Comparative evaluation of diagnostic performance of Xpert between paired IS and GW in children <3.5 years in Cape Town, SA

Transcription

1 Comparative evaluation of diagnostic performance of Xpert between paired IS and GW in children <3.5 years in Cape Town, SA Name: Dr. Erick Bunyasi Research fellow: IDM 03/11/ :34:14 1

2 03/11/ :34:14 2

3 Presentation Outline Background Objectives Study population & design Results Discussion

4 Background [1]: TB Burden TB: 8.6 M new cases and 1.3 M deaths pa globally 1. Incidence of TB in Africa 255/ 10 5 per annum 1. BCG: consistent high VE against childhood TBM & miliary TB, but variable VE against adulthood PTB 2 03/11/ :34:14 REF: 1= WHO, 2013; 2=Trunz B.B. et al

5 Background [2]: TB diagnostics Smear microscopy: Labor intensive, low sensitivity & specificity, fast turn-around time, cheap. TB culture: Enables sensitivity testing; long turn around time [ltfu]; expensive; most labor intensive, relatively low sensitivity and specificity. Xpert test: simple-to-use [min training req; hands on time < 2min]; quick turn-around time [<2hrs], highly sensitive and specific, contamination reduced by closed cartridges; expensive; not optimized for f- up. 03/11/ :34:14 5

6 Primary objective To compare diagnostic accuracy [Sensitivity and Specificity] of Xpert test between paired Induced Sputum [IS] & Gastric Washout [GW] in children <3.5 years 03/11/ :34:14 6

7 Study population & design Source population: Children < 3.5 years from Worcester district in WCP [ ] Study design: Cross-sectional study 03/11/ :34:14 7

8 Statistical analysis Exploratory data analysis: histograms, frequency tables, mean [&SD], median[&iqr], %[&95%CI] as appropriate. Diagnostic accuracy: Sn, Sp, & CI determined using Wilson score method McNemar s χ 2 test: compared paired samples Wilcoxon sign-rank test: mttp culture IS1/2; GW1/2; IS/GW Kruskal Wallis test: compared mttp across levels defined 03/11/ :34:14 by semi-quantitative Xpert results/bands 8

9 Study profile 03/11/ :34:14 9 [1214 admission events * 4 specimens per admission=4856 specimens in total]

10 Table 1: Culture & Xpert results summary Specimen Positive Xpert Positive culture Positive culture or results [%, 95% CI] results[%, 95% CI] Xpert 2 result [%, CI] IS1 7/1157[<1;0-1] 17/1107[2;1-2] 18/1093[2;1-3] IS2 4/1144[<1;0-1] 8/1127[1;0-1] 9/1105[1;0-2] IS1 or IS2 8/1173[<1;0-1] 19/1174[2;1-3] 27/2198[1%;1-2] GW1 4/1154[<1;0-1] 16/1094[1;1-2] 18/1068[2;1-3] GW2 11/1151[1;1-2] 16/1135[1;1-2] 22/1115[2;1-3] GW1 or GW2 13/1174[1;1-2] 25/1183[2;1-3] 40/2183[2;1-2] Any of IS1, IS2, 18/1175[2;1-2] 36/1188[3;2-4] 54/2064[3;2-3] GW1 or GW2 1 03/11/ :34:14 10

11 Table 2: Descriptive statistics: cult & Xpert GeneXpert result M. tb culture result Total [N; %] Negative [N; %] Positive [N: %] Not detected 4314 [99] 36 [69] 4350 [99] Very low [CT 28] 5 [<1] 15 [29] 20 [<1] Low [CT 22 - < 28] 1 [<1] 1 [2] 2 [<1] Medium [CT 16 - < 22] 1 [<1] 0 [0] 1 [<1] High [CT <16] 1 [<1] 0 [0] 1 [<1] Total 4322 [100] 52 [100] 4374 [100] 03/11/ :34:14 11

12 Table 3 Test performance characteristics of Xpert MTB/RIF assay and smear microscopy compared to culture 03/11/ :34:14 12

