Automated real-time nucleic acid amplification technology...
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Automated real-time nucleic acid amplification technology for rapid
and simultaneous detection of tuberculosis and rifampicin resistance:
Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB
in adults and children
Global TB ProgrammeWorld Health OrganizationAvenue Appia 20, CH-1211 Geneva-27, Switzerland
Information Resource Centre HTM/GTB:Email: [email protected]: www.who.int/tb
ISBN 978 92 4 150633 5
POLICY UPDATE
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AC
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MOLECULAR DIAGNOSTICS
TUBERCULOSISDRUG-RESISTANCE
NEW DIAGNOSTIC TESTS RIF
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PIC
INP
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PID
TB
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RESISTANCEDIAGNOSIS
MYCOBACTERIUM
TB
TB/HIV
COVER policy_update_OK.indd 1 11/04/2014 14:50
Automated real-time nucleic acid amplification technology for rapid and simultaneous detection
of tuberculosis and rifampicin resistance:Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB
in adults and children
Policy update
WHO Library Cataloguing-in-Publication Data
Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF assay for the diagnosis of pulmonary and extra-pulmonary TB in adults and children. Policy update.
Revision of Automated real-time nucleic acid amplification technology for rapid and simultaneous detec-tion of tuberculosis and rifampicin resistance: Xpert MTB/RIF system. Policy statement. Geneva, World Health Organization, 2011.
1.Tuberculosis, Multidrug-resistant - diagnosis. 2.Tuberculosis - diagnosis. 3.Rifampin - pharmacology. 4.Mycobacterium tuberculosis - isolation and purification. 5.HIV infections - diagnosis. 6.Sensitivity and specificity. 7.Guideline. I. World Health Organization.
ISBN: 978 92 4 150633 5 (NLM classification: WF 310)
© World Health Organization 2013
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Contents
EXECUTIVE SUMMARY XI
WHO’s pOlicy recOmmendatiOns XV
1. BACKGROUND 1
2. METHODS 3
2.1 eVidence syntHesis 3
2.2 eXpert GrOup meetinG 7
2.3 eXternal reVieW 7
2.4 preparinG tHe pOlicy update 7
3. SCOPE 8
3.1 date Of reVieW: 2017 8
4. EVIDENCE BASE FOR POLICY FORMULATION 9
4.1 Using Xpert MtB/riF to diagnose pUlMonary tB and riFaMpicin resistance in adUlts 9
4.1.1 usinG Xpert mtB/rif as a replacement test fOr smear micrOscOpy 10
4.1.2 usinG Xpert mtB/rif as an add-On test fOllOWinG micrOscOpy 12
4.1.3 usinG Xpert mtB/rif tO detect smear-pOsitiVe culture-pOsitiVe tB 12
4.1.4 usinG Xpert mtB/rif tO detect smear-neGatiVe culture-pOsitiVe tB 12
4.1.5 usinG Xpert mtB/rif tO detect pulmOnary tB in HiV-neGatiVe and HiV- pOsitiVe indiViduals 12
4.1.6 usinG Xpert mtB/rif tO detect rifampicin resistance 14
4.1.7 effect Of tHe VersiOn Of tHe Xpert mtB/rif assay 15
4.1.8 accuracy Of tHe Xpert mtB/rif G4 cartridGe 15
4.1.9 accuracy Of tHe reference standards 16
4.2 Using Xpert MtB/riF to diagnose eXtrapUlMonary tB and riFaMpicin resistance in adUlts and children 17
4.2.1 detectinG lympH nOde tB in samples frOm BiOpsy Or fine-needle aspiratiOn 18
4.2.2 detectinG pleural tB in pleural fluid 19
4.2.3 detectinG tB in samples Of csf 20
4.2.4 detectinG tB in Gastric fluid 22
4.2.5 detectinG tB in tissue samples 22
4.2.6 detectinG rifampicin resistance 23
4.3 Using Xpert MtB/riF to diagnose tB and riFaMpicin resistance in children 23
4.3.1 usinG Xpert mtB/rif tO diaGnOse pulmOnary tB in cHildren 24
4.3.2 Xpert mtB/rif cOmpared WitH smear micrOscOpy 26
4.3.3 perfOrmance Of Xpert mtB/rif in smear-pOsitiVe and smear-neGatiVe cHildren 27
4.3.4 Xpert mtB/rif in cHildren aGed 0–4 years and 5–15 years 29
4.3.5 Xpert mtB/rif in HiV-pOsitiVe and HiV-neGatiVe cHildren 30
4.3.6 usinG Xpert mtB/rif tO detect peripHeral lympH nOde tB in cHildren 32
4.3.7 usinG Xpert mtB/rif tO detect tB meninGitis in cHildren 32
4.3.8 usinG Xpert mtB/rif tO detect rifampicin resistance in cHildren 32
4.4 aFFordaBility and cost eFFectiveness oF Using Xpert MtB/riF to diagnose tB 33
5. WHO’S POLICY RECOMMENDATIONS 38
5.1 usinG Xpert mtB/rif tO diaGnOse pulmOnary tB and rifampicin resistance in adults and cHildren 38
5.2 usinG Xpert mtB/rif tO diaGnOse eXtrapulmOnary tB and rifampicin resistance in adults and cHildren 39
6. IMPLEMENTATION CONSIDERATIONS 39
6.1 researcH needs 42
6.2 plans fOr suppOrtinG scale-up Of tHe implementatiOn Of Xpert mtB/rif 42
7. GRADE TABLES 44
ANNEXES 74
anneX 1. memBers Of tHe eXpert GrOup 74
anneX 2. WHO staff memBers 76
anneX 3. memBers Of tHe strateGic and tecHnical adVisOry GrOup fOr tuBerculOsis (staG-tB) 76
anneX 4. declaratiOns Of interests 78
Tables
taBle 1. meta-analysis Of tHe sensitiVity and specificity Of Xpert mtB/rif in diaGnOsinG eXtrapulmOnary tB and rifampicin resistance in adults and cHildren cOmpared aGainst culture as a reference standard as Well as aGainst a cOmpOsite reference standard, By type Of eXtrapulmOnary specimen xiii
taBle 2. pOOled sensitiVity and specificity Of tHe Xpert mtB/rif assay fOr detectinG pulmOnary tB and rifampicin resistance 12
taBle 3. meta-analysis Of tHe estimated sensitiVity and specificity Of smear micrOscOpy in diaGnOsinG pulmOnary tB, peripHeral lympH nOde tB and tB meninGitis in cHildren cOmpared aGainst culture as a reference standard in puBlisHed and unpuBlisHed studies 27
taBle 4. meta-analysis Of tHe sensitiVity and specificity Of Xpert mtB/rif in diaGnOsinG pulmOnary tB, peripHeral lympH nOde tB and tB meninGitis cOmpared aGainst culture as a reference standard in smear-neGatiVe and smear-pOsitiVe cHildren in puBlisHed and unpuBlisHed studies 29
taBle 5. meta-analysis cOmparinG Xpert mtB/rif fOr diaGnOsinG pulmOnary tB, peripHeral lympH nOde tB and tB meninGitis usinG culture as a reference standard in HiV-pOsitiVe and HiV-neGatiVe cHildren, stratified By smear status 31
taBle 6. metareGressiOn mOdel fOr Xpert mtB/rif usinG samples Of eXpectOrated Or induced sputum frOm cHildren, cOntrOllinG fOr smear status and HiV status 31
taBle 7. OVerVieW Of studies cOmparinG tHe cOsts Of usinG Xpert mtB/rif and fOllOW-On tests WitH current diaGnOstic alGOritHms fOr diaGnOsinG tB and mdr-tB 34
taBle 8. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in diaGnOsinG pulmOnary tB in adults 44
taBle 9. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in diaGnOsinG pulmOnary tB in sputum smear-pOsitiVe adults 45
taBle 10. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in diaGnOsinG pulmOnary tB in sputum smear-neGatiVe adults 46
taBle 11. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in diaGnOsinG pulmOnary tB in adults liVinG WitH HiV 47
taBle 12. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in diaGnOsinG pulmOnary tB in adults WitHOut HiV infectiOn 48
taBle 13. Grade eVidence prOfile: tHe incremental yield Of Xpert mtB/rif cOmpared WitH micrOscOpy in patients WitH culture-cOnfirmed tB 49
taBle 14. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in diaGnOsinG pulmOnary tB in adults as an add-On test fOllOWinG neGatiVe sputum-smear micrOscOpy 50
taBle 15. sensitiVity Of Xpert mtB/rif in smear-neGatiVe culture-cOnfirmed pulmOnary tB in indiViduals, By HiV status 51
taBle 16. Grade eVidence prOfile: additiOnal yield Of Xpert mtB/rif OVer micrOscOpy in smear-neGatiVe tB 51
taBle 17. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in detectinG rifampicin resistance, WHere Xpert mtB/rif replaces pHenOtypic culture-Based druG-susceptiBility testinG as tHe initial test 52
taBle 18. accuracy Of Xpert mtB/rif in detectinG tB in lympH nOde fluid and tissue (a. eVidence prOfile, B. summary Of findinGs) 53
taBle 19. accuracy Of Xpert mtB/rif in detectinG tB in pleural fluid (a. eVidence prOfile, B. summary Of findinGs) 55
taBle 20. accuracy Of Xpert mtB/rif in detectinG tB in cereBrOspinal fluid (a. eVidence prOfile, B. summary Of findinGs) 57
taBle 21. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in detectinG tB in Gastric fluid 59
taBle 22. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in detectinG tB in tissue samples 60
taBle 23. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in detectinG rifampicin resistance in nOnrespiratOry specimens 61
taBle 24. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in detectinG tB in cHildren cOmpared WitH culture as a reference standard (a. eXpectOrated sputum and induced sputum, B. Gastric laVaGe Or aspirate, c. summary Of findinGs) 62
taBle 25. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in detectinG tB in cHildren cOmpared WitH a clinical reference standard (a. eXpectOrated sputum and induced sputum, and Gastric laVaGe and aspirate, B. summary Of findinGs) 63
taBle 26. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in detectinG tB in cHildren fOllOWinG neGatiVe smear micrOscOpy (a. eVidence prOfile, B. summary Of findinGs, c. additiOnal yield Of Xpert mtB/rif OVer micrOscOpy) 64
taBle 27. incremental yield Of Xpert mtB/rif cOmpared WitH smear micrOscOpy in cHildren WitH culture-cOnfirmed tB (a. eXpectOrated sputum and induced sputum, B. Gastric laVaGe Or aspirate) 70
taBle 28. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in detectinG rifampicin resistance in respiratOry specimens frOm cHildren 71
taBle 29. Grade eVidence prOfile: accuracy Of Xpert mtB/rif in detectinG peripHeral lympH nOde tB in cHildren 72
taBle 30. Grade eVidence prOfile and summary Of findinGs: accuracy Of Xpert mtB/rif in detectinG tB meninGitis in cHildren 73
Figures
FigUre 1. steps in usinG tHe Xpert mtB/rif assay 2
FigUre 2. selectiOn Of studies eValuatinG tHe accuracy Of Xpert mtB/rif in diaGnOsinG pulmOnary tB and rifampicin resistance in adults: flOW diaGram Of studies identified By tHe initial literature searcHes 9
FigUre 3. selectiOn Of studies eValuatinG tHe accuracy Of Xpert mtB/rif in diaGnOsinG pulmOnary tB and rifampicin resistance in adults: flOW diaGram Of studies identified By tHe updated literature searcH 10
FigUre 4. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif fOr detectinG pulmOnary tB in 27 studies (36 study centres) 11
FigUre 5. fOrest plOts Of tHe sensitiVity and specificity Of Xpert mtB/rif fOr detectinG pulmOnary tB in HiV-neGatiVe indiViduals suspected Of HaVinG tB (9 studies, 18 study centres) and HiV-pOsitiVe indiViduals suspected Of HaVinG tB (10 studies, 16 centres) 13
FigUre 6. fOrest plOts Of tHe sensitiVity and specificity Of Xpert mtB/rif fOr detectinG rifampicin resistance WHen Xpert mtB/rif Was used as an initial test replacinG pHenOtypic culture-Based druG-susceptiBility testinG in 24 studies (33 study centres). (studies are presented in Order Of decreasinG sensitiVity and decreasinG numBer Of true-pOsitiVe results) 14
FigUre 7. selectiOn Of studies eValuatinG tHe accuracy Of Xpert mtB/rif in diaGnOsinG eXtrapulmOnary tB and detectinG rifampicin resistance in adults and cHildren: flOW diaGram Of studies included in tHe reVieW 17
FigUre 8. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif in detectinG eXtrapulmOnary tB in lympH nOde samples (tissue Or aspirate) cOmpared WitH culture as tHe reference standard 18
FigUre 9. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif in detectinG eXtrapulmOnary tB in lympH nOde samples (tissue Or aspirate) cOmpared WitH a cOmpOsite reference standard 19
FigUre 10. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif in detectinG tB usinG pleural fluid cOmpared WitH culture as a reference standard 20
FigUre 11. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif in detectinG tB in pleural fluid cOmpared WitH a cOmpOsite reference standard 20
FigUre 12. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif in detectinG tB in cereBrOspinal fluid cOmpared WitH culture as a reference standard 21
FigUre 13. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif in detectinG tB in cereBrOspinal fluid cOmpared WitH a cOmpOsite reference standard 21
FigUre 14. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif in detectinG tB in Gastric fluid cOmpared WitH culture as a reference standard 22
FigUre 15. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif in detectinG tB in tissue samples (OtHer tHan frOm a lympH nOde) cOmpared WitH culture as a reference standard 23
FigUre 16. selectiOn Of studies eValuatinG tHe accuracy Of Xpert mtB/rif in diaGnOsinG tB and rifampicin resistance in cHildren: flOW diaGram Of studies included in tHe reVieW 24
FigUre 17. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif in detectinG pulmOnary tB, peripHeral lympH nOde tB and tB meninGitis in cHildren cOmpared aGainst culture as a reference standard, By study and specimen type 25
FigUre 18. fOrest plOt Of tHe sensitiVity and specificity Of smear micrOscOpy in detectinG pulmOnary tB, peripHeral lympH nOde tB and tB meninGitis in cHildren cOmpared aGainst culture as a reference standard , By study and specimen type 26
FigUre 19. fOrest plOt Of tHe sensitiVity Of Xpert mtB/rif in diaGnOsinG pulmOnary tB, peripHeral lympH nOde tB and tB meninGitis in smear-pOsitiVe and smear-neGatiVe cHildren, By study and specimen type 28
FigUre 20. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif in detectinG pulmOnary tB, peripHeral lympH nOde tB and tB meninGitis in HiV-pOsitiVe and HiV-neGatiVe cHildren, By study and specimen type 30
FigUre 21. fOrest plOt Of tHe sensitiVity and specificity Of Xpert mtB/rif fOr detectinG resistance tO rifampicin, peripHeral lympH nOde tB and tB meninGitis in cHildren, By study and specimen type 32
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE ix
Abbreviations
AFB acid-fast bacilli
CI confidence interval
CrI credible interval
CRS composite reference standard
CSF cerebrospinal fluid
DOI Declaration of Interests
DST drug-susceptibility testing
FIND Foundation for Innovative New Diagnostics
FNA fine needle aspiration
GRADE Grading of Recommendations Assessment, Development and Evaluation
HIV human immunodeficiency virus
MDR-TB multidrug-resistant tuberculosis
MGIT mycobacterial growth indicator tube
NAAT nucleic acid amplification test
PCR polymerase chain reaction
PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses
rpoB gene encoding for the ß-subunit of the DNA-dependent RNA polymerase of Mycobacterium tuberculosis
QUADAS Quality Assessment of Diagnostic Accuracy Studies
STAG-TB Strategic and Technical Advisory Group for Tuberculosis
TB tuberculosis
WHO World Health Organization
XDR-TB extensively drug-resistant tuberculosis
x XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Acknowledgements
This document was prepared by a WHO Steering Group comprising Christopher Gilpin, Karin Weyer, Wayne van Gemert and Fuad Mirzayev (all from WHO’s Global TB Programme) on the basis of con-sensus agreed at an Expert Group Meeting convened by WHO in Geneva during 20–21 May 2013.
The findings and recommendations from the meeting were presented to WHO’s Strategic and Techni-cal Advisory Group for Tuberculosis (STAG-TB) in June 2013 (Annex 3). STAG-TB agreed with the recommendations made by the Expert Group on using Xpert MTB/RIF to diagnose TB and rifampicin resistance in pulmonary and extrapulmonary TB in adults and children, and advised WHO to produce a policy update.
This document was finalized following consideration of all comments and suggestions from the partici-pants of the Expert Group and the members of STAG-TB.
WHO gratefully acknowledges the contributions of the Chairperson of the Expert Group (Holger Schünemann), the members of the Expert Group (Annex 1) and STAG-TB, as well as the WHO staff members who developed this policy update (Annex 2). Karen Steingart (systematic reviewer for pul-monary TB), Claudia Denkinger (systematic reviewer for extrapulmonary TB), Anne Detjen and Anna Mandalakas (systematic reviewers for paediatric TB) and Andrea Pantoja (reviewer for affordability and cost effectiveness of the test ) are thanked for preparing the systematic reviews and presenting their findings to the members of the Expert Group.
Funding from the United States Agency for International Development is gratefully acknowledged through USAID-WHO Consolidated Grant No. GHA-G-00-09-00003/US 2012 0392.
