HD, CG, HSV, Low risk for TP 2 High risk for NG, HD, HSV, Low risk for TP 3 High risk for HD, HSV, Low risk for TP 4 High risk for CT, HD, HSV, Low risk for TP 5 High risk for CT, NG, HD, CG, HSV, Low risk for TP 6 High risk for HSV, Low risk for CT, NG, TP 7 High risk for NG, Low risk for TP Recommendations from WHO as depicted by Vickerman contrasting 1994 and 2003 algorithms.[59] 273. Results Quite rare to have an explicit evaluation of WHO algorithms[12] 28 Web Annex E. Systematic review for syndromic management of genital ulcer disease 293. Results Chinese algorithm[19] 30 Web Annex E. Systematic review for syndromic management of genital ulcer disease Cote d’Ivoire[61] 313. Results GUD algorithm used in Botswana[56] 32 Web Annex E. Systematic review for syndromic management of genital ulcer disease Chinese algorithm[18] 333. Results Brazil algorithm[85] 34 Web Annex E. Systematic review for syndromic management of genital ulcer disease India’s algorithm[16] 353. Results Rwanda (1998 publication)[86] 36 Web Annex E. Systematic review for syndromic management of genital ulcer disease Aetiology of GUD 155 patients attending outpatient department in hospital, Swaziland (1979)[87] • 65 HD • 25 TP • 18 LGV • 17 HSV • 5 Mixed • 0 none 19 primary health centre, Ethiopia, (2001)[68] • 2 TP 100 patients from STI clinic in Kenya (1980)[20] • 6 mixed • 48 HD • 6 HSV • 10 TP • 0 LGV • 36 no infections 307 people from STI clinic in Taiwan, China (2002-2004)[34] • 21 TP 210 people from STI clinic in Rwanda (1986)[98] • 37 TP • 32 HSV • 24 HD • 13 LGV • 29 Mixed • 75 none 227 people from STI clinic in China (2000-2001) [19] • 78 TP • 43 HSV • 28 TP + HSV • 76 no diagnosis • 0 HD 96 people from STI clinic in China (1998-1999) [18] • 23 TP • 33 HSV • 40 – no pathogen • 0 HD 76 people presenting at medical centre in Mozambique (2005)[99] • 47 HSV • 3 LGV • 3 HD • 0 CG (donovanosis) • 0 TP • 23 no diagnosis • 2 mixed infection (HSV and LGV) 42 women from the health centre and hospital dispensary in Rwanda (1994)[86] • 34 TP 38 men from the health centre and hospital dispensary in Rwanda (1994)[86] • 37 TP 81 men from STI clinics in the Dominican Republic(1995-6)[7] • 5% TP • 26% HD • 43% HSV 63 men from STI clinics in Peru (1995-6)[7] • 10% TP • 5% HD • 43% HSV 194 patients from STI clinics in India (2008-9) [16] • 76 HSV • 27 TP • 17 Mixed • 1 HD 373. Results 202 patients from general outpatients clinic in Uganda (1999-2001)[38] • 80 HSV-2 • 7 TP • 5 HD • 15 multiple 100 patients from rural Uganda (xx)[36] • 61 HSV-2 • 5 TP • 3 HSV-1 • 1 HD • 1 multiple 398 patients from STI clinic in Malawi (2004- 2006)[100] • 67% HSV2 (serology) • 15% TP • 15% HD • 6% LGV • 6% mixed • 20% no aetiology 59 patients attending primary care in the Central African Republic (1993)[58] • 16 HD • 20 TP • 19 HSV • 10 (2 organisms or more) 298 from STI clinic in the USA (1992-1994)[101] • 102 HSV • 75 TP • 65 HD • 62 negative • 7 mixed 240 patients in South Africa in hospital in South Africa (?published 1990)[21] • 29 no diagnosis • 37 – mixed • 147 HD • 7 HSV • 52 TP • 8 LGV • 1 CG 90 patients attending STI clinic in India (2010- 11)[24] • 6 TP • 66 HSV • 0 HD • 0 LGV • 0 Donovanosis 105 patients attending STI clinic Lesotho (1993- 4)[102] • 56% HD • 23% syphilis • 26% HSV 587 people attending STI clinic in South Africa (2000-2001)[83] • 48% HSV • 14% TP • 11% CT-LGV • 10% HD • 1% CG 156 people attending STI clinic in Brazil (1995) [85] • 31% TP 70 people attending “clinics” in Zimbabwe (2015)[79] • 17 HSV • 8 TP • 1 CT-LGV • 0 HD 778 people attending STI clinic in Malawi (1992-3)[78] • 129/758 TP • 204/778 HD 100 people attending STI clinic in Lesotho (1993-4)[15] • 56 HD • 26 HSV • 23 TP • 7 CT 38 Web Annex E. Systematic review for syndromic management of genital ulcer disease 137 people attending STD clinic in Malawi (1998-1999)[52] • 47 HSV • 41 HD • 5 TP 136 people attending STD clinic in Malawi (unclear, published 2003)[103] • 3% TP • 30% HD • 35% HSV 304 people from Jamaica[9] • 158 HSV • 72 HD • 31 TP 446 men from a sexual health clinic in the USA (1990-1992)[13] • 45 TP • 118 HD • 57 HSV 98 patients from urban STD clinic in Uganda (date unclear, before 1995)[104] • 48 HSV • 11/89 TP 61 attendees of public STD clinic with GUD in Madagascar (1992-93)[105] • 56% syphilis • 29% LGV • 20% chancroid • 2% HSV 196 attendees of STD clinic with GUD Madagascar (1997)[8] • 61 HD (chancroid) • 51 TP • 15 HSV • 3 TP and HSV • 2 HD and TP • 1 HD and HSV 778 people of STD clinic in Malawi (1992-93)[71] • 204 HD • 137 TP 100 people from STI clinic in South Africa (1988-9)[106] • 40 TP • 18 HSV • 16 CG • 14 • HD • 6 LGV • 18 none • 13 multiple 201 people from STI clinic in India (2008-9)[107] • 49 HSV • 20 TP • 3 CG • 30 HD • 1 LGV 100 men from STI clinic in South Africa (1989) [108] • 29 TP • 12 HD • 9 CG • 9 HSV • 3 LGV • 14 Mixed • 24 none 104 patients, STI clinic, Gambia (before 1987) [88] • 54 HD • 23 TP • 7 LGV • 6 HSV • 28 no • 15 mixed 516 people from STI clinics in the USA (1994) [109] • 16 HD • 51 TP • 320 HSV • 13 Mixed • 116 none 393. 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APPENDIX A – SEARCH RESULTS 5.1 Genital ulcers syndromes The search retrieved a total of 14,190- results. 4286 (30%) were identified as duplicates. The number of results pre-and post-deduplication is listed in the table below. Database name Diagnostic accuracy: Total number of results Diagnostic accuracy: Number of results once duplicates removed Other papers: Total number of results Other papers: Number of results once duplicates removed Ovid SP Medline and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1753 1748 941 940 OvidSP Embase 4687 3564 2590 2063 OvidSP Global Health 1159 428 398 202 OvidSP Northern Light Life Sciences Conference Abstracts 60 30 74 39 Ebsco CINAHL Plus 526 120 470 209 Ebsco Africa-Wide Information 287 26 63 13 Clarivate Analytics Web of Science Core Collection 893 346 216 108 BIREME/PAHO/WHO Virtual Health Library LILACS 44 41 29 27 Total 9409 6303 4781 3601 For more information, contact: World Health Organization Department of Global HIV, Hepatitis and STI Programme 20, avenue Appia 1211 Geneva 27 Switzerland Email: hiv-aids@who.int www.who.int/hiv