13 Specimens Sensitivity Specificity PPV [x/n{ %[95%CI ]}] NPV [x/n{ %[95%CI ]}] [x/n{ %[95%CI ]}] [x/n{ %[95%CI ]}] a. GeneXpert MTB/RIF vs. culture [Positive M.tb Xpert vs. culture [Reference standard +ve: Any positive M.tb culture on IS1 or IS2 or GW1 or GW2] culture for any of IS1 or IS2 or GW1 or GW2 taken as the reference standard against Xpert results for each of the specimens indicated in the first column] IS1 7/31[23%;11-40] 908/908[100%;99-100] 7/7[100%;65-100] 908/932[97%;96-98] IS2 4/31[13%;5-29] 903/903[100%;99-100] 4/4[100%;51-100] 903/930[97%;96-98] IS1 or IS2 1 8/30[27%;14-44] 893/893[100%;99-100] 8/8[100%;68-100] 893/915[98%;96-98] GW1 3/32[9%;3-24] 902/903[100%;99-100] 3/4[75%;30-95] 902/931[97%;96-98] GW2 6/31[19%;9-36] 902/906[100%;99-100] 6/10[60%;31-83] 902/927[97%;96-98] GW1 or GW2 3 7/31[23%;11-40] 885/890[99%;99-100] 7/12[58%;32-81] 885/909[97%;96-98] IS1 or IS2 or GW1 or GW2 5 12/31[39%;24-56] 865/870[99%;99-100] 12/17[71%;47-87] 865/884[98%;97-99] No regard to specimen/ timing 16/52[31%;20-44] 4314/4322[100%; ] 16/24[67%;47-82] 4314/4374[99%;98-99] GeneXpert MTB/RIF vs. culture [Similar permutation of specimens for Xpert and M.tb culture] IS1 6/16[38%;19-61] 1075/1076[100%; ] 6/7[86%;49-97] 1075/1085[99%;98-100] IS2 3/8[38%;14-70] 1096/1097[100%; ] ¾[75%;30-95] 1096/1101[100%;99-100] IS1 or IS2 1 8/18[44%;25-66] 1009/1009[100%; ] 8/8[100%;68-100] 1009/1019[99%;98-100] GW1 2/14[14%;4-40] 1050/1051[100%; ] 2/3[67%;21-94] 1050/1062[99%; ] GW2 5/14[36%;16-61] 1093/1098[100%;99-100] 5/10[50%;24-76] 1093/1102[99%;99-100] GW1 or GW2 3 5/20[25%;11-47] 984/990[99%;99-100] 5/11[46%;21-72] 984/999[99%;98-99] Any of 4 specimens 12/31[39%;24-56] 865/870[99%;99-100] 12/17[71%;47-87] 865/884[98%;97-99] No regard to specimen/ timing 16/52 [31%; 20-44] 4314/4322 [100%; ] 16/24 [67%; 47-82] 4314/4350 [99%;99-99] Smear microscopy for AAFB vs. culture Any of 4 specimens 0/32[0%;0-11] 916/919[100%;99-100] 0/3[0%;0-56] 916/948[97%;95-98] No regard 03/11/2014 to specimen/ 21:34:14 0/57[0%;0-6] 4399/4403[100%; ] 0/4[0%;0-49] 4399/4456[99%;98-99] 13 timing

14 Specimens Sensitivity Specificity PPV [x/n{ %[95%CI ]}] NPV [x/n{ %[95%CI ]}] [x/n{ %[95%CI ]}] [x/n{ %[95%CI ]}] Xpert vs. culture [Reference standard +ve: Any positive M.tb culture on IS1 or IS2 or GW1 or GW2] IS1 7/31[23%;11-40] 908/908[100%;99-100] 7/7[100%;65-100] 908/932[97%;96-98] IS2 4/31[13%;5-29] 903/903[100%;99-100] 4/4[100%;51-100] 903/930[97%;96-98] IS1 or IS2 1 8/30[27%;14-44] 893/893[100%;99-100] 8/8[100%;68-100] 893/915[98%;96-98] GW1 3/32[9%;3-24] 902/903[100%;99-100] 3/4[75%;30-95] 902/931[97%;96-98] GW2 6/31[19%;9-36] 902/906[100%;99-100] 6/10[60%;31-83] 902/927[97%;96-98] GW1 or GW2 3 7/31[23%;11-40] 885/890[99%;99-100] 7/12[58%;32-81] 885/909[97%;96-98] IS1 or IS2 or GW1 or GW2 5 12/31[39%;24-56] 865/870[99%;99-100] 12/17[71%;47-87] 865/884[98%;97-99] No regard to specimen/ timing 16/52[31%;20-44] 4314/4322[100%; ] 16/24[67%;47-82] 4314/4374[99%;98-99] GeneXpert MTB/RIF vs. culture [Similar permutation of specimens for Xpert and M.tb culture] IS1 6/16[38%;19-61] 1075/1076[100%; ] 6/7[86%;49-97] 1075/1085[99%;98-100] IS2 3/8[38%;14-70] 1096/1097[100%; ] ¾[75%;30-95] 1096/1101[100%;99-100] IS1 or IS2 1 8/18[44%;25-66] 1009/1009[100%; ] 8/8[100%;68-100] 1009/1019[99%;98-100] GW1 2/14[14%;4-40] 1050/1051[100%; ] 2/3[67%;21-94] 1050/1062[99%; ] GW2 5/14[36%;16-61] 1093/1098[100%;99-100] 5/10[50%;24-76] 1093/1102[99%;99-100] GW1 or GW2 3 5/20[25%;11-47] 984/990[99%;99-100] 5/11[46%;21-72] 984/999[99%;98-99] Any of 4 specimens 12/31[39%;24-56] 865/870[99%;99-100] 12/17[71%;47-87] 865/884[98%;97-99] No regard to specimen/ timing 16/52 [31%; 20-44] 4314/4322 [100%; ] 16/24 [67%; 47-82] 4314/4350 [99%;99-99] Smear microscopy for AAFB vs. culture Any of 4 specimens 0/32[0%;0-11] 916/919[100%;99-100] 0/3[0%;0-56] 916/948[97%;95-98] No regard 03/11/2014 to specimen/ 21:34:15 0/57[0%;0-6] 4399/4403[100%; ] 0/4[0%;0-49] 4399/4456[99%;98-99] 14 timing

15 McNemar s χ 2 test: All IS vs GW Xpert on IS vs Xpert on GW P-value= 0.47 Only pairs with either culture or Xpert +ve result P-value= 0.63 Conclusion: significant difference No Conclusion: No significant difference 03/11/ :34:15 15

16 Evaluation of TTP Specimen No of culture Median TTP [days] TTP IQR [days] positive specimens with TTP IS IS GW GW IS1 + IS GW1 + GW All specimens Wilcoxon signed-rank test: Combined IS vs combined GW P-value= Conclusion: No significant difference in TTP between IS & GW 03/11/ :34:15 16

17 Consistency of findings with literature Sens observed lower than that in other studies Lower Sn possibly due to young age of pax, less severe TB & less comorbidities due to trial setting, samples used, use of unpaired samples Few similar studies: design [paired specimens], n, HIV prev, & [esp] age 03/11/ :38:47 17

18 Nicol et al 2011* Variable Nicol et al This study Objective; Comparison of Xpert & Smear Xpert between IS & GW Age [years] Specimen Only IS Paired IS & GW HIV prevalence 18% [95% CI: 14-22] NA Smear +ve rate 4% <1% Sensitivity of Xpert in smear -ve IS [IS1/2] In HIV -ve: 49% 44%[CI 25-66] {ref; 8/18} In HIV +ve: 18% [ NA Sensitivity of Xpert in smear +ve IS [IS1/2] In HIV -ve: 100% NA Specificity of Xpert in smear ve IS [IS1/2] In HIV -ve: 98% 100% In HIV +ve:* NA Specificity of Xpert in smear +ve IS [IS1/2] In HIV -ve: 100% NA *Lancet Infect Dis 2011;11: /11/ :38:47 18

19 Limitations in our study Few +ve TB disease events [*wide CI for Sn; correl between semi-quantitative Xpert assay results & TTP; comparative accuracy in dx of MDRTB NA] Only HIV-ve children enrolled in trial, thus our findings are not generalizable to HIV+ve children in this or similar settings [*Mixed findings in lit of Xpert accuracy in HIV-/+; HIV burden] Imperfect reference std [Nb] 03/11/ :38:47 19

20 Summary No sig diff in diagnostic accuracy of Xpert assay between paired IS and GW specimens in HIV-ve children aged <3.5 yrs in a high TB & HIV burden setting. Sn of 44% [CI: 25-66] and Sp of 100% [CI: ] for Xpert when done on 2 IS. Sn of 25% [CI: 11-47] and Sp of 99% [CI: ] for Xpert when done on 2 GW. 03/11/ :38:47 20

21 References 1 WHO global TB report 2013 [WHO, 2013]. 2 Trunz B.B. et al. Effect of BCG vaccination on childhood TB [The Lancet 2006; 367(9517): ]. 3 Tameris MD, Hatherill M., et al. Safety & VE of MVA85A; RCT [The Lancet 2013; 381(9871): ]. 03/11/ :34:15 21

22 Acknowledgements South African Tuberculosis Vaccine Initiative for my research fellowship Supervisors: Dr. Michele Tameris & Prof. Mark IDM SATVI team at UCT & Worcester 03/11/ :34:15 22

23 Thanks 03/11/ :34:16 23

24 03/11/ :34:16 24