Declarations of Interests
The members of the Expert Group, technical resource consultants and members of STAG-TB completed Declarations of Interests (DOIs). These were reviewed by the WHO Steering Group prior to the meeting of the Expert Group and prior to preparing the current policy update. The review of each DOI assessed whether an interest had been declared and, if so, whether it was insignificant or potentially significant. If the interest was assessed as being significant or potentially significant, the declaration was referred to WHO’s Legal Department, and their advice on the meeting’s procedures was followed. A summary of DOI statements is provided in Annex 4. Selected individuals with intellectual or research involvement in Xpert MTB/RIF, or both, were invited as observers to provide technical input and answer technical questions. These individuals did not participate in the GRADE evaluation process at the meeting nor in the final discussions when recommendations were developed. Also, they were not involved in develop-ing the report of the Expert Group’s meeting, nor in preparing documentation for the STAG-TB or in drafting WHO’s policy update.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE xi
Executive summary
The global priorities for tuberculosis (TB) care and control are to improve case-detection and to detect cases earlier, including cases of smear-negative disease which are often associated with coinfection with the human immunodeficiency virus (HIV) and young age, and to enhance the capacity to diagnose multidrug-resistant tuberculosis (MDR-TB). In September 2010, the World Health Organization (WHO) convened an Expert Group to review the evidence on the accuracy of the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, United States) for the purpose of formulating recommendations to guide the use of the test. Policy recommendations on using Xpert MTB/RIF were issued by WHO early in 2011,1 supported by an operational how-to document2 and a checklist for implementation at the country level.3
WHO’s current policies and guidance recommend that Xpert MTB/RIF be used as an initial diagnostic test in individuals suspected of having MDR-TB or HIV-associated TB (strong recommendation, moderate quality of evidence). The guidance also provides a conditional recommendation that Xpert MTB/RIF be used as a follow-on test to smear microscopy in settings where MDR-TB or HIV are of lesser concern, especially for further testing of smear-negative specimens. In acknowledgement of the difficulties of obtaining microbiological confirmation of the diagnosis in children, this recommendation generalizes from data on adults to include the use of Xpert MTB/RIF in children.
Since 2010, more than 85 peer-reviewed research papers have been published on using Xpert MTB/RIF to diagnose pulmonary, extrapulmonary and paediatric TB, and studies continue to be performed. Given the amount of additional data on Xpert MTB/RIF that have emerged since 2010, an update of WHO’s policies and guidance was warranted. WHO’s Global TB Programme therefore commissioned three systematic reviews to update and revise the guidance; these reviews examined the utility of Xpert MTB/RIF in diagnosing TB and rifampicin resistance in pulmonary, extrapulmonary and paediatric TB. Published studies on the affordability and cost effectiveness of Xpert MTB/RIF were also reviewed. WHO convened an Expert Group to review the evidence at Les Pensierès, Veyrier-du-Lac, France during 20–21 May 2013. The major findings and recommendations of this Expert Group are summarized below, and a detailed meeting report is available at:http://www.who.int/tb/laboratory/policy_statements/en/
1 Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system. Policy statement. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501545_eng.pdf).
2 Rapid implementation of the Xpert MTB/RIF diagnostic test. Technical and operational ‘how-to’: practical considerations. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501569_eng.pdf).
3 Prerequisites to country implementation of Xpert MTB/RIF and key action points at country level: checklist. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/hq/2011/WHO_HTM_TB_2011.12_eng.pdf).
xii XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Using Xpert MTB/RIF to diagnose pulmonary TB and rifampicin resistance in adults
Twenty seven unique studies involving 9 558 participants were included in the review. The reference standards for detecting pulmonary TB were solid culture or liquid culture. The reference standard for detecting rifampicin resistance was phenotypic culture-based drug-susceptibility testing (DST).
When used as an initial diagnostic test replacing smear microscopy, Xpert MTB/RIF achieved an overall pooled sensitivity of 88% (95% credible interval [CrI], 84–92%)4 and a pooled specificity of 99% (95% CrI, 98– 99%) (22 studies, 9008 participants).
When used as an add-on test following a negative smear-microscopy result, Xpert MTB/RIF yielded a pooled sensitivity of 68% (95% CrI, 61–74%) and a pooled specificity of 99% (95% CrI, 98–99%) (23 studies, 7151 participants).
For smear-positive culture-positive TB, the pooled sensitivity of Xpert MTB/RIF was 98% (95% CrI, 97–99%) (23 studies, 1 952 participants); for smear-negative culture-positive TB, the pooled sensitivity was 68% (95% CrI, 61–74%) (23 studies, 7 151 participants).
For people living with HIV, the pooled sensitivity of Xpert MTB/RIF was 79% (95% CrI, 70–86%) (7 studies, 1 789 participants); for people without HIV infection, the pooled sensitivity was 86% (95% CrI, 76–92%) (7 studies, 1470 participants).
When used to detect rifampicin resistance, Xpert MTB/RIF achieved a pooled sensitivity of 95% (95% CrI, 90–97%) (17 studies, 555/2624 total specimens) and a pooled specificity of 98% (95% CrI, 97–99%) (24 studies, 2414 specimens, including true negatives and false positives).
Using Xpert MTB/RIF to diagnose extrapulmonary TB and rifampicin resistance in adults and children
Fifteen published studies and 7 unpublished studies, involving 5 922 samples, were included in the review. The majority of studies (59%) were performed in settings with a high burden of TB. Due to the heterogeneity of sample types included in the studies, prespecified subgroups of samples (pleural fluid, lymph node samples [biopsy and aspirate combined], other tissues and cerebrospinal fluid [CSF]) were included in the meta-analysis with a comparison against culture and against a composite reference standard (CRS). In the different studies, the CRS included some combination of a nucleic acid amplification test (NAAT) other than Xpert MTB/RIF, histology, smear, culture, biochemical testing, presenting signs, or a response to treatment with anti-TB therapy (Table 1).
4 The credible interval (CrI) is the Bayesian equivalent of the confidence interval, or CI.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE xiii
Table 1. Meta-analysis of the sensitivity and specificity of Xpert MTB/RIF in diagnosing extrapulmonary TB and rifampicin resistance in adults and children compared against culture as a reference standard as well as against a composite reference standard, by type of extrapulmonary specimen
Specimen type Comparison(No. of studies, No. of samples)
Median (%) pooled sensitivity (pooled 95% CrI)
Median (%) pooled specificity (pooled 95% CrI)
Lymph node tissue and aspirate
Xpert MTB/RIF compared against culture(14 studies, 849 samples)
84.9 (72–92)
92.5 (80–97)
Xpert MTB/RIF compared against a composite reference standard(5 studies, 1 unpublished)
83.7 (74–90)
99.2 (88–100)
Cerebrospinal fluid
Xpert MTB/RIF compared against culture (16 studies, 709 samples)
79.5 (62–90)
98.6 (96–100)
Xpert MTB/RIF compared against a composite reference standard(6 studies, 512 samples)
55.5 (51–81)
98.8 (95–100)
Pleural fluid
Xpert MTB/RIF compared against culture(17 studies, 1385 samples)
43.7 (25–65)
98.1 (95–99)
Xpert MTB/RIF compared against a composite reference standard(7 studies, 698 samples)
17 (8–34)
99.9 (94–100)
Gastric lavage and aspirate
Xpert MTB/RIF compared against culture(12 studies, 1258 samples)
83.8 (66–93)
98.1 (92–100)
Other tissue samples
Xpert MTB/RIF compared against culture(12 studies, 699 samples)
81.2 (68–90)
98.1 (87–100)
CrI, credible interval; the CrI is the Bayesian equivalent of the confidence interval.
The data for additional sample types (such as, ascitic fluid, pericardial fluid, urine, blood and stool) were limited and therefore not considered in the analysis.
xiv XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Using Xpert MTB/RIF to diagnose pulmonary TB and rifampicin resistance in children
Sixteen studies (12 published and 4 unpublished) were included in the review. All studies were performed at higher levels of care, and the children included in the studies were mainly inpatients.
Pulmonary TB was evaluated in 13 studies that included 2603 participants. The overall pooled sensitivity of Xpert MTB/RIF compared against culture as a reference standard in children presumed to have TB was 66% in 10 studies where expectorated sputum or induced sputum was used (95% CrI, 52–77%); the pooled sensitivity was 66% in 7 studies where samples from gastric lavage or aspiration were used (95% CrI, 51–81%). The pooled specificity of Xpert MTB/RIF compared against culture as the reference standard was at least 98%, with narrow confidence intervals.
The pooled sensitivity of Xpert MTB/RIF in culture-negative specimens from children compared against clinical TB used as the reference standard was very low at 4% for samples of expectorated or induced sputum (8 studies), and 15% for samples from gastric lavage or aspiration (3 studies), both sensitivities had wide confidence intervals. It is likely that the apparently poor performance of Xpert MTB/RIF was the result of a reference standard for clinical TB that lacked specificity. The sensitivity of Xpert MTB/RIF to detect rifampicin resistance in specimens from children was 86% (95% CrI, 53–98%).
Affordability and cost effectiveness of using Xpert MTB/RIF to diagnose TB
Twelve published papers were identified that compared the costs of current diagnostic algorithms for diagnosing TB and MDR-TB with the costs of using Xpert MTB/RIF as the initial diagnostic test or as a follow-on test to microscopy . The setting for the majority of analyses was South Africa; two studies in-cluded other countries in sub-Saharan Africa (Botswana, Lesotho, Namibia, Swaziland and Uganda); one study included countries in the former Soviet Union; and one global analysis included all countries. Seven of the 12 studies analysed costs, and 5 were cost–effectiveness analyses. Wide variations in the methods used, the underlying assumptions, and the intended use of Xpert MTB/RIF made a systematic review impossible.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE xv
WHO’s policy recommendations
Box 1. Using Xpert MTB/RIF to diagnose pulmonary TB and rifampicin resistance in adults and children
These recommendations should be read in conjunction with the remarks in section 5.1.
• Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic test in adults suspected of having MDR-TB or HIV-associated TB (strong recommendation, high-quality evidence).
• Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic test in children suspected of having MDR-TB or HIV-associated TB (strong recommendation, very low-quality evidence).
• Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initial diagnostic test in all adults suspected of having TB (conditional recommendation acknowledging resource implications, high-quality evidence).
• Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initial diagnostic test in all children suspected of having TB (conditional recommendation acknowledging resource implications, very low-quality evidence).
• Xpert MTB/RIF may be used as a follow-on test to microscopy in adults suspected of having TB but not at risk of MDR-TB or HIV-associated TB, especially when further testing of smear-negative specimens is necessary (conditional recommendation acknowledging resource implications, high-quality evidence).
Box 2. Using Xpert MTB/RIF to diagnose extrapulmonary TB and rifampicin resistance in adults and children
These recommendations should be read in conjunction with the remarks in section 5.2.
• Xpert MTB/RIF should be used in preference to conventional microscopy and culture as the initial diagnostic test for CSF specimens from patients suspected of having TB meningitis (strong recommendation given the urgency for rapid diagnosis, very low-quality evidence).
• Xpert MTB/RIF may be used as a replacement test for usual practice (including conventional microscopy, culture or histopathology) for testing specific nonrespiratory specimens (lymph nodes and other tissues) from patients suspected of having extrapulmonary TB (conditional recommendation, very low-quality evidence).
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 1
POLICY UPDATE
1. Background
The global priorities for tuberculosis (TB) care and control are to improve case-detection and to detect cases earlier, including cases of smear-negative disease which are often associated with coinfection with the human immunodeficiency virus (HIV) and young age, and to enhance capacity to diagnose multidrug-resistant tuberculosis (MDR-TB). In September 2010, the World Health Organization (WHO) convened an Expert Group to review the evidence on the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, United States) in order to formulate recommendations on using the test. Policy recommendations on using the Xpert MTB/RIF assay were issued by WHO early in 20115, supported by an operational how-to document6 and a checklist for implementation at the country level7.
WHO’s current policies and guidance recommend that Xpert MTB/RIF be used as an initial diagnostic test in individuals suspected of having MDR-TB or HIV-associated TB (strong recommendation, moderate quality of evidence). The guidance also provides a conditional recommendation that Xpert MTB/RIF be used as a follow-on test to smear microscopy in settings where MDR-TB or HIV are of lesser concern, especially for further testing of smear-negative specimens. In acknowledgement of the difficulties of obtaining microbiological confirmation of the diagnosis in children, the recommendation generalizes from data on adults to include the use of Xpert MTB/RIF in children.
Extrapulmonary TB accounts for about 25% of all cases of TB and an even higher
percentage of cases in children and in people who are immunocompromised. Diagnosing extrapulmonary TB is often challenging, requiring the clinician to obtain specimens for microscopy, culture and histopathology from the suspected sites of involvement. However, the availability of these tests is limited and the need for alternative tests to use to diagnose TB in nonrespiratory samples is great. In 2011, the global burden of TB in children was estimated to be 500 000 cases, representing approximately 6% of all cases of TB. However, in all likelihood this burden has been underestimated due to the difficulties associated with obtaining microbiological confirmation of the diagnosis of TB in children.
The Xpert MTB/RIF assay remains the only fully automated cartridge-based real-time DNA-based test that can detect both TB and resistance to rifampicin in less than 2 hours, and it is the the only mature technology representing a new generation of automated platforms for molecular diagnosis.
Since 2010, at least 85 peer-reviewed research papers have been published about using Xpert MTB/RIF to diagnose pulmonary, extrapulmonary and paediatric TB, and studies continue to be performed. Given the amount of additional data on Xpert MTB/RIF that have emerged since 2010, an update of WHO’s policies and guidance was warranted. WHO’s Global TB Programme therefore commissioned three systematic reviews to update and revise the guidance; these reviews assessed the utility of Xpert MTB/RIF
5 Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system. Policy statement. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501545_eng.pdf).
6 Rapid implementation of the Xpert MTB/RIF diagnostic test. Technical and operational ‘how-to’: practical considerations. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501569_eng.pdf).
7 Prerequisites to country implementation of Xpert MTB/RIF and key action points at country level: checklist. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/hq/2011/WHO_HTM_TB_2011.12_eng.pdf).
2 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
for diagnosing TB and rifampicin resistance in pulmonary, extrapulmonary and paediatric TB. Published studies on the affordability and cost effectiveness of Xpert MTB/RIF were also reviewed. WHO convened an Expert Group to review the evidence at Les Pensierès, Veyrier-du-Lac, France, during 20–21 May 2013.
Xpert MTB/RIF is an automated polymerase chain reaction (PCR) test (that is, a molecular test) utilizing the GeneXpert platform (Cepheid, Sunnyvale, CA, United States). Xpert MTB/RIF is a single test that can detect both Mycobacterium tuberculosis complex and rifampicin resistance within 2 hours after starting the assay, with minimal hands-on technical time (Figure 1). Unlike conventional nucleic acid amplification tests (NAATs), in Xpert MTB/RIF sample processing, PCR amplification and detection are integrated into a single self-enclosed test unit, which is the Xpert MTB/RIF cartridge. Following sample loading, all steps in the assay are automated and
contained within the cartridge. In addition, the assay’s sample reagent, used to liquefy sputum, is tuberculocidal (that is, it has the ability to kill TB bacteria), which largely eliminates concerns about biosafety during the test procedure. These features allow the technology to be taken out of a central laboratory or reference laboratory and to be used nearer to patients. However, Xpert MTB/RIF requires an uninterrupted and stable electrical power supply, temperature control and yearly calibration of the instrument’s modules8.
The test procedure may be used directly on clinical specimens, either fresh sputum samples or sputum pellets (also called sputum sediment), which are obtained after decontaminating and concentrating the sputum. In both cases, the test material is combined with the reagent, mixed by hand or vortex, and incubated at room temperature for 15 minutes. After incubation, 2 ml of the treated sample are transferred to the cartridge, and the run is initiated.
Figure 1. Steps in using the Xpert MTB/RIF assaya
a Figure used with permission from the Foundation for Innovative New Diagnostics (FIND).
8 Rapid implementation of the Xpert MTB/RIF diagnostic test. Technical and operational ‘how-to’:practical considerations. Geneva; World Health Organization, 2011(http://whqlibdoc.who.int/publications/2011/9789241501569_eng.pdf).
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 3
Xpert MTB/RIF uses molecular beacon technology to detect rifampicin resistance. Molecular beacons are nucleic acid probes that recognize and report the presence or absence of the normal, rifampicin-susceptible wild-type sequence of the rpoB gene of TB. Five different coloured beacons are used, each covering a separate nucleic acid sequence within the amplified rpoB gene. When a beacon binds to the matching sequence, it fluoresces (or lights up), which indicates the presence of one of the gene sequences that is characteristic of rifampicin-susceptible TB. If a beacon fails to bind
to the matching sequence or if binding is delayed, the sample is potentially resistant to rifampicin. The number of positive beacons and the timing of their detection (when the fluorescent signal rises above a predetermined baseline cycle threshold), as well as the results of sample processing controls, allow the test to distinguish among the following results: no TB; TB detected, rifampicin resistance detected; TB detected, no rifampicin resistance detected; TB detected, rifampicin resistance indeterminate; and an invalid result.
2. Methods
2.1 Evidence synthesis
In May 2013, a guideline development group (referred to as the Expert Group in this document) was convened by WHO’s Global TB Programme to assess the data on Xpert MTB/RIF with a view to updating WHO’s 2011 policy recommendations on its use. WHO commissioned three systematic reviews on the use of Xpert MTB/RIF to diagnose pulmonary, extrapulmonary and paediatric TB and to detect rifampicin resistance, as well as a review of the affordability and cost effectiveness of Xpert MTB/RIF.
In accordance with WHO’s standards for assess-ing evidence when formulating policy recommen-dations, the Grading of Recommendations As-sessment, Development and Evaluation (GRADE)
system9 was used for the evidence synthesis pro-cess to provide a systematic, structured framework for evaluating both the accuracy of the test and the test’s impact on patients and public health. The evaluations used the GRADE system to deter-mine the quality of the evidence and provide in-formation on the strength of the recommendations using a priori questions (that is, PICO questions) agreed by the Expert Group. PICO refers to the following four elements that should be included in questions that govern a systematic search of the evidence: the Population targeted by the action or intervention; the Intervention; the Comparator; and the Outcome.The PICO questions for each review are given in Box 3.
9 Schünemann HJ et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies.BMJ, 2008, 336:1106-1110.
4 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Box 3. PICO questions for the four systematic reviews evaluating the accuracy of the Xpert MTB/RIF assay in diagnosing TB
Review 1. Updated systematic review: Xpert MTB/RIF for diagnosis of pulmonary tuberculosis and rifampicin resistance in adults1. What is the diagnostic accuracy of Xpert MTB/RIF for detection of pulmonary TB in adults, where Xpert MTB/RIF is used as a replacement test for smear microscopy? 2. What is the diagnostic accuracy of Xpert MTB/RIF for detection of pulmonary TB in adults, where Xpert MTB/RIF is used as an add-on test following a negative smear-microscopy result?3. What is the diagnostic accuracy of Xpert MTB/RIF for detection of smear-positive pulmonary TB in adults?4. What is the diagnostic accuracy of Xpert MTB/RIF for detection of smear-negative (culture-positive) pulmonary TB in adults?5. What is the diagnostic accuracy of Xpert MTB/RIF for detection of pulmonary TB in people living with HIV (adults)?6. What is the diagnostic accuracy of Xpert MTB/RIF for detection of pulmonary TB in adults without HIV infection?7. What is the diagnostic accuracy of Xpert MTB/RIF for detection of rifampicin resistance, where Xpert MTB/RIF is used as an initial test replacing phenotypic culture-based drug-susceptibility testing?
Review 2. Systematic review: Xpert MTB/RIF for diagnosis of tuberculosis and detection of rifampicin resistance on nonrespiratory samples (extrapulmonary TB)1. What is the diagnostic accuracy of Xpert MTB/RIF overall compared with culture for nonrespiratory specimens, where Xpert MTB/RIF is used as a replacement test for usual practice?a
2. What is the diagnostic accuracy of Xpert MTB/RIF overall compared with a combined clinical and laboratory reference standard for nonrespiratory specimens, where Xpert MTB/RIF is used as a replacement test for usual practice? 2a. What is the diagnostic accuracy of Xpert MTB/RIF for lymph node fluid and tissue, where Xpert MTB/RIF is used as a replacement test for usual practice?2b. What is the diagnostic accuracy of Xpert MTB/RIF for pleural fluid, where Xpert MTB/RIF is used as a replacement test for usual practice?2c. What is the diagnostic accuracy of Xpert MTB/RIF for cerebrospinal fluid, where Xpert MTB/RIF is used as a replacement test for usual practice?2d. What is the diagnostic accuracy of Xpert MTB/RIF for gastric fluid, where Xpert MTB/RIF is used as a replacement test for usual practice? 2e. What is the diagnostic accuracy of Xpert MTB/RIF for tissue samples, where Xpert MTB/RIF is used as a replacement test for usual practice? 3. What is the diagnostic accuracy of Xpert MTB/RIF for detection of rifampicin resistance in nonrespiratory specimens, where Xpert MTB/RIF is used as an initial test replacing phenotypic culture-based drug-susceptibility testing?
Review 3. Systematic review: Xpert MTB/RIF for diagnosis of tuberculosis and rifampicin resistance in children1. What is the diagnostic accuracy of Xpert MTB/RIF for detection of TB in children compared with culture, where Xpert MTB/RIF is used as a replacement test for usual practice?b
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 5
2. What is the diagnostic accuracy of Xpert MTB/RIF for detection of TB in children compared with a combined clinical and laboratory reference standard, where Xpert MTB/RIF is used as a replacement test for usual practice? 3. What is the diagnostic accuracy of Xpert MTB/RIF for detection of TB in children, where Xpert MTB/RIF is used as an add-on test following a negative smear-microscopy result? 4. What is the diagnostic accuracy of Xpert MTB/RIF compared with smear microscopy for detection of TB in children?5. What is the diagnostic accuracy of Xpert MTB/RIF for detection of rifampicin resistance in children, where Xpert MTB/RIF is used as an initial test replacing phenotypic culture-based drug-susceptibility testing?6. What is the diagnostic accuracy of Xpert MTB/RIF for detection of peripheral lymph node TB in children, where Xpert MTB/RIF is used as a replacement test for usual practice? 7. What is the diagnostic accuracy of Xpert MTB/RIF for detection of TB meningitis in children, where Xpert MTB/RIF is used as a replacement test for usual practice?
Review 4. Systematic review: Affordability, cost effectiveness and resource implications for Xpert MTB/RIF scale up1. For which diagnostic and screening algorithms is the Xpert MTB/RIF assay an affordable and a cost-effective intervention?
a Most analyses were performed using two reference standards: culture (the current reference standard) and a combined clinical and laboratory reference standard chosen by the study’s authors (given the technical limitations of using culture for diagnosis).b Given the difficulties of diagnosing TB in children, usual practice refers to customary practice in the field, which may vary from setting to setting. The usual practice for children (aged 0–15 years) suspected of having intrathoracic TB (that is, pulmonary, pleural, and mediastinal or hilar lymph node TB) normally requires bacteriological confirmation through examination of sputum (obtained by expectoration, gastric washings, or induction) for smear microscopy and culture. In the event of negative bacteriological results, a diagnosis of TB may be based on the presence of abnormalities consistent with TB on chest radiography, a history of exposure to an infectious case, evidence of TB infection (that is, a positive tuberculin skin test or interferon-g release assay) and clinical findings suggestive of TB. For children suspected of having extrapulmonary TB, appropriate specimens from the suspected sites of involvement may be obtained for microscopy, and for culture and histopathological examination.
Three systematic reviews were conducted according to the standards outlined by the Cochrane Collaboration in the Cochrane handbook.10 A comprehensive search of the following databases was performed: Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Thomson Reuters (formerly ISI) Web of Knowledge, Medion, LILACS, BIOSIS and Scopus. Searches of the metaRegister of Controlled Trials and the search portal of WHO’s International Clinical Trials Registry were also performed to identify any continuing trials. Searches included all studies without restrictions on language.
A comprehensive search of the literature for studies on the cost effectiveness and affordability of Xpert MTB/RIF included PubMed, the Health Economics Evaluation Database, the United Kingdom’s National Health Service Economic Evaluation Database, the Cost-effectiveness Analysis Registry and the Research Papers in Economics database.
Where feasible, meta-analysis was used to summarize the results of independent studies, and these results have been displayed as forest plots. Where meta-analysis was not feasible due to heterogeneity, the evidence has been presented in a narrative synthesis.
10 Higgins JPT, Green S, eds. Cochrane handbook of systematic reviews for interventions, version 5.1.0. Cochrane Collaboration, 2011 (available at http://www.cochrane-handbook.org).
6 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Each reviewer prepared GRADE evidence profiles for each PICO question. GRADE evidence profiles were prepared to assess the diagnostic accuracy of Xpert MTB/RIF for each systematic review. In systematic reviews that assess the accuracy of diagnostic tests, the choice of an optimal reference standard is critical, since the reference standard is used to determine the presence or absence of the target condition. The reference standards used for the different systematic reviews are described below.
• Using Xpert MTB/RIF to detect pulmonary TB and rifampicin resistance: the reference standards used were conventional culture and drug-susceptibility testing (DST). Culture using either solid media or commercial liquid media, as recommended by WHO, was considered to be an acceptable reference standard. The reference methods for DST for rifampicin resistance were those recommended by WHO, and these included molecular line probe assays.
• Using Xpert MTB/RIF to detect extrapulmonary TB in adults and children: the reference standard used was either conventional culture (as described above) or a composite reference standard (CRS) defined by the authors of the individual studies that were included in the systematic review; in the different studies the CRS included some combination of NAAT other than Xpert MTB/RIF, histology, smear, culture, biochemical testing, presenting signs, or a response to treatment with anti-TB therapy.
• Using Xpert MTB/RIF to detect TB and rifampicin resistance in children: the reference standard used was either conventional culture (as described above) or a clinical TB reference standard, recognizing the limitations of mycobacterial culture in children. Children were categorized as positive using the clinical TB standard if they had started anti-TB therapy as a result of a clinical diagnosis of
TB. This broad clinical reference standard was chosen in order to accommodate the heterogeneous methods and clinical definitions used in the studies. Children assigned to the group clinical not TB (that is, negative according to the reference standard clinical TB) either (1) did not have another diagnosis assigned, or (2) did not start anti-TB treatment but nonetheless improved, or their condition did not worsen after at least 1 month of follow-up after enrolment.
Using the GRADE framework, results for sensitivity and specificity were used as proxy measures for outcomes seen as important to patients; these outcomes were based on the relative importance or impact of false-positive and false-negative results. Poor sensitivity would result in false-negative results so that patients with TB or MDR-TB would be missed, and this would have negative consequences in terms of morbidity, mortality and transmission of disease. Poor specificity would result in false-positive results so that patients without TB or MDR-TB would be prescribed unnecessary treatment, and this would have negative consequences that might include serious adverse events related to treatment with second-line anti-TB agents.
Rates for true positives, true negatives, false positives and false negatives were calculated based on pretest probabilities – that is, an assumed prevalence of TB of 2.5%, 5% and 10% among patients suspected to have TB who were being screened, and an assumed prevalence of rifampicin resistance of 5% and 15% (as a proxy for MDR-TB) among patients with confirmed TB.
The evaluation of the impact on patients was based on a balance among the following values:
• true positives – the benefit to patients from rapid diagnosis and treatment;
• true negatives – the benefit to patients who would be spared unnecessary treatment; the benefit of reassurance and alternative diagnosis;
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 7
• false positives – the likelihood of anxiety and morbidity caused by additional testing, unnecessary treatment, or both; the chance that a false positive may halt further diagnostic evaluation;
• false negatives – the increased risk of morbidity and mortality, and the continued risk of community transmission of TB.
For each outcome, the quality of evidence according to GRADE was initially regarded as high since all studies were cross-sectional or cohort studies, prospectively enrolling patients suspected of having TB or MDR-TB. The quality of the evidence and the limitations of the studies were assessed using six GRADE criteria: (1) study design, (2) risk of bias, (3) directness, (4) inconsistency, (5) imprecision, and (6) publication or reporting bias.
Each review used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS -2) tool to appraise the studies.11 This tool consists of four domains: patient selection, index test, reference standard, and flow and timing.
2.2 Expert Group meeting
PICO questions were drafted by the WHO Steering Group and were presented to the Expert Group for discussion and modification. The Steering Group also prepared an initial list of relevant outcomes, including desirable effects and undesirable effects, and requested the Expert Group to identify any other important outcomes.
A webinar was conducted with members of the Expert Group prior to the meeting to refine and finalize the proposed outcomes seen as important to patients, and to rate their relative importance. The following outcomes for each PICO question were determined, and the ratings of their importance were unanimously agreed by the Expert Group:
• critical outcomes – diagnostic accuracy as reflected by true-positive, true-negative, false-positive and false-negative results; time to diagnosis;
• important outcome – cost.
The meeting was chaired by an expert in evidence synthesis. Decisions were based on consensus. Concerns raised by members were noted and included in the final report of the meeting. The detailed report was prepared by the Steering Group; the report went through several iterations before being finally signed off by members of the Expert Group.
2.3 External review
The findings and recommendations from the Expert Group’s meeting were presented in June 2013 to WHO’s Strategic and Technical Advisory Group for TB (STAG-TB), members of which served as the external review group. STAG-TB agreed with the Expert Group’s recommendations, and advised WHO to develop and disseminate an updated policy on using Xpert MTB/RIF to diagnose TB and rifampicin resistance in pulmonary and extrapulmonary TB in adults and children. STAG-TB also recommended that WHO should continue its global coordination and implementation plan aimed at scaling up the use of the Xpert MTB/RIF assay.12
2.4 Preparing the policy update
The draft policy update, which was based on the consensus recommendations made by the Expert Group, was subsequently prepared by the Steering Group and circulated to the Expert Group and members of STAG-TB following an iterative process similar to that described above.
11 Whiting PF et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Annals of Internal Medicine, 2011, 155:529-536.12 Strategic and Technical and Advisory Group for Tuberculosis (STAG-TB): report of the 13th meeting. Geneva, World Health Organization, 2013 (WHO/HTM/TB/2013.09) available at http://www.who.int/tb/advisory_bodies/STAG_report2013.pdf)
8 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
3. Scope
This document replaces WHO’s 2011 policy statement on Xpert MTB/RIF13, and provides a pragmatic summary of the updated evidence and recommendations on using Xpert MTB/RIF to diagnose pulmonary and extrapulmonary TB, and to detect rifampicin resistance in adults and children. It should be read in conjunction with the detailed findings from the 2013 report of the Expert Group’s meeting14 and the framework for implementing TB diagnostics. These documents are available at http://www.who.int/tb/dots/laboratory/policy/en; they provide guidance on implementing the diagnostic tools and methods approved by WHO within the context of a country’s infrastructure, resources, epidemiology of TB and MDR-TB, and on TB policy reform. This policy update will be supported by the second edition of WHO’s Xpert MTB/RIF implementation manual (a publication derived from the guidance on policy).15
None of the existing tools for diagnosing TB are mutually exclusive, and they can be implemented in various combinations in screening and diagnostic algorithms, which can be tailored to be highly specific to each country’s settings and resources. Therefore, input from experts working in TB laboratories is needed to define the most cost-effective and efficient algorithms for individual countries; these algorithms should be guided by WHO’s standards and procedures, and
implemented within a framework of integrated activities aimed at strengthening laboratories.
This policy guidance should be used to support the implementation of Xpert MTB/RIF technology to diagnose TB and detect rifampicin resistance within TB and TB–HIV programmes. The policies are intended to be used by managers and laboratory directors working in these programmes in coordination with external laboratory consultants, donor agencies, technical advisers, laboratory technicians, procurement officers for laboratory equipment, service providers in the private sector, relevant government sectors, and implementation partners that are involved in country-level strengthening of TB laboratories. Individuals responsible for programme planning, budgeting, mobilizing resources and implementing training activities for TB and TB–HIV diagnostic services may also benefit from this document.
3.1 Date of review: 2017
Additional data from implementation sites will be reviewed annually, and the guidance will continue to be refined based on more extensive field evaluations of the new technology that will be conducted after implementation; these evaluations will include country-specific cost–effectiveness and cost–benefit analyses.
13 Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system. Policy statement. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501545_eng.pdf).14 Using the Xpert MTB/RIF assay to detect pulmonary and extrapulmonary tuberculosis and rifampicin resistance in adults and children: Expert Group meeting report. Geneva, World Health Organization, 2013 (available at http://www.who.int/tb/laboratory/policy_statements/en/)15 Xpert MTB/RIF implementation manual. Technical and operational ‘how-to’: practical considerations. 2nd ed. Geneva, World Health Organization, 2014 (available at http://www.who.int/tb/laboratory/policy_statements/en/)
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 9
4. Evidence base for policy formulation
4.1 Using Xpert MTB/RIF to diagnose pulmonary TB and rifampicin resistance in adults
A Cochrane review published 31 January 201316 evaluated 18 studies (Figure 2). An additional literature search was performed on
7 February 2013, which identified 9 additional studies (Figure 3). From the combined literature searches, 27 relevant studies in 36 study centres (26 published studies and 1 unpublished study) were identified and evaluated.
Figure 2. Selection of studies evaluating the accuracy of Xpert MTB/RIF in diagnosing pulmonary TB and rifampicin resistance in adults: flow diagram of studies identified by the initial literature searches
139 records identified through database search
25 September 2011
5 additional records identified through other sources
137 records screened after duplicates removed
60 full-text articles assessed for eligibility
18 studies included in qualitative synthesis
15 studies included in meta-analysis of TB detection; 11 studies
included in meta-analysis of detection of rifampicin resistance
81 records identified through database search 15 December 2011; no new
records identified
42 full-text articles excludedReasons• Abstract only: 10• Case–control study: 1• Correspondence with authors: 1• Cost-effectiveness analysis: 1• Could not obtain: 1• Duplicate data: 1• Editorial or comment article: 13 • Extrapulmonary TB: 5• Paediatric TB: 1• Review article: 6• Technical article: 2
77 records excluded based on title and abstract
16 Steingart KR et al. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database of Systematic Reviews, 2013, (1):CD009593 (doi:10.1002/14651858.CD009593.pub2).
10 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Figure 3. Selection of studies evaluating the accuracy of Xpert MTB/RIF in diagnosing pulmonary TB and rifampicin resistance in adults: flow diagram of studies identified by the updated literature search
343 records identified through database search
7 February 2013
2 additional records identified through other sources
130 records screened after duplicates removed
54 full-text articles assessed for eligibility
9 studies included in qualitative synthesis
7 studies included in quantitative synthesis
(meta-analysis)
45 full-text articles excludedReasons• Extrapulmonary TB: 7• Paediatric TB: 6• Correspondence with authors: 5• Duplicate data: 4• Impact study: 4• Study did not enrol patients
suspected of having TB: 3• Technical article: 3• Case–control study: 2• Case report: 2• Editorial or comment article: 2• Data insufficient: 2• Treatment monitoring: 2• Abstract: 1• Reference standard not satisfied: 1• Relevance: 1
76 records excluded based on title and abstract
To assess the accuracy of Xpert MTB/RIF in detecting TB, data were reviewed from 27 studies that included 9558 participants; 22 of the studies, involving 9008 participants, were included in the meta-analysis. Five studies that enrolled primarily smear-positive or smear-
negative patients were excluded. The pooled sensitivity of Xpert MTB/RIF for detecting TB was 88% (95% credible interval [CrI], 84–92%); the pooled specificity for detecting TB was 99% (95% CrI, 98–99%) (Figure 4).17
17 The credible interval (CrI) is the Bayesian equivalent of the confidence interval (CI).
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 11
Figure 4. Forest plot of the sensitivity and specificity of Xpert MTB/RIF for detecting pulmonary TB in 27 studies (36 study centres)a
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval.
a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
4.1.1 Using Xpert MTB/RIF as a replacement test for smear microscopy
Twenty-one studies (8 880 participants) provided data that compared the sensitivity of Xpert MTB/RIF with smear microscopy. For smear microscopy, the pooled sensitivity was 65% (95% CrI, 57–
72%). For Xpert MTB/RIF, the pooled sensitivity was 88% (95% CrI, 84–92%). Therefore, in comparison with smear microscopy, Xpert MTB/RIF increased TB detection among culture-confirmed cases by 23% (95% CrI, 15–32%) (Table 2).
12 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Table 2. Pooled sensitivity and specificity of the Xpert MTB/RIF assay for detecting pulmonary TB and rifampicin resistance
Type of analysis (No. of studies, No. of participants)
Median (%) pooled sensitivity (95% CrI)
Median (%) pooled specificity (95% CrI)
Xpert MTB/RIF used as an initial test for TB detection replacing microscopy (22, 9008)
88 (84–92) 99 (98–99)
Xpert MTB/RIF used as an add-on test for TB detection following a negative smear-microscopy result (23, 7151)
68 (61–74) 99 (98–99)
Xpert MTB/RIF used as an initial test for detecting rifampicin resistance replacing conventional drug-susceptibility testing as the initial testa
95 (90–97) 98 (97–99)
CrI, credible interval; the CrI is the Bayesian equivalent of the confidence interval.
a The pooled sensitivity estimates and specificity estimates for detecting rifampicin resistance were determined separately by univariate analyses. The pooled sensitivity analysis included 17 studies (555 participants); the pooled specificity analysis included 24 studies (2414 participants).
4.1.2 Using Xpert MTB/RIF as an add-on test following microscopy
When Xpert MTB/RIF was used as an add-on test following a negative smear-microscopy result (23 studies, 7 151 participants), the pooled sensitivity was 68% (95% CrI, 61–74%); the pooled specificity was 99% (95% CrI, 98– 99%). In other words, 68% of smear-negative culture-confirmed cases of TB were detected using Xpert MTB/RIF following smear microscopy, which increased case-detection by 68% (95% CrI, 61–74%) in this group (Table 2).
4.1.3 Using Xpert MTB/RIF to detect smear-positive culture-positive TB
There was little variation in the sensitivity estimates (95–100%) for studies reporting data on smear-positive cases (24 studies, 33 study centres, 2071 participants). In the meta-analysis, the pooled sensitivity for smear-positive culture-positive TB was very high at 98% (95% CrI, 97–99% (23 studies, 1952 participants). Estimates of the pooled specificity of Xpert MTB/RIF were not performed because participants in the smear-positive subgroup were considered to be true cases of TB.
4.1.4 Using Xpert MTB/RIF to detect smear-negative culture-positive TB
Twenty four studies (33 study centres, 7 247 participants) reported data on smear-negative cases. There was considerable variability in the sensitivity estimates (range, 43–100% ). Specificity estimates showed less variation (range, 86–100%). The meta-analysis included 23 studies that allowed for direct comparison between subgroups that were smear-positive and those that were smear-negative. The pooled estimate of sensitivity for smear-negative culture-positive TB was 68% (95% CrI, 61–74%).
4.1.5 Using Xpert MTB/RIF to detect pulmonary TB in HIV-negative and HIV- positive individuals
Nine studies (18 study centres, 2555 participants) reported data on HIV-negative individuals, and 10 studies (16 study centres, 2378 participants) reported on HIV-positive individuals (Figure 5). There was variability in sensitivity in both the HIV-negative subgroup (range, 56–100%) and HIV-positive subgroup (range, 0–100%). The small number of participants in several studies may have contributed to some of the variability. Specificity varied less than sensitivity in both subgroups: from 96% to 100% in the HIV-negative subgroup, and from 92% to 100% in the HIV-positive subgroup.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 13
Figure 5. Forest plots of the sensitivity and specificity of Xpert MTB/RIF for detecting pulmonary TB in HIV-negative individuals suspected of having TB (9 studies, 18 study centres) and HIV-positive individuals suspected of having TB (10 studies, 16 centres)a
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval. a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
The meta-analysis included 7 studies that provided data on both HIV-negative individuals (1470 participants) and HIV-positive individuals (1789 participants). The pooled sensitivity for the HIV-negative subgroup was 86% (95% CrI, 76–92%); for the HIV-positive subgroup it was 79% (95% CrI, 70–86%) .
The corresponding pooled specificities were similar: for the HIV-negative subgroup the specificity was 99% (95% CrI, 98–100%); for the HIV-positive subgroup it was 98% (95% CrI, 96–99%). When adjusting for the percentage of smear-positive patients in each study, the impact
of the HIV covariate decreased, suggesting that some of the differences between the HIV-positive subgroup and the HIV-negative subgroup could be attributed to differences in smear status.
Five studies reported data from which it was possible to assess the accuracy of Xpert MTB/RIF in HIV-positive individuals with culture-positive smear-negative TB. The sensitivity of Xpert MTB/RIF in HIV-positive individuals with smear-negative culture-positive TB ranged from 43% to 93%; in HIV-positive individuals with smear-positive culture-positive TB it ranged from 91% to 100%. Data were sufficient to perform a univariate meta-
14 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
analysis to assess the sensitivity of Xpert MTB/RIF. Among people living with HIV, the pooled sensitivity of Xpert MTB/RIF for smear-negative culture-positive TB was 61% (95% CrI, 42–79%) compared with 97% (95% CrI, 91–99%) for smear-positive culture-positive TB; this was a statistically significant result (data not shown). Hence, among people who are coinfected with HIV and TB, those with smear-positive disease were more likely to be diagnosed with TB using Xpert MTB/RIF than those with smear-negative disease.
4.1.6 Using Xpert MTB/RIF to detect rifampicin resistance
Of the 27 studies, 24 studies (33 study centres, 2 969 participants) provided data on detecting
rifampicin resistance, and included 555 rifampicin-resistant specimens. Figure 6 shows the forest plots of sensitivity and specificity for this analysis. Although there was variability in the estimates of sensitivity (range, 33–100%), in general the poorer estimates of sensitivity were related to study centres that had only a low number of rifampicin-resistant specimens. There was less variability in specificity (range, 83–100%). The pooled sensitivity by univariate analysis was 95% (95% CrI, 90–97%); the pooled specificity was 98% (95% CrI, 97–99%). The pooled sensitivity and specificity were the same when bivariate analysis was used for the subset of studies that provided data on both sensitivity and specificity (17 studies, 2624 participants).
Figure 6. Forest plots of the sensitivity and specificity of Xpert MTB/RIF for detecting rifampicin resistance when Xpert MTB/RIF was used as an initial test replacing phenotypic culture-based drug-susceptibility testing in 24 studies (33 study centres)a
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval.
a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 15
4.1.7 Effect of the version of the Xpert MTB/RIF assay
The basis in the Xpert MTB/RIF system for detecting rifampicin resistance is the difference between the first M. tuberculosis-specific beacon or probe (the early-cycle threshold) and the last beacon (the late-cycle threshold). This difference is referred to as the delta-cycle threshold. The original configuration of the Xpert MTB/RIF system reported rifampicin resistance when the delta-cycle threshold was higher than 3.5 cycles; rifampicin sensitivity was reported when the delta-cycle threshold was 3.5 cycles or lower (using the Xpert MTB/RIF G1 cartridge). After May 2010, the manufacturer modified the delta-cycle threshold cut-off value to improve the specificity of Xpert MTB/RIF in detecting rifampicin resistance (using the Xpert MTB/RIF G2 and G3 cartridges). Another modification was implemented in late 2011 (using the Xpert MTB/RIF G4 cartridge), which changed the molecular beacon sequence of Probe B to improve detection of rifampicin resistance when there were fluctuations in the annealing temperature. Changes to fluidics and software virtually eliminated the signal-loss detection error (known as the 5011 error), and allowed high sensitivity and specificity to be maintained when detecting TB and rifampicin resistance. These enhancements to the assays were considered to be part of a routine process of product improvement. Cepheid, the Foundation for Innovative New Diagnostics (FIND) and the University of Medicine and Dentistry of New Jersey will continue to monitor the clinical performance of the Xpert MTB/RIF test. By 2013, the G4 cartridges were the only type of cartridge available.
The effect of the version of Xpert MTB/RIF on the sensitivity and specificity for detecting rifampicin resistance was investigated. The pooled sensitivity for studies using Xpert MTB/RIF G2, G3 or G4 cartridges (13 studies) was 93% (95% CrI, 87–97%); for studies using the Xpert MTB/RIF G1 cartridge (4 studies) it was 97% (95%
CrI, 91–99%) . The pooled specificity for studies using Xpert MTB/RIF G2, G3 or G4 cartridges (15 studies) was 98% (95% CrI, 96–99%); for studies using the Xpert MTB/RIF G1 cartridge (4 studies) it was 99% (95% CrI, 98–100%). The overlapping credible intervals indicate that there was no statistically significant difference in the estimates of either sensitivity or specificity for the Xpert MTB/RIF G1 cartridge when compared with later versions of the cartridge.
4.1.8 Accuracy of the Xpert MTB/RIF G4 cartridge
Two studies used the Xpert MTB/RIF G4 cartridge and provided data suitable to determine specificity. One study observed a specificity of 100% (10/10 tests) (95% confidence interval [CI], 69–100%); the second study reported a specificity of 95% (42/44 tests) (95% CI, 85–99%) (Figure 6).
FIND evaluated the diagnostic accuracy of the G4 cartridge18 in a study that tested 233 archived sputum specimens that had been stored in Borstel, Germany, and were from individuals suspected of having TB; additionally, there were 184 frozen sediments from Lima, Peru, that were positive for acid-fast bacilli (AFB), as well as frozen sputum specimens from a further 231 patients consecutively enrolled from Baku, Azerbaijan. All of the samples were shipped to and tested in Germany using the G4 cartridge. Fresh sputum samples from 30 patients were tested using both the G3 cartridge and the G4 cartridge in Kampala, Uganda; a further 218 specimens were evaluated using both the G3 cartridge and the G4 cartridge in Cape Town, South Africa.
The reference standard used across all sites included at least one Löwenstein–Jensen culture and at least one culture using the BACTEC MGIT (mycobacterial growth indicator tube) 960 Mycobacterial Detection System (Becton Dickinson, Franklin Lakes, NJ, United States), with M. tuberculosis species confirmed using Capilia (Tauns Laboratories, Shizuoka, Japan), GenoType
18 Report: performance of Xpert MTB/RIF version G4 assay. Geneva, Foundation for Innovative New Diagnostics, 2011 (available at: http://www.stoptb.org/wg/gli/assets/documents/map/findg4cartridge.pdf).
16 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
MTBDRplus (Hain Lifescience, Nehren, Germany) or GenoType Mycobacterium CM/AS (Hain Lifescience, Nehren, Germany). Conventional testing for rifampicin resistance was performed using either the Löwenstein–Jensen proportion method or the BACTEC MGIT 960 and, in a few cases, using only the Genotype MTBDRplus assay. Genetic sequencing was performed on results discordant between Xpert MTB/RIF and conventional DST. Six patients (smear-negative and culture-negative) were started on anti-TB treatment and excluded from the analysis. Genetic sequencing was used to resolve discordant results to determine sensitivity and specificity.
The overall sensitivity for rifampicin-resistant TB was 98.9% (87/88 tests) (95% CI, 93.8–99.8%); the overall specificity for rifampicin-sensitive TB was 99.8% (433/434 tests) (95% CI, 98.7– 100.0%). For four cases in which results were discordant (Xpert MTB/RIF identified samples as rifampicin-sensitive but DST identified them as resistant), the rpoB region was sequenced; the discordant results resolved in three of these cases in favour of Xpert MTB/RIF. For nine cases in which results were discordant and Xpert MTB/RIF identified the specimens as rifampicin resistant but DST identified them as rifampicin sensitive, sequencing of the rpoB region was performed; discordant results resolved in eight of these cases in favour of Xpert MTB/RIF.
4.1.9 Accuracy of the reference standards
Culture is regarded as the best reference standard for active TB, and was the reference standard used for TB in the systematic review on pulmonary TB. Phenotypic culture-based DST methods, using WHO’s recommended critical concentrations, were the reference standards for rifampicin resistance.19
Three recent studies have raised concerns about using phenotypic DST to detect rifampicin
resistance, in particular the automated BACTEC MGIT 960 system. Van Deun and colleagues reported that the BACTEC 460 and the BACTEC MGIT 960 missed certain strains associated with low-level rifampicin resistance.20 Using Xpert MTB/RIF and gene sequencing, Williamson and colleagues identified four patients (three with clinical information available) whose TB isolates contained mutations to the rpoB gene but whose results from the BACTEC MGIT 960 indicated that the isolates were rifampicin susceptible. In this study, 2/49 (4.1%) patients whose isolates did not have apparent rpoB gene mutations experienced treatment failure compared with 3/3 (100%) patients whose isolates did have rpoB gene mutations and had been deemed rifampicin-susceptible using phenotypic methods.21
In a study involving retreatment patients, Van Deun and colleagues found that disputed rpoB mutations conferring low-grade resistance were often missed by rapid phenotypic DST, particularly with the BACTEC MGIT 960 system, but to a lesser extent also by conventional slow DST.22
The authors suggested this may be the reason for the perceived insufficient specificity of molecular DST for rifampicin. Although the study involved retreatment patients, the results also appear to be similar for individuals newly diagnosed with TB (A Van Deun, personal communication, 2013).
Therefore, using only phenotypic DST as a reference to determine the specificity of a molecular method of DST may underestimate the specificity of the molecular method of DST. In light of these findings, it is unclear whether and to what extent Xpert MTB/RIF might outperform phenotypic methods of DST in assessing rifampicin resistance.
WHO continues to collect and evaluate emerging data on this issue, and will formally review the
19 Policy guidance on drug-susceptibility testing (DST) of second-line antituberculosis drugs. Geneva, World Health Organization, 2008 (WHO/HTM/TB/2008.392).20 Van Deun A et al. Mycobacterium tuberculosis strains with highly discordant rifampin susceptibility test results. Journal of Clinical Microbiology, 2009,47:3501–3506.21 Williamson DA et al. An evaluation of the Xpert MTB/RIF assay and detection of false-positive rifampicin resistance in Mycobacterium tuberculosis. Diagnostic Microbiology and Infectious Disease, 2012 , 74:207–209.22 Van Deun A et al. Rifampicin drug resistance tests for tuberculosis: challenging the gold standard. Journal of Clinical Microbiology, 2013, 51:2633–2640.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 17
accuracy of phenotypic resistance standards for DST once sufficient data become available.
4.2 Using Xpert MTB/RIF to diagnose extrapulmonary TB and rifampicin resistance in adults and children
A literature search was performed for published and unpublished reports of studies made available
from 1 January 2007 until 14 December 2012. From the literature searches, 22 relevant studies that included 5922 specimens were identified. Figure 7 shows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) diagram with the flow of the studies.
Figure 7. Selection of studies evaluating the accuracy of Xpert MTB/RIF in diagnosing extrapulmonary TB and detecting rifampicin resistance in adults and children: flow diagram of studies included in the review
194 potentially relevant citations identified in electronic databases
143 excluded at screening step 1Reason: Not relevant based on assessment of title and abstract
51 complete papers retrieved for more detailed evaluation
22 papers (or studies) included in the
systematic review
8 unpublished papers or collections of data added• 6 about to be published• 2 studies continuing
1 unpublished paper or collection of data excludedReasonDid not include any sample type that contributed to the subgroups being analysed
36 excluded at screening step 2 Reasons• < 10 samples per type of extrapulmonary TB: 10• Specificity results lacking: 0 • Abstract only: 12 • Cost–effectiveness analysis: 0 • Did not contain samples of extrapulmonary TB: 5• Duplicate data: 1• Editorial or comment: 2• Inappropriate reference standard: 3• Outcome lacking: 0 • Review article: 3• Technical: 0
18 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Thirteen studies (59%) were conducted in low-income and middle-income countries. All studies were performed in tertiary care centres or reference laboratories. Two studies (one by Bates and one by Walters) included only children;23 nine studies included no children. In the remaining 11 studies the percentages of children in the study population ranged from 2% to 34%. Three published studies and four unpublished studies included only one type of sample (for example, only pleural fluid). The remainder of the studies included varying percentages of different types of samples. Twelve studies reported on only one sample per patient; the other studies either reported on multiple samples per patient or did not report the number of samples per patient. Six studies used frozen, archived samples ; 15 used fresh samples; and 1 study used both fresh and frozen samples.
The studies reviewed were diverse with respect to both the different types of samples tested and their relative percentages in each study. The heterogeneity in the performance characteristics of Xpert MTB/RIF, primarily in sensitivity, across the different types of samples was substantial. Therefore, combining these studies to obtain an overall estimate of the accuracy of Xpert MTB/
RIF in diagnosing extrapulmonary TB would not be meaningful.
An analysis of predefined subgroups of sample types (that is, pleural fluid, lymph node aspirate or tissue, CSF, gastric fluid, and tissue other than lymph node) was undertaken to account for the heterogeneity among the studies. Data on the smear status of samples were not available for the individual types of samples. Therefore, samples included in the subgroups were either smear positive, smear negative or of unknown smear status.
4.2.1 Detecting lymph node TB in samples from biopsy or fine-needle aspiration
Fourteen studies were identified that tested the accuracy of Xpert MTB/RIF on samples from lymph node biopsies or fine-needle aspiration (FNA) compared against culture as a reference standard (Figure 8). A meta-analysis was performed for each sample type if at least 4 studies had at least 10 samples in each study. For the 11 studies with more than 10 samples (total, 849 samples) the estimates for sensitivity ranged from 50% to 100%. The pooled sensitivity across studies was 84.9% (95% CI, 72.1–92.4%); the pooled specificity was 92.5% (95% CI, 80.3–97.4%).
Figure 8. Forest plot of the sensitivity and specificity of Xpert MTB/RIF in detecting extrapulmonary TB in lymph node samples (tissue or aspirate) compared with culture as the reference standarda
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval.
a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
23 Additional information about the studies can be found in the annexes to Using the Xpert MTB/RIF assay to detect pulmonary and extrapulmonary tuberculosis and rifampicin resistance in adults and children: Expert Group meeting report. Geneva, World Health Organization, 2013 (available at: http://www.who.int/tb/laboratory/policy_statements/en/)
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 19
Five studies (one unpublished) assessed the accuracy of Xpert MTB/RIF on samples from lymph nodes compared against an author-defined CRS (Figure 9). In the different studies the CRS included some combination of NAAT other than Xpert MTB/RIF, histology, smear,
culture, biochemical testing, presenting signs,
or a response to treatment with anti-TB therapy.
The pooled sensitivity was estimated to be
83.7% (95% CI, 73.8–90.3%), and the pooled
specificity was 99.2% (95% CI, 88.4–100%).
Figure 9. Forest plot of the sensitivity and specificity of Xpert MTB/RIF in detecting extrapulmonary TB in lymph node samples (tissue or aspirate) compared with a composite reference standarda
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval.
a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
Studies that used fresh samples showed a slightly higher sensitivity and a lower specificity than those that used frozen samples; however, the precision of these estimates was low because data were limited. Only nine studies included information on the prevalence of HIV, and only two studies included more than 10% HIV-positive patients. Accuracy estimates for these studies did not differ substantially from those that included fewer HIV-positive patients. Given the limited amount of data for the group that had a prevalence of HIV greater than 10%, a summary estimate was not determined.
4.2.2 Detecting pleural TB in pleural fluid
Seventeen studies (1385 samples, 217 culture positive) provided data that could be used to estimate the sensitivity and specificity of Xpert MTB/RIF in testing pleural fluid. Results from the assessment of the accuracy of Xpert MTB/RIF using samples from pleural biopsy were integrated into the assessment of Xpert MTB/RIF for testing tissue biopsies of all kinds other than
lymph node.
The sensitivity of Xpert MTB/RIF in testing pleural fluid varied from 0% to 100% among the studies. The outliers at the lower end of the range and the upper end were studies with few culture-confirmed cases of TB. One study was excluded from the meta-analysis because the sensitivity could not be estimated; a second study was also excluded because it included fewer than 10 specimens of pleural fluid. The pooled sensitivity was low at 43.7%, with wide confidence intervals (95% CI, 24.8–64.7%); the pooled specificity was high at 98.1% (95% CI, 95.3–99.2%) (Figure 10).
Seven studies (4 published and 3 unpublished) with 698 samples (188 culture positive) evaluated Xpert MTB/RIF in testing pleural fluid compared with a CRS. In the different studies the CRS included some combination of NAAT other than Xpert MTB/RIF, histology, smear, culture, biochemical testing, presenting signs, or a response to treatment with anti-TB therapy. Compared with studies that used culture as the
20 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Figure 10. Forest plot of the sensitivity and specificity of Xpert MTB/RIF in detecting TB using pleural fluid compared with culture as a reference standarda
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval.a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
reference standard, the CRS subgroup yielded an even lower pooled sensitivity (17.0%; 95% CI, 7.5–34.2%), albeit with a high specificity (99.9%; 95% CI, 93.7–100.0%) (Figure 11).
Pleural fluid is not regarded as a suitable specimen for the microbiological diagnosis of pleural TB. Pleural biopsy is the preferred sample type for diagnosing pleural TB.
Figure 11. Forest plot of the sensitivity and specificity of Xpert MTB/RIF in detecting TB in pleural fluid compared with a composite reference standarda
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval.a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
4.2.3 Detecting TB in samples of CSF
In total, 709 CSF samples in 16 studies were tested with Xpert MTB/RIF, and the results were compared against culture as a reference standard (13 studies had more than 10 samples, and 10 of these provided information on both sensitivity and specificity). Only 117 culture-confirmed cases of TB were found. Estimates of sensitivity varied
widely and ranged from 51% to 100%; one study with 19 samples (3 false negatives) was an outlier at 0%. The pooled sensitivity across studies was 79.5% (95% CI, 62.0–90.2%) and the pooled specificity was 98.6% (95% CI, 95.8–99.6%), suggesting good performance of Xpert MTB/RIF in detecting TB in CSF when tested against culture as a reference standard (Figure 12).
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 21
Ten of the sixteen studies comparing Xpert MTB/RIF with culture as a reference standard used a concentration step in processing the sample. Six studies did not use a concentration step. A concentration step appeared to increase the
sensitivity of Xpert MTB/RIF (82%; 95% CI, 71–93% for concentrated samples versus 56%; 95% CI 36-77% for unconcentrated samples), although the confidence intervals overlapped. The use of a concentration step did not affect the specificity.
Figure 12. Forest plot of the sensitivity and specificity of Xpert MTB/RIF in detecting TB in cerebrospinal fluid compared with culture as a reference standarda
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval.a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
Only 6 studies (3 unpublished) assessed the accuracy of using Xpert MTB/RIF to test CSF samples compared against an author-defined CRS; sensitivity estimates ranged from 20% to 86% (Figure 13). The pooled sensitivity was estimated to be 55.5% (95% CI, 44.2–66.3%), and the
pooled specificity was estimated to be 98.8% (95% CI, 94.5–99.8%). The reduced sensitivity of Xpert MTB/RIF compared with the CRS versus culture as a reference standard suggests that either the CRS was too broad or that culture as the single reference standard is inadequate.
Figure 13. Forest plot of the sensitivity and specificity of Xpert MTB/RIF in detecting TB in cerebrospinal fluid compared with a composite reference standarda
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval.a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
4.2.4 Detecting TB in gastric fluid
Twelve studies (1258 samples) examined the performance of Xpert MTB/RIF in samples of
gastric fluid and compared the results against culture as a reference standard (8 studies had more than 10 samples). Two studies included only children. The remaining 10 studies included
22 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
adults and children (the proportion of children included across sample types ranged from 0% to 33.5%). One study with 788 samples that had valid results using Xpert MTB/RIF accounted for 62.6% of all gastric-fluid samples. The estimates of sensitivity varied from 69% to 100%; specificity
varied from 98% to 100%, with one unpublished
study an outlier reporting 52% specificity. The
pooled sensitivity across studies was 83.8% (95%
CI, 65.9–93.2%), and the pooled specificity
was 98.1% (95% CI, 92.3–99.5%) (Figure 14).
Figure 14. Forest plot of the sensitivity and specificity of Xpert MTB/RIF in detecting TB in gastric fluid compared with culture as a reference standarda
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval.
a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
All studies used a concentration step during specimen processing and prior to using the Xpert MTB/RIF assay; therefore, this was not considered to be a source of heterogeneity within the data. The condition of the gastric-fluid specimen (fresh versus frozen) did not appear to affect the performance of Xpert MTB/RIF. The five studies testing fresh specimens achieved a pooled sensitivity of 83% (95% CI, 71–93%). A further three studies used frozen specimens and had a pooled sensitivity of 79% (95% CI, 57–100%). The condition of the specimen (fresh or frozen) did not affect the specificity.
4.2.5 Detecting TB in tissue samples
There were 12 studies (699 samples) that tested Xpert MTB/RIF using tissue samples from any
site other than a lymph node, and compared the results against culture as a reference standard (10 studies had more than 10 samples). The estimates of sensitivity varied widely and ranged from 42% to 100%. The pooled estimate of sensitivity was calculated as 81.2% (95% CI, 67.7–89.9%). The pooled specificity was 98.1% (95% CI, 87.0–99.8%) (Figure 15).
The condition of the specimen (fresh versus frozen) did not appear to affect the performance of Xpert MTB/RIF. The five studies testing fresh specimens achieved a pooled sensitivity of 79% (95% CI, 64–94%). A further three studies used frozen specimens and had a pooled sensitivity of 76% (95% CI, 58–94%). The condition of the specimen (fresh or frozen) did not affect the specificity.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 23
Figure 15. Forest plot of the sensitivity and specificity of Xpert MTB/RIF in detecting TB in tissue samples (other than from a lymph node) compared with culture as a reference standarda
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval.
a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
4.2.6 Detecting rifampicin resistance
Data on detecting rifampicin resistance were used only from published studies because data collection was incomplete in some of the unpublished studies. Furthermore, data from a study were included only if DST had been done for all samples that were positive by culture and Xpert MTB/RIF because the selective confirmation of results could have introduced bias.
In total, data on resistance testing were available for 566 samples from 13 studies. Forty one samples were confirmed to be rifampicin resistant by phenotypic DST. Given the limited amount of data, no summary estimate was calculated. The average prevalence of rifampicin resistance across the studies was 5.4%, with the highest prevalence reported from India (25.6%). Xpert MTB/RIF did not identify 2 of the 41 phenotypically rifampicin-resistant samples. Six of the 41 samples that were identified as rifampicin resistant by Xpert MTB/RIF were identified as susceptible by phenotypic DST. Five of these six samples underwent sequencing of the rpoB gene, and four were found to have a
mutation in the same region of the rpoB gene at codon 533. Hence, Xpert MTB/RIF detected four additional rifampicin-resistant strains that would have been missed by phenotypic DST alone.
See section 4.1.9 for more information about the accuracy of the reference standards used to detect rifampicin resistance.
4.3 Using Xpert MTB/RIF to diagnose TB and rifampicin resistance in children
An electronic literature search was performed initially on 24 January 2013. In total, 39 articles were identified. Of these, 26 were excluded based on a review of their title and abstract. Of the remaining 12 articles that underwent a full-text review, 10 were included in this review. An additional 2 published studies were included that had been identified during a final electronic search conducted on 3 April 2013. An additional four unpublished studies were included that had been identified by querying networks of people working in childhood TB and contacting authors. In total, 16 studies were included (Figure 16).
24 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Figure 16. Selection of studies evaluating the accuracy of Xpert MTB/RIF in diagnosing TB and rifampicin resistance in children: flow diagram of studies included in the review
39 articles identified through initial database search
January 29, 2013
39 articles screened by title and abstract
12 full text articles assessed for eligibility
16 studies included (12 published, 4 unpublished)
for qualitative analysis/synthesis• 13 pulmonary TB• 6 Rifampicin resistance• 4 peripheral lymph node TB• 5 TB meningitis
26 articles excluded based on title and
abstract
2 full-text articles excluded
(> 15 years only)
2 published articles included after final
database search and review on 3 April, 2013
4 unpublished studies identified and included
through additional searches
4.3.1 Using Xpert MTB/RIF to diagnose pulmonary TB in children
The utility of Xpert MTB/RIF in diagnosing paediatric pulmonary TB was evaluated in 13 studies that included 2603 participants. Studies either collected the same specimen type from all children or different types of specimens from different subgroups of children (for example, samples of expectorated sputum were collected from older children; samples of induced sputum or gastric lavage or aspirate were collected from younger children). In three studies different types of specimens were collected from each child. As a result, a total of 3347 specimens
were assessed: expectorated sputum (4 studies, 270 children), induced sputum (7 studies, 1279 children), nasopharyngeal aspirate (1 study, 474 children), gastric lavage or aspirate (6 studies, 1324 children).
For samples of expectorated sputum, sensitivity varied from 55% to 90%; for induced sputum sensitivity varied from 40% to 100%; and for gastric lavage or aspirate it varied from 40% to 100%. Confidence intervals overlapped for each specimen type, suggesting that no specimen type was superior. Specificities for all studies and specimen types ranged from 93% to 100% (Figure 17).
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 25
Figure 17. Forest plot of the sensitivity and specificity of Xpert MTB/RIF in detecting pulmonary TB, peripheral lymph node TB and TB meningitis in children compared against culture as a reference standard, by study and specimen typea
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval; ES, expectorated sputum; GLA, gastric lavage or aspirate; IS, induced sputum; NPA, nasopharyngeal aspirate.
a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
One study examined the yield of specimens of nasopharyngeal aspirate. The sensitivity of Xpert MTB/RIF for these specimens was 44% (95% CI, 33–55%). In the same group of children, the sensitivity for induced sputum was 60% (95% CI, 49–70%).
The sensitivity and specificity of Xpert MTB/RIF were compared against mycobacterial culture as the reference standard as well as against the clinical TB reference standard.
4.3.1.1 Differences in the reference standards used
In all of the studies included in the review, 13.2% of children had culture-confirmed TB. The proportion of children with culture-confirmed TB varied by study and specimen type (range, 0–54.2%). In the majority of studies (9/13; 69%), multiple cultures were performed on samples from single participants. Hence, the definition of culture positive was based on the presence of at least one positive culture result
out of as many as six cultures performed. The average bacteriological yield in studies using multiple cultures was increased compared with the group of four studies that defined a participant as culture-positive based only on one culture result. Studies also used different culture techniques, but the impact of this potential source of bias was not evaluated.
Children were categorized as positive using the clinical TB reference standard if they were culture negative and had started anti-TB therapy based on a clinical diagnosis of TB. This broad clinical reference standard was chosen in order to accommodate the heterogeneous study methods and clinical definitions used in the studies. Children assigned to the group clinical not TB (that is, negative according to the clinical TB reference standard) either (1) did not have another diagnosis assigned, or (2) did not start anti-TB treatment but nonetheless improved or did not worsen after at least 1 month of follow-up after enrolment.
26 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
4.3.1.2 Accuracy of Xpert MTB/RIF compared with culture
The pooled sensitivity of Xpert MTB/RIF compared against culture was 66% for samples of expectorated or induced sputum (95% CrI, 52–77%), and 66% for samples of gastric lavage or aspirate (95% CrI, 51–81%). The width of the credible intervals indicated there was a high level of heterogeneity among the studies. The specificity values for Xpert MTB/RIF compared against culture as the reference standard were all at least 98%, with narrow credible intervals.
4.3.1.3 Accuracy of Xpert MTB/RIF compared with clinical TB as the reference standard
The sensitivity of Xpert MTB/RIF in culture-negative samples from paediatric patients compared against clinical TB as the reference standard was 4% for samples of expectorated or induced sputum and 15% for gastric lavage or aspirate, with all confidence intervals being wide and
therefore indicating a high level of heterogeneity. It is likely that the apparently poor performance of Xpert MTB/RIF was the result of a clinical TB reference standard that lacked specificity. The specificity values of Xpert MTB/RIF compared against the clinical TB reference standard were at least 99%, with narrow confidence intervals.
4.3.2 Xpert MTB/RIF compared with smear microscopy
The diagnostic accuracy of smear microscopy was calculated and compared against culture as the reference standard. Sensitivities varied from 30% to 60% for samples of expectorated sputum, 0% to 50% for induced sputum, 0% to 50% for gastric lavage or aspirate, and the sensitivity was 18% in the one cohort providing samples of nasopharyngeal aspirate. The 95% confidence intervals were wide and overlapping. The specificity was 95% or higher for all studies and specimen types (Figure 18).
Figure 18. Forest plot of the sensitivity and specificity of smear microscopy in detecting pulmonary TB, peripheral lymph node TB and TB meningitis in children compared against culture as a reference standard , by study and specimen typea
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval; ES, expectorated sputum; GLA, gastric lavage or aspirate; IS, induced sputum; NPA, nasopharyngeal aspirate.
a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 27
For expectorated and induced sputum the pooled sensitivity was 29% (95% CrI, 16–42%); for gastric lavage or aspirate it was 22% (95% CrI, 12–35%); the pooled credible intervals were wide for both expectorated or induced sputum and gastric lavage or aspirate, indicating a high
level of heterogeneity. The pooled specificity of
Xpert MTB/RIF for samples of gastric lavage or
aspirate was 99% (95% CrI, 97–100%); for
expectorated and induced sputum it was 100%
(95% CrI, 99–100%) (Table 3).
Table 3. Meta-analysis of the estimated sensitivity and specificity of smear microscopy in diagnosing pulmonary TB, peripheral lymph node TB and TB meningitis in children compared against culture as a reference standard in published and unpublished studies
ComparisonSpecimen type (No. of studies, No. of children)
Median (%) pooled sensitivity (pooled 95% CrI)
Median (%) pooled specificity (pooled 95% CrI)
Smear microscopy compared against culture as a reference standard (published and unpublished studies)
Expectorated sputum and induced sputum (10, 1546)
29 (16–42)
100 (99–100)
Gastric lavage or aspirate (7, 1319)
22 (12–35)
99 (97–100)
CrI, credible interval; the CrI is the Bayesian equivalent of the confidence interval.
These data suggest that in comparison with smear microscopy, the sensitivity of Xpert MTB/RIF was 37% higher if performed on samples of expectorated or induced sputum and 44% higher if performed on samples of gastric lavage or aspirate.
4.3.3 Performance of Xpert MTB/RIF in smear-positive and smear-negative children
Seven studies reporting data from 1083 children were included in the analysis of using Xpert MTB/RIF to test samples of expectorated or induced sputum.
Six studies with data from 1259 children were included in the analysis of using Xpert MTB/RIF to test samples of gastric lavage or aspirate. All studies that were included reported results for both smear-positive and smear-negative children (Figure 19).
The sensitivity of Xpert MTB/RIF on samples of expectorated or induced sputum from children with smear-negative results ranged from 25% to 86%. In contrast, the sensitivity of Xpert MTB/RIF in testing samples of either expectorated or induced sputum from smear-positive children ranged from 92% to 100%.
The pooled estimate of sensitivity for smear-positive children was 96% (95% CrI, 90–99%); for smear-negative children it was 55% (95% CrI, 41–69%).
The findings were similar when Xpert MTB/RIF was used to test samples of gastric lavage or aspirate: for smear-positive children the overall sensitivity was 95% (95% CrI, 83–99%), and for smear-negative children it was 62% (95% CrI, 44–80%). The credible intervals were wide (indicating variability), but did not overlap (Table 4).
28 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Figure 19. Forest plot of the sensitivity of Xpert MTB/RIF in diagnosing pulmonary TB, peripheral lymph node TB and TB meningitis in smear-positive and smear-negative children, by study and specimen typea
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval; ES, expectorated sputum; GLA, gastric lavage or aspirate; IS, induced sputum.
a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 29
Table 4. Meta-analysis of the sensitivity and specificity of Xpert MTB/RIF in diagnosing pulmonary TB, peripheral lymph node TB and TB meningitis compared against culture as a reference standard in smear-negative and smear-positive children in published and unpublished studies
ComparisonSpecimen type (No. of studies, No. of children)
Median (%) pooled sensitivity (pooled 95% CrI)
Median (%) pooled specificity (pooled 95% CrI)
Xpert MTB/RIF in smear-positive children
Expectorated sputum or induced sputum (7, 68)a
96 (90–99) c
Gastric lavage or aspirate (6, 32)b
95 (83–99) c
Xpert MTB/RIF in smear-negative children
Expectorated sputum or induced sputum (7, 1008)a
55 (41–69)
98 (96–99)
Gastric lavage or aspirate (6, 1204)b
62 (44–80)
99 (97–99)
CrI, credible interval; the CrI is the Bayesian equivalent of the confidence interval; additional information about the studies can be found in the annexes to Using the Xpert MTB/RIF assay to detect pulmonary and extrapulmonary tuberculosis and rifampicin resistance in adults and children: Expert Group meeting report. Geneva, World Health Organization, 2013 (available at: http://www.who.int/tb/laboratory/policy_statements/en/)
a This analysis included studies by Bates 2013, Nhu 2013, Nicol 2011, Rachow 2012 (expectorated sputum only), Sekadde 2013, an unpublished study by Walters and Zar 2012.b This analysis included studies by Bates 2013, Causse 2011, an unpublished study by Chisti, Nhu 2013, Tortoli 2012 and Walters 2012.c There were not enough data to calculate specificity.
As expected, smear status was associated with the performance of Xpert MTB/RIF, indicating that the sensitivity of Xpert MTB/RIF was greater in children who had a higher mycobacterial burden than in those with paucibacillary disease. Xpert MTB/RIF detected 55% of smear-negative culture-positive children from samples of expectorated or induced sputum, and 62% of smear-negative culture-positive children from samples of gastric lavage or aspirate.
4.3.4 Xpert MTB/RIF in children aged 0–4 years and 5–15 years
Five of the seven studies reported results for children aged 0–4 years and 5–15 years. Data from 976 children were included in the analysis of using Xpert MTB/RIF to test samples of expectorated or
induced sputum. The estimated accuracy of Xpert MTB/RIF in testing samples of gastric lavage or aspirate was reported only for children aged 0–4 years (5 studies, 957 children).
The sensitivity of Xpert MTB/RIF in both age groups ranged from 0% to 100%. The pooled sensitivity among children aged 0–4 years was 57% for Xpert MTB/RIF used to test samples of expectorated or induced sputum (95% CrI, 36–74%) and gastric lavage or aspirate (95% CrI, 38–75%). The pooled sensitivity for samples of expectorated or induced sputum was higher in children aged 5–15 years (83%; 95% CrI, 68–92%). The pooled specificity was at least 98% for all groups assessed, with relatively narrow credible intervals.
30 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
4.3.5 Xpert MTB/RIF in HIV-positive and HIV-negative children
Seven studies reporting data from 1074 children
were included in the analysis of the accuracy of
Xpert MTB/RIF in testing samples of expectorated
or induced sputum. All studies reported results for both HIV-positive and HIV-negative children.
The sensitivity of the test among HIV-positive children ranged from 20% to 100%; among HIV-negative children it ranged from 33% to 100% (Figure 20).
Figure 20. Forest plot of the sensitivity and specificity of Xpert MTB/RIF in detecting pulmonary TB, peripheral lymph node TB and TB meningitis in HIV-positive and HIV-negative children, by study and specimen typea
TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval; ES, expectorated sputum; GLA, gastric lavage or aspirate; IS, induced sputum.
a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
The pooled sensitivity among HIV-positive children (75%; 95% CrI, 57–88%) was higher than the sensitivity for HIV-negative children (57%; 95% CrI, 41–71%); however, the credible intervals were wide and overlapping. The pooled specificity was 98% for both groups.An analysis of the performance of Xpert MTB/
RIF stratified by smear status and HIV status demonstrated that the test had high sensitivity among smear-positive children regardless of their HIV status. The sensitivity of Xpert MTB/RIF was lowest among HIV-negative children, although the credible intervals were wide and overlapping (Table 5).
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 31
Table 5. Meta-analysis comparing Xpert MTB/RIF for diagnosing pulmonary TB, peripheral lymph node TB and TB meningitis using culture as a reference standard in HIV-positive and HIV-negative children, stratified by smear status
CategorySpecimen type (No. of studies, No. of children)
Pooled sensitivity (%) (95% CrI)
HIV positive and smear positive Expectorated sputum or induced sputum (5, 21)a
97 (85–100)
HIV positive and smear negativeExpectorated sputum or induced sputum (5, 25)a
69 (46–87)
HIV negative and smear positiveExpectorated sputum or induced sputum (5, 29)a
94 (81–99)
HIV negative and smear negativeExpectorated sputum or induced sputum (5, 85)a
48 (29–67)
CrI, credible interval; the CrI is the Bayesian equivalent of the confidence interval; additional information about the studies can be found in the annexes to Using the Xpert MTB/RIF assay to detect pulmonary and extrapulmonary tuberculosis and rifampicin resistance in adults and children: Expert Group meeting report. Geneva, World Health Organization, 2013 (available at: http://www.who.int/tb/laboratory/policy_statements/en/)
a The studies included in this analysis were Bates 2013, Nicol 2011, Rachow 2012 (expectorated sputum), Sekadde 2013 and Zar 2012.
A metaregression model that simultaneously controlled for smear status and HIV status using Xpert MTB/RIF to test samples of expectorated or induced sputum showed that the odds of test positivity were fourfold greater in smear-positive
children than in smear-negative children. The odds of Xpert MTB/RIF positivity were not statistically significant for HIV-positive children compared with HIV-negative children (Table 6).
Table 6. Metaregression model for Xpert MTB/RIF using samples of expectorated or induced sputum from children, controlling for smear status and HIV status
Node Mean SD MC error 2.5% Median 97.5%
Beta 0 0.06201 0.385 0.0054 –0.8159 –0.064 0.7059
Beta 1 (HIV) 0.5863 0.5551 0.008862 –0.4919 0.5789 1.705
Beta 2 (Smear) 3.98 1.076 0.02855 2.159 3.878 6.399
Pool
ed s
ensit
ivity
Smear negative and HIV negative
0.485 0.09264 0.0013 0.3066 0.484 0.6695
Smear positive and HIV negative
0.9694 0.03031 6.402 0.8873 0.9785 0.9983
Smear negative and HIV positive
0.6213 0.1101 0.001197 0.3944 0.6257 0.8216
Smear positive and HIV positive
0.988 0.01977 3.951 0.9284 0.9879 0.9991
SD, standard deviation.
32 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
There were insufficient data to perform a meta-analysis comparing the performance of Xpert MTB/RIF when using samples of gastric lavage or aspirate from HIV-positive and HIV-negative children.
4.3.6 Using Xpert MTB/RIF to detect peripheral lymph node TB in children
The use of samples from FNA or lymph node biopsy to diagnose peripheral lymph node TB was evaluated in five studies. Two studies were excluded from the meta-analysis because their samples included fewer than five participants. Therefore, the analysis included 3 studies with data from 172 children (Figure 21). The pooled sensitivity of Xpert MTB/RIF compared against culture as the reference standard was 86% (95% CrI, 65–96%); the pooled specificity was 81% (95% CrI, 54–93%). Credible intervals were wide for both sensitivity and specificity, indicating heterogeneity.
4.3.7 Using Xpert MTB/RIF to detect TB meningitis in children
The use of CSF to diagnose TB meningitis was evaluated in five studies that included 61 children.
In total 7/61 (11.5%) children had TB meningitis confirmed by CSF culture. Of these, 3 children were positive by Xpert MTB/RIF (3/61; 4.9%). Two studies were excluded from the meta-analysis because they did not include any culture-positive children. One of the remaining studies had a subgroup sample size that included fewer than five children. Hence, there were insufficient data to calculate sensitivity from the two remaining studies in which 2/6 (33%) culture-positive children had positive results from Xpert MTB/RIF (Figure 21). The pooled specificity, which included 3 studies and 51 children, was 95% (95% CrI, 81–99%), with relatively wide credible intervals.
4.3.8 Using Xpert MTB/RIF to detect rifampicin resistance in children
In total, seven studies provided data on using Xpert MTB/RIF to detect rifampicin resistance (Figure 21). Four studies used conventional phenotypic DST, and three used line probe assays. A meta-analysis of 3 studies that included 176 participants showed a pooled sensitivity of 86% (95% CrI, 53%-98%) and a pooled specificity of 98% (95% CrI, 94–100%).
Figure 21. Forest plot of the sensitivity and specificity of Xpert MTB/RIF for detecting resistance to rifampicin, peripheral lymph node TB and TB meningitis in children, by study and specimen typea
RIF, rifampicin; TP, true positive; FP, false positive; FN, false negative; TN, true negative; CI, confidence interval; FNA, fine needle aspiration; CSF, cerebrospinal fluid. a The figure shows the estimated sensitivity and specificity of each study (blue square) and its 95% CI (black horizontal line). The names of unpublished studies have been obscured. Values for test results are the number of each type of result (true positive, false positive, false negative, true negative).
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 33
4.4 Affordability and cost effectiveness of using Xpert MTB/RIF to diagnose TB
Twelve published papers were identified that compared the costs of using Xpert MTB/RIF and follow-on tests to diagnose TB and MDR-TB with current diagnostic algorithms. The setting for most of these analyses was South Africa (10 studies); 2 of these studies also included other countries in sub-Saharan Africa (Botswana, Lesotho, Namibia, Swaziland and Uganda); 1 study included countries in the former Soviet Union; and 1 global analysis was done (Table 7).
On a global level, the review of the evidence showed that using Xpert MTB/RIF to diagnose TB and MDR-TB was cost effective for all individuals suspected of having TB including those suspected to be coinfected with HIV when compared with current practices. Using Xpert MTB/RIF to diagnose MDR-TB would cost US$ 0.09 billion per year globally, which is less than the cost of conventional diagnostics used globally and in all countries that have a high burden of TB.
Diagnosing TB in HIV-positive people using Xpert MTB/RIF would cost about US$ 0.10 billion per
year, and would cost less than the conventional diagnostics used globally in almost all of the countries with a high burden of TB. Testing everyone who has signs and symptoms of TB would cost almost US$ 0.47 billion per year globally, which is much more than the cost of conventional diagnostics. Nevertheless, in European countries, Brazil and South Africa, the cost would represent less than 10% of current funding for TB programmes.
Introducing Xpert MTB/RIF to diagnose MDR-TB and to diagnose TB in HIV-positive people is warranted in many countries. Using it to test everyone who has signs and symptoms of TB is affordable in several middle-income countries, but its financial viability in low-income countries would require large increases in TB funding or further reductions in the price of the test, or both.
At the country level, the majority of costing and cost–effectiveness studies were from South Africa, so there remains a need for further evidence to be collected from other countries and epidemiological settings.
34 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATETa
ble
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XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 35W
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F as
firs
t-line
test
Tim
e ta
ken
to o
btai
n a
diag
nosis
(d
urat
ion
of
diag
nosti
c pa
thw
ay)
No
Scal
ing
up X
pert
MTB
/RI
F ad
ds 3
5% m
ore
to
budg
et in
201
1 (U
S$
293
milli
on v
ersu
s U
S$
218
milli
on);
scal
e-up
in
crea
ses
subs
tant
ially
th
e nu
mbe
r of T
B ca
ses
and
MD
R-TB
ca
ses
diag
nose
d, a
nd
patie
nts
starte
d on
tre
atm
ent
Mey
er-
Rath
et
al 2
011
(pol
icy
brie
f)
Cos
t of s
calin
g up
us
e of
Xpe
rt M
TB/
RIF
natio
nally
Sout
h A
frica
A
ll in
divi
dual
s su
spec
ted
to
have
TB
Smea
r mic
rosc
opy,
C
XR fo
r spu
tum
sm
ear-
nega
tive
indi
vidu
als,
cu
lture
Xper
t MTB
/RI
F as
firs
t-line
test
Tim
e ta
ken
to o
btai
n a
diag
nosis
(d
urat
ion
of
diag
nosti
c pa
thw
ay)
No
Ann
ual a
dditi
onal
bu
dget
requ
ired
is ar
ound
US$
34–
79
milli
on fo
r acc
eler
ated
sc
ale-
up
36 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATEPa
ntoj
a
et a
l 20
12
Cos
t ana
lysis
of
usin
g Xp
ert M
TB/
RIF
for t
arge
t pop
ulat
ions
Glo
bal
anal
ysis,
an
d 36
co
untri
es
with
a
high
bu
rden
of
TB a
nd
a hi
gh
burd
en o
f M
DR-
TB
All
indi
vidu
als
susp
ecte
d to
hav
e TB
T,
HIV
-pos
itive
in
divi
dual
s su
spec
ted
to h
ave
TB,
indi
vidu
als
susp
ecte
d to
ha
ve M
DR-
TB
Smea
r mic
rosc
opy,
C
XR fo
r spu
tum
sm
ear-
nega
tive
indi
vidu
als,
cu
lture
, DST
Xper
t MTB
/RI
F as
firs
t-line
test
for e
ach
targ
et
popu
latio
n
1 ye
arN
oU
sing
Xper
t MTB
/RI
F to
dia
gnos
e M
DR-
TB a
nd T
B in
HIV
-po
sitiv
e in
divi
dual
s co
sts le
ss th
an c
urre
nt
conv
entio
nal d
iagn
osis;
us
ing
Xper
t MTB
/RIF
for
all i
ndiv
idua
ls su
spec
ted
to h
ave
TB is
muc
h m
ore
costl
y bu
t is
affo
rdab
le
in m
iddl
e-in
com
e co
untri
esSc
hnip
pel
et a
l 20
12
Plac
emen
t of X
pert
MTB
/RI
F: c
ost a
t la
bora
tory
leve
l and
at
clin
ic le
vel
Sout
h A
frica
A
ll in
divi
dual
s su
spec
ted
to
have
TB
Not
app
licab
leXp
ert M
TB/
RIF
at la
bora
tory
le
vel a
nd a
t cl
inic
leve
l
1 ye
arN
oC
ost o
f Xpe
rt M
TB/
RIF
at p
oint
-of-tr
eatm
ent
(clin
ic) l
evel
is 5
1%
mor
e ex
pens
ive
than
pl
acem
ent a
t sub
distr
ict
labo
rato
ries
(US$
10
7 m
illion
ver
sus
US$
71
milli
on)
Schn
ippe
l et
al
2013
Cos
t of a
sec
ond
Xper
t MTB
/RI
F te
st to
in
divi
dual
s w
ho w
ere
nega
tive
by fi
rst X
pert
MTB
/RI
F
Sout
h A
frica
H
IV-p
ositi
ve
indi
vidu
als
susp
ecte
d to
ha
ve T
B
Cul
ture
for i
ndiv
idua
ls ne
gativ
e by
Xpe
rt M
TB/
RIF
Seco
nd X
pert
MTB
/RI
F te
st fo
r ind
ivid
uals
nega
tive
by fi
rst
Xper
t MTB
/RI
F
Tim
e ta
ken
to o
btai
n a
diag
nosis
(d
urat
ion
of
diag
nosti
c pa
thw
ay)
No
Cos
t per
TB
patie
nt o
n tre
atm
ent o
f offe
ring
seco
nd X
pert
MTB
/RI
F te
st to
thos
e w
ho
initi
ally
teste
d ne
gativ
e is
12%
less
than
of
ferin
g al
tern
ativ
e cu
lture
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 37Th
eron
et
al 2
012
Acc
urac
y an
d co
st of
tests
use
d in
co
mbi
natio
n w
ith
Xper
t MTB
/RI
F
Sout
h A
frica
A
ll in
divi
dual
s su
spec
ted
to
have
TB
Smea
r mic
rosc
opy,
C
XR, i
nter
fero
n γ
rele
ase
assa
ys (a
djun
ct
tests
)
Xper
t MTB
/RI
F co
mbi
ned
with
ad
junc
t tes
ts
Not
av
aila
ble
No
Usin
g Xp
ert M
TB/
RIF
for i
ndiv
idua
ls w
ho a
re
sput
um s
mea
r-neg
ativ
e ha
d th
e lo
wes
t cos
t of
any
strat
egy,
and
the
high
est a
ccur
acy
Van
Rie
et
al 2
013
Cos
t, yi
eld
and
turn
arou
nd ti
me
of
usin
g Xp
ert M
TB/
RIF
to d
iagn
ose
sput
um
smea
r-neg
ativ
e in
divi
dual
s
Sout
h A
frica
A
ll in
divi
dual
s su
spec
ted
to h
ave
TB:
sput
um s
mea
r-ne
gativ
es
Smea
r mic
rosc
opy
and
cultu
re
Xper
t MTB
/RI
F us
ed to
te
st sp
utum
sm
ear-n
egat
ive
indi
vidu
als
susp
ecte
d to
ha
ve T
B
Not
av
aila
ble
No
Cos
t per
cas
e di
agno
sed
is sim
ilar i
n bo
th s
trate
gies
; Xpe
rt M
TB/
RIF
is co
st-sa
ving
fo
r pat
ient
s
ART
, ant
iretro
vira
l the
rapy
; MD
R-TB
, mul
tidru
g-re
sista
nt tu
berc
ulos
is; C
XR, c
hest
X-ra
y; D
ST, d
rug-
susc
eptib
ility
testi
ng.
a A
dditi
onal
info
rmat
ion
abou
t the
stu
dies
can
be
foun
d in
the
anne
xes
to U
sing
the
Xper
t MTB
/RI
F as
say
to d
etec
t pul
mon
ary
and
extra
pulm
onar
y tu
berc
ulos
is an
d rif
ampi
cin
resis
tanc
e in
adu
lts a
nd
child
ren:
Exp
ert G
roup
mee
ting
repo
rt. G
enev
a, W
orld
Hea
lth O
rgan
izat
ion,
201
3 (a
vaila
ble
at: h
ttp:/
/w
ww
.who
.int/
tb/
labo
rato
ry/
polic
y_sta
tem
ents/
en/
).
38 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
5. WHO’s policy recommendations
The GRADE process confirmed that there is a solid evidence base to support the widespread use of Xpert MTB/RIF to detect TB and rifampicin resistance. WHO therefore recommends the use of Xpert MTB/RIF as described below.
5.1 Using Xpert MTB/RIF to diagnose pulmonary TB and rifampicin resistance in adults and children
• Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic test in adults suspected of having MDR-TB or HIV-associated TB (strong recommendation, high-quality evidence).
• Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic test in children suspected of having MDR-TB or HIV-associated TB (strong recommendation, very low-quality evidence).
• Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initial diagnostic test in all adults suspected of having TB (conditional recommendation acknowledging resource implications, high-quality evidence).
• Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initial diagnostic test in all children suspected of having TB (conditional recommendation acknowledging resource implications, very low-quality evidence).
• Xpert MTB/RIF may be used as a follow-on test to microscopy in adults suspected of having TB but who are not at risk of MDR-TB or HIV-associated TB, especially when further testing of smear-negative specimens is necessary (conditional recommendation acknowledging resource implications, high-quality evidence).
RemarksThese recommendations apply to the use of Xpert MTB/RIF for specimens of processed and unprocessed sputum.
These recommendations also apply to specimens of gastric lavage and aspirate from adults and children; the recommendation for adults is based on the generalization of data from children.
These recommendations support the use of a single sputum specimen for diagnostic testing, acknowledging that processing multiple specimens increases the sensitivity of Xpert MTB/RIF but has resource implications.
Children suspected of having pulmonary TB but who have had a single negative result by Xpert MTB/RIF should undergo further diagnostic testing, and a child for whom there is a high clinical suspicion of TB should be treated even if an Xpert MTB/RIF result is negative or if the test is not available.
Conventional microscopy and culture remain essential for monitoring therapy and for performing DST for anti-TB agents other than rifampicin (including for isoniazid and second-line anti-TB agents).
Expanding the scope of the use of Xpert MTB/RIF and its placement in diagnostic algorithms will have significant implications for operational implementation, and its use should be phased in within the context of national strategic plans for TB.
Emerging data have shown that Xpert MTB/RIF detects some rifampicin-resistant strains that are identified as susceptible by phenotypic DST. Sequencing these discordant results usually resolves in favour of Xpert MTB/RIF, and patients missed by phenotypic DST have poor treatment outcomes on first-line treatment.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 39
5.2 Using Xpert MTB/RIF to diagnose extrapulmonary TB and rifampicin resistance in adults and children
• Xpert MTB/RIF should be used in preference to conventional microscopy and culture as the initial diagnostic test for CSF specimens from patients suspected of having TB meningitis (strong recommendation given the urgency of rapid diagnosis, very low-quality evidence).
• Xpert MTB/RIF may be used as a replacement test for usual practice (including conventional microscopy, culture or histopathology) for testing specific nonrespiratory specimens (lymph nodes and other tissues) from patients suspected of having extrapulmonary TB (conditional recommendation, very low-quality evidence).
RemarksIndividuals suspected of having extrapulmonary TB but who have had a single negative result from Xpert MTB/RIF should undergo further diagnostic testing, and those for whom there is a high clinical suspicion for TB (especially children) should be treated even if an Xpert MTB/RIF result is negative or if the test is not available.
For CSF specimens, Xpert MTB/RIF should be preferentially used instead of culture if the sample
volume is low or if additional specimens cannot be obtained in order to make a quick diagnosis. If sufficient volume of material is available, concentration methods should be used to increase the yield.
Pleural fluid is a suboptimal sample for the bacterial confirmation of pleural TB regardless of the method used. A pleural biopsy is the preferred sample. The sensitivity of Xpert MTB/RIF in testing samples of pleural fluid is very low. Nevertheless, any individual with a positive result from pleural fluid tested by Xpert MTB/RIF should be treated for pleural TB; those with a negative result from Xpert MTB/RIF should have other tests.
Conventional microscopy and culture are essential for monitoring therapy and for performing DST for anti-TB agents other than rifampicin (including for isoniazid and second-line anti-TB agents).
Emerging data have shown that Xpert MTB/RIF detects some rifampicin-resistant strains that are found to be susceptible by phenotypic DST. Sequencing these discordant results usually resolves in favour of Xpert MTB/RIF, and patients missed by phenotypic DST have poor treatment outcomes on first-line treatment.
These recommendations do not apply to samples of stool, urine or blood, given the lack of data on the utility of Xpert MTB/RIF for these specimens.
6. Implementation considerations
A range of implementation issues were identified that need to be addressed to ensure that the use of Xpert MTB/RIF will be optimal.
• Although Xpert MTB/RIF is suitable for use at all levels of the health system, and testing with Xpert MTB/RIF does not require additional laboratory equipment, the sophisticated nature of the device requires
care in handling – that is, a stable and uninterrupted electrical supply is necessary to avoid interrupting the procedure and losing results; security against theft is necessary as is adequate storage space for the cartridges; staff must be assigned to perform the testing; and biosafety procedures must be put in place that are similar to those used for microscopy.
40 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
• Scaling up the implementation of Xpert MTB/RIF does not eliminate the need for capacity for conventional TB microscopy, culture and DST. Microscopy or culture, or both, remain essential for monitoring treatment since molecular tests based on DNA detection have not been shown to be suitable. Therefore, Xpert MTB/RIF should not be used to monitor treatment. In addition, conventional culture and DST are required to detect resistance to anti-TB agents other than rifampicin.
• The decision to scale-up the implementation of Xpert MTB/RIF should be made by ministries of health within the context of national plans for managing TB, MDR-TB and HIV-associated TB; plans for scale-up should consider the country’s specific epidemiology, the screening strategies used, how to ensure timely access to quality-assured first-line and second-line anti-TB agents, and whether care-delivery mechanisms are appropriate.
• Countries already using the molecular line probe assay to rapidly diagnose rifampicin resistance may introduce Xpert MTB/RIF at lower levels of the laboratory service, given that the line probe assay is suitable for high-throughput testing at the central or regional laboratory level (for additional information, see http://www.who.int/tb/laboratory/policy_statements/en/).
• The negative predictive value of Xpert MTB/RIF24 used to test for rifampicin resistance is more than 99% both in settings with a low prevalence of rifampicin resistance and in those with a high prevalence of rifampicin resistance – that is, a negative result accurately excludes the possibility of rifampicin resistance and no further testing is needed to confirm the negative results.
• The positive predictive value25 of Xpert MTB/RIF used to test for susceptibility to rifampicin exceeds 90% in settings or patient groups where the underlying prevalence of rifampicin resistance is greater than 15%. In settings or patient groups where rifampicin resistance is rare, the positive predictive value is adversely affected. The positive predictive values ranges from 71% to 84% in settings where the prevalence of rifampicin resistance is between 5% and 10%, and it diminishes to less than 70% when the prevalence of underlying rifampicin resistance falls below 5%. The positive predictive value can be greatly improved by engaging in a careful risk assessment for individual patients and by using targeted testing.
• It is important to differentiate between new cases of TB and previously treated cases; previously treated cases have a much higher likelihood of MDR-TB. Even in groups in which the prevalence of MDR-TB is low, testing previously treated TB cases with Xpert MTB/RIF will result in a high positive predictive value for detecting rifampicin resistance. Testing new cases not at risk for MDR-TB in groups in which the prevalence of MDR-TB is low will result in a lower positive predictive value for rifampicin susceptibility.
• It is uncommon to detect rifampicin resistance in groups in which there is a low prevalence of MDR-TB. In patients in a low-prevalence group who initially test positive by Xpert MTB/RIF, a second Xpert MTB/RIF test may be used to control for preanalytical and postanalytical errors, and to improve the clinicians’ confidence in deciding on an appropriate regimen. – In patients whose Xpert MTB/RIF result repeatedly detects rifampicin resistance,
24 The negative predictive value for rifampicin resistance is the proportion of cases diagnosed as rifampicin-susceptible that are truly susceptible.25 The positive predictive value for rifampicin resistance is the proportion of cases diagnosed as rifampicin-resistant that are truly resistant.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 41
a WHO-recommended treatment regimen for MDR-TB (including isoniazid) should be initiated and optimized following confirmatory testing for rifampicin resistance and additional DST to test for resistance to isoniazid and second-line anti-TB agents. – Patients with discordant results for rifampicin resistance reported by Xpert MTB/RIF should be commenced on a WHO-recommended regimen of first-line agents.
• Based on the considerations above, confirmatory testing for rifampicin resistance in groups with a low prevalence of MDR -TB shown by Xpert MTB/RIF using other genotypic testing or conventional DST techniques may be unreliable and can produce discordant results which require resolution by DNA sequencing (section 4.1.9).
• Because Xpert MTB/RIF detects resistance only to rifampicin, countries with documented or suspected cases of extensively drug-resistant TB (XDR-TB) should establish or expand their capacity for conventional culture and DST for second-line agents to ensure quality assured testing of second-line agents, following WHO’s policy guidance.
• Scale-up of Xpert MTB/RIF should be implemented within the context of national plans for laboratory strengthening, considering that the GeneXpert system may also provide a technology platform for other diagnostic services, and reduce the costs involved in providing integrated laboratory services.
• Xpert MTB/RIF cartridges and the specimen reagent should be stored at 2–28 ˚C, following the manufacturer’s recommendations. The cartridges are bulky and require substantial storage space.
• The maximum capacity of a single, 4-module GeneXpert instrument is 16–20 specimens per day. Therefore, busier sites will either need several 4-module instruments or larger instruments (16 modules or more),
and these additional requirements will have associated implications for cost and storage.
• The manufacturer’s recommended ambient operating temperature for the GeneXpert instrument is limited to a maximum of 30 °C. In settings where the ambient temperature regularly exceeds 30 ˚C, the room where the assay is being done may need to be air conditioned.
• The Xpert MTB/RIF cartridges have a shelf-life of 12 months, posing a challenge in relatively inaccessible areas that have complex customs-clearance procedures. Therefore, inventory will need to be managed carefully by considering the usage, shelf-life and lead time for the delivery of orders.
• The GeneXpert modules require annual calibration, which must be performed by an authorized service provider or carried out by exchanging the modules. A remote calibration option is available from the manufacturer. This option does not require that modules be exchanged, and it can be done using a specially designed calibration kit. The calibration kit contains special cartridges that can be run on each module (without a sample) when calibration is due. During this run (which lasts approximately 20 minutes), the instrument will be automatically calibrated. However, if this calibration fails, it will be necessary to exchange the module. The calibration kit has the same shelf-life as the usual cartridges; in 2013 the cartridges and kit could be ordered together at the preferential pricing of US$ 450.00 for a kit sufficient to calibrate up to 4 modules.
• The initial capital cost for the GeneXpert unit (US$ 17 000 per 4-module desktop unit or US$ 17 500 per 4-module laptop unit) is significantly higher than the cost of microscopy (around US$ 1 500 per microscope), but it is much lower than
42 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
for conventional culture and DST (up to US$ 1.4 million for a new laboratory or up to US$ 300 000 for an established laboratory), given the need for extensive biosafety equipment and the infrastructure required for conventional testing.
• A detailed commercial sales contract and customer support plan should be negotiated with the supplier, guaranteeing an ample and continual supply of cartridges, customs clearance, maintenance and calibration, and appropriate repair and replacement.
• Mechanisms for rapidly reporting Xpert MTB/RIF results to clinicians, and offering timely access to appropriate treatment, must be established to provide patients with the benefits of an early diagnosis.
• Health-care staff must be trained how to properly select persons to test with the Xpert MTB/RIF assay in different epidemiological settings; they must also be trained to interpret the results of rifampicin-resistance testing for persons with and without risk factors for drug-resistant TB, understand when to initiate a WHO-recommended MDR-TB regimen based on the results from Xpert MTB/RIF, and how to use additional testing (either a second Xpert MTB/RIF assay or another test) to ensure early initiation of the appropriate WHO-recommended first-line regimen or MDR-TB treatment regimen.
6.1 Research needs
A series of operational research questions have been identified related to the introduction and scale-up of Xpert MTB/RIF, and its impact on the diagnosis of TB, MDR-TB and the management of patients.
No additional studies, at country level, on the diagnostic accuracy of Xpert MTB/RIF are needed.
Further operational research should focus on the following priorities:
• evaluation of diagnostic algorithms in different epidemiological and geographical settings, and patient populations;
• country-specific cost–effectiveness and cost–benefit analyses of Xpert MTB/RIF in different programmatic settings;
• prospective evaluations of using Xpert MTB/RIF for nonrespiratory specimens, including blood, urine and stool;
• evaluation of the impact of Xpert MTB/RIF in reducing the diagnostic delay and the time until appropriate treatment is initiated;
• evaluation of the impact of Xpert MTB/RIF on case-detection, treatment access and treatment outcomes in hard-to-reach populations.
6.2 Plans for supporting scale-up of the implementation of Xpert MTB/RIF
WHO will continue to evaluate the usefulness and impact of Xpert MTB/RIF, with active collaboration from the Global Laboratory Initiative of the Stop TB Partnership26, the WHO and Global Laboratory Initiative’s TB Supranational Reference Laboratory Network, and several organizations that have implemented the Xpert MTB/RIF system (including technical agencies, research organizations, nongovernmental organizations and donors). Implementing organizations are brought together by WHO during an annual meeting to share their experiences, identify operational constraints and solutions, and contribute to the global collection of data by WHO on the scale-up of Xpert MTB/RIF in different settings.
In addition, WHO’s Global TB Programme maintains a website27 dedicated to monitoring the roll-out of Xpert MTB/RIF in order to inform and facilitate coordination among implementing organizations including countries, technical
26 For additional information, see http://www.stoptb.org/wg/gli/.27 For additional information, see http://www.who.int/tb/laboratory/mtbrifrollout.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 43
agencies, nongovernmental agencies and other partners.
A second edition of WHO’s implementation document for Xpert MTB/RIF is being developed by WHO’s Global TB Programme based on this policy update; it will be disseminated widely through e-mail and on the web sites of stakeholders. The Xpert MTB/RIF implementation manual outlines the requirements for systematic scale-up of Xpert MTB/RIF in varying epidemiological and resource settings. The document suggests ways to developing diagnostic algorithms and manage patients; it also discusses the operational and logistical aspects that need to be addressed during implementation of Xpert MTB/RIF. This policy update will also be incorporated into a comprehensive training package on Xpert MTB/RIF (being developed by WHO and the Global Laboratory Initiative) that will be made available to country and technical partners.
WHO and the Global Drug Facility have initiated
a unified forecasting initiative for Xpert MTB/RIF that collects forecasts of orders from major programmes and projects; these forecasts are submitted quarterly to the manufacturer. Reliable forecasting is needed to ensure effective scale-up of Xpert MTB/RIF by aiding the manufacturer in planning to meet demand.
Given the public-health importance and the ease of use of the Xpert MTB/RIF technology, expanded uptake at country level is anticipated and, therefore, the impact on TB case-detection will be monitored by WHO’s Global TB Programme. In addition, improvements in diagnosing drug-resistant TB using this technology will need to be accompanied by scale-up of access to appropriate treatment, and it will be essential that scale-up is closely coordinated with care-delivery mechanisms at the country level. Therefore, implementation of the new policy guidance will be harmonized with the Global TB Programme’s efforts to scale-up treatment of MDR-TB.
Box 4. Online resources
Strategic and Technical Advisory Group for Tuberculosis (STAG-TB): report of the 13th meeting. Geneva, World Health Organization, 2013 (WHO/HTM/TB/2013.09)(http://www.who.int/entity/tb/advisory_bodies/STAG_report2013.pdf).
Using the Xpert MTB/RIF assay to detect pulmonary and extrapulmonary tuberculosis and rifampicin resistance in adults and children: Expert Group meeting report. Geneva, World Health Organization, 2013 (available at http://www.who.int/tb/laboratory/policy_statements/en/).
Policy framework for implementing new tuberculosis diagnostics. Geneva, World Health Organization, 2010(available at: http://www.who.int/tb/laboratory/whopolicy_framework_mar2011.pdf).
Xpert MTB/RIF implementation manual. Technical and operational ‘how-to’: practical considerations, 2nd ed. Geneva, World Health Organization, 2014 (available at http://www.who.int/tb/laboratory/policy_statements/en/).
Xpert MTB/RIF training package. Geneva, Global Laboratory Initiative, 2014 (available at http://www.stoptb.org/wg/gli/).
44 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE7.
GRA
DE ta
bles
Tabl
e 8.
GRA
DE
evid
ence
pro
file:
acc
urac
y of
Xpe
rt M
TB/R
IF in
dia
gnos
ing
pulm
onar
y TB
in a
dults
PIC
O q
uesti
on: W
hat i
s th
e di
agno
stic
accu
racy
of X
pert
MTB
/RI
F fo
r det
ectio
n of
pul
mon
ary
TB in
adu
lts, w
here
Xpe
rt M
TB/
RIF
is us
ed a
s a
repl
acem
ent
test
for s
mea
r mic
rosc
opy?
Parti
cipa
nts:
Adu
lts s
uspe
cted
of h
avin
g pu
lmon
ary
TB. S
ettin
g: M
ainl
y in
term
edia
te-le
vel l
abor
ator
ies
and
prim
ary
heal
th-c
are
faci
litie
s.Ta
rget
con
ditio
n: P
ulm
onar
y TB
. Ref
eren
ce s
tand
ard:
Sol
id c
ultu
re o
r liq
uid
cultu
re.
Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
: 22
(900
8). P
oole
d se
nsiti
vity
: 88%
(95%
CrI,
84–
92%
); po
oled
spe
cific
ity: 9
9% (9
5% C
rI, 9
8– 9
9%)
Out
com
eSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
a
Lim
itatio
nsIn
dire
ctne
ss I
ncon
sist
ency
Impr
ecis
ion
Publ
icat
ion
bias
Prev
alen
ce
25/1
000b
Prev
alen
ce
50/1
000b
Prev
alen
ce
100/
1000
bPr
eval
ence
30
0/10
00b
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-se
ctio
nal
Non
ecN
oned
Non
e N
one
Und
etec
tede
Hig
h
22(2
1–23
)44
(42–
46)
88(8
4–92
)26
4(2
52–2
76)
False
neg
ativ
es
(indi
vidu
als
inco
rrect
ly
clas
sified
as
not h
avin
g TB
)
Cro
ss-
sect
iona
l N
onec
Non
edN
one
Non
eU
ndet
ecte
deH
igh
3
(2–4
)6
(4–8
)12
(8–1
6)36
(24–
48)
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cl
assifi
ed a
s ha
ving
TB
Cro
ss-
sect
iona
l N
onec
Non
edN
one
Non
eU
ndet
ecte
deH
igh
10
(10–
20)
10(1
0–19
)9
(9–1
8)7
(7–1
4)
True
neg
ativ
es
(indi
vidu
als
with
out T
B)C
ross
-se
ctio
nal
Non
ecN
one4
Non
eN
one
Und
etec
tede
Hig
h
965
(956
–965
)94
1 (9
31–9
41)
891
(882
–891
)69
3(6
86–6
93)
CrI,
cre
dibl
e in
terv
al.
a Th
e ex
pect
ed n
umbe
r of X
pert
MTB
/RI
F re
sults
was
bas
ed o
n th
e se
nsiti
vity
and
spe
cific
ity e
stim
ates
cal
cula
ted
from
a c
ompa
rison
with
cul
ture
for d
iffer
ent p
reva
lenc
es o
f TB.
b Th
e es
timat
es o
f TB
prev
alen
ce w
ere
prov
ided
by
the
WH
O S
teer
ing
Gro
up.
c Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
The
maj
ority
of s
tudi
es e
nrol
led
indi
vidu
als
cons
ecut
ivel
y, a
nd a
sses
sed
the
resu
lt of
the
refe
renc
e sta
ndar
d bl
inde
d to
the
resu
lt fro
m X
pert
MTB
/RI
F. Th
e Xp
ert M
TB/
RIF
resu
lt is
auto
mat
ed a
nd w
as c
onsid
ered
blin
ded
in a
ll stu
dies
. d
The
ratin
g of
the
qual
ity o
f the
evi
denc
e m
ay b
e lo
wer
ed if
ther
e ar
e im
porta
nt d
iffer
ence
s in
the
tests
stu
died
and
in th
e ex
perti
se o
f tho
se a
pply
ing
the
tests
in th
e stu
dies
com
pare
d w
ith th
e se
tting
s fo
r whi
ch th
e re
com
men
datio
ns a
re in
tend
ed. T
he m
ajor
ity o
f stu
dies
(15/
22; 6
8%) e
valu
ated
Xpe
rt M
TB/
RIF
in s
ettin
gs w
here
it w
as in
tend
ed to
be
used
. Alth
ough
stu
dies
of d
iagn
ostic
acc
urac
y m
ay n
ot p
rovi
de d
irect
evi
denc
e ab
out p
atie
nt-im
porta
nt o
utco
mes
, tw
o stu
dies
pro
vide
d in
form
atio
n ab
out t
he ti
me
until
trea
tmen
t ini
tiatio
n. In
Boe
hme
2011
, for
sm
ear-n
egat
ive
cultu
re-p
ositi
ve T
B,
the
med
ian
dela
y un
til b
egin
ning
trea
tmen
t bef
ore
Xper
t MTB
/RI
F w
as in
trodu
ced
was
56
days
(int
erqu
artil
e ra
nge
[IQR]
, 39
–81
days
) com
pare
d w
ith 5
day
s (IQ
R, 2
–8 d
ays)
afte
r Xpe
rt M
TB/
RIF
was
intro
duce
d. In
Van
Rie
201
3, fo
r sm
ear-n
egat
ive
cultu
re-p
ositi
ve T
B pa
tient
s w
ith p
ositi
ve re
sults
from
Xpe
rt M
TB/
RIF,
treat
men
t was
beg
un o
n th
e sa
me
day
com
pare
d w
ith a
fter 1
3 da
ys fo
r pa
tient
s di
agno
sed
by o
ther
met
hods
.e
One
unp
ublis
hed
study
was
incl
uded
in th
e an
alys
is. N
o fo
rmal
ass
essm
ent o
f pub
licat
ion
bias
was
con
duct
ed u
sing
met
hods
suc
h as
funn
el p
lots
or re
gres
sion
tests
bec
ause
suc
h te
chni
ques
hav
e no
t be
en fo
und
to b
e he
lpfu
l in
studi
es o
f dia
gnos
tic a
ccur
acy.
How
ever
, rep
ortin
g bi
as w
as c
onsid
ered
to b
e m
inim
al s
ince
Xpe
rt M
TB/R
IF is
a ne
w te
st th
at h
as h
ad c
onsid
erab
le a
ttent
ion
and
scru
tiny.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 45Ta
ble
9. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
iagn
osin
g pu
lmon
ary
TB in
spu
tum
sm
ear-
posi
tive
adul
ts
PIC
O q
uesti
on: W
hat i
s th
e di
agno
stic
accu
racy
of X
pert
MTB
/RI
F fo
r det
ectio
n of
pul
mon
ary
TB in
sm
ear-p
ositi
ve in
divi
dual
s?Pa
rtici
pant
s: A
dults
who
are
sm
ear p
ositi
ve a
nd c
ultu
re p
ositi
ve
Setti
ng: M
ainl
y in
term
edia
te-le
vel l
abor
ator
ies
and
prim
ary
heal
th-c
are
faci
litie
s Ta
rget
con
ditio
n: P
ulm
onar
y TB
Re
fere
nce
stand
ard:
Sol
id c
ultu
re o
r liq
uid
cultu
reN
umbe
r of s
tudi
es (n
umbe
r of p
artic
ipan
ts): 2
3 (1
952)
Pool
ed s
ensit
ivity
: 98%
(95%
CrI,
97–
99%
); po
oled
spe
cific
ity: N
ot e
stim
ated
Out
com
eSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
Lim
itatio
nsIn
dire
ctne
ss
Inco
nsis
tenc
yIm
prec
isio
nPu
blic
atio
n bi
asPr
eval
ence
25
/100
0Pr
eval
ence
50
/100
0Pr
eval
ence
10
0/10
00
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-se
ctio
nal
Non
eaN
oneb
Non
ecN
one
Und
etec
tedd
Hig
h
25(2
4-25
)49
(49-
50)
98(9
7-99
)Fa
lse n
egat
ives
(in
divi
dual
s in
corre
ctly
cl
assifi
ed a
s no
t hav
ing
TB)
Cro
ss-
sect
iona
l N
onea
Non
ebN
onec
Non
eU
ndet
ecte
ddH
igh
1
(0-1
)1
(1-2
)2
(1-3
)
False
pos
itive
se (in
divi
dual
s in
corre
ctly
cl
assifi
ed a
s ha
ving
TB
––
––
––
––
––
True
neg
ativ
ese
(indi
vidu
als
with
out T
B)–
––
––
––
––
–
CrI,
cre
dibl
e in
terv
al.
a Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
The
maj
ority
of s
tudi
es e
nrol
led
indi
vidu
als
cons
ecut
ivel
y, a
nd a
sses
sed
the
resu
lt of
the
refe
renc
e sta
ndar
d bl
inde
d to
the
resu
lt fro
m X
pert
MTB
/RI
F. Th
e Xp
ert M
TB/
RIF
resu
lt is
auto
mat
ed a
nd w
as c
onsid
ered
blin
ded
in a
ll stu
dies
. b
The
maj
ority
of s
tudi
es (1
6/23
; 70%
) eva
luat
ed X
pert
MTB
/RI
F in
set
tings
whe
re it
was
inte
nded
to b
e us
ed. A
lthou
gh s
tudi
es o
f dia
gnos
tic a
ccur
acy
may
not
pro
vide
dire
ct e
vide
nce
abou
t pat
ient
-im
porta
nt o
utco
mes
, the
qua
lity
of th
e ev
iden
ce w
as n
ot d
owng
rade
d.c
The
estim
ates
of s
ensit
ivity
wer
e hi
ghly
con
siste
nt.
d O
ne u
npub
lishe
d stu
dy w
as in
clud
ed in
the
anal
ysis.
No
form
al a
sses
smen
t of p
ublic
atio
n bi
as w
as c
ondu
cted
usin
g m
etho
ds s
uch
as fu
nnel
plo
ts or
regr
essio
n te
sts b
ecau
se s
uch
tech
niqu
es h
ave
not b
een
foun
d to
be
help
ful f
or s
tudi
es o
f dia
gnos
tic a
ccur
acy.
How
ever
, re
porti
ng b
ias
was
con
sider
ed to
be
min
imal
sin
ce X
pert
MTB
/RI
F is
a ne
w te
st th
at h
as h
ad c
onsid
erab
le a
ttent
ion
and
scru
tiny.
e Th
e po
oled
spe
cific
ity fo
r Xpe
rt M
TB/
RIF
was
not
esti
mat
ed in
thes
e stu
dies
bec
ause
alm
ost a
ll pa
rtici
pant
s w
ere
cons
ider
ed to
be
true
posit
ives
for T
B.
46 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATETa
ble
10. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
iagn
osin
g pu
lmon
ary
TB in
spu
tum
sm
ear-
nega
tive
adul
ts
PIC
O q
uesti
on: W
hat i
s th
e di
agno
stic
accu
racy
of X
pert
MTB
/RI
F fo
r det
ectio
n of
cul
ture
-con
firm
ed p
ulm
onar
y TB
in s
mea
r-neg
ativ
e in
divi
dual
s?Pa
rtici
pant
s: A
dults
who
wer
e sm
ear-n
egat
ive
and
susp
ecte
d of
hav
ing
pulm
onar
y TB
Se
tting
: Mai
nly
inte
rmed
iate
-leve
l lab
orat
orie
s an
d pr
imar
y he
alth
-car
e fa
cilit
ies
Targ
et c
ondi
tion:
Pul
mon
ary
TB
Refe
renc
e sta
ndar
d: S
olid
cul
ture
or l
iqui
d cu
lture
Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
: 23
(715
1)
Pool
ed s
ensit
ivity
: 68%
(95%
CrI,
61–
74%
); po
oled
spe
cific
ity: 9
9% (9
5% C
rI, 9
8–99
%)
Out
com
eSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
smea
r-ne
gativ
e in
divi
dual
s te
sted
(95%
CrI)
Lim
itatio
nsIn
dire
ctne
ss
Inco
nsis
tenc
yIm
prec
isio
nPu
blic
atio
n bi
asPr
eval
ence
25
/100
0Pr
eval
ence
50
/100
0Pr
eval
ence
10
0/10
00
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-se
ctio
nal
Non
eaN
oneb
Serio
us (–
1)c
Non
edU
ndet
ecte
deM
oder
ate
17
(15-
19)
34(3
1-37
)68
(61-
74)
False
neg
ativ
es
(indi
vidu
als
inco
rrect
ly
clas
sified
as
not h
avin
g TB
)
Cro
ss-
sect
iona
l N
onea
Non
ebSe
rious
(–1)
cN
oned
Und
etec
tede
Mod
erat
e
8(7
-10)
16(1
3-20
)32
(26-
39)
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cl
assifi
ed a
s ha
ving
TB
Cro
ss-
sect
iona
l N
onea
Non
ebN
one
Non
eU
ndet
ecte
deH
igh
10
(10-
20)
10(1
0-19
)9
(9-1
8)
True
neg
ativ
es
(indi
vidu
als
with
out T
B)C
ross
-se
ctio
nal
Non
eaN
oneb
Non
eN
one
Und
etec
tede
Hig
h
965
(956
-965
)94
1(9
31-9
41)
891
(882
-891
)
CrI,
cre
dibl
e in
terv
al.
a Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
The
maj
ority
of s
tudi
es e
nrol
led
indi
vidu
als
cons
ecut
ivel
y, a
nd a
sses
sed
the
resu
lts o
f the
refe
renc
e sta
ndar
d bl
inde
d to
the
resu
lt fro
m X
pert
MTB
/RI
F. Th
e Xp
ert M
TB/
RIF
resu
lt is
auto
mat
ed a
nd w
as c
onsid
ered
blin
ded
in a
ll stu
dies
. b
The
maj
ority
of s
tudi
es (1
6/23
; 70%
) eva
luat
ed X
pert
MTB
/RI
F in
set
tings
whe
re it
was
inte
nded
to b
e us
ed. A
lthou
gh s
tudi
es o
f dia
gnos
tic a
ccur
acy
may
not
pro
vide
dire
ct e
vide
nce
abou
t pat
ient
-im
porta
nt o
utco
mes
, the
qua
lity
of th
e ev
iden
ce w
as n
ot d
owng
rade
d.c
Ther
e w
as s
ome
varia
bilit
y in
sen
sitiv
ity e
stim
ates
acr
oss
studi
es.
This
hete
roge
neity
cou
ld n
ot b
e ex
plai
ned
by s
tudy
qua
lity
or b
y re
mov
ing
the
study
by
Law
n 20
11 fr
om th
e an
alys
is. T
he s
tudy
by
Law
n, w
hich
foun
d th
e lo
wes
t sen
sitiv
ity, e
valu
ated
the
use
of X
pert
MTB
/RI
F to
scr
een
HIV
-pos
itive
pat
ient
s w
ith a
dvan
ced
imm
unod
efici
ency
, reg
ardl
ess
of th
eir s
ympt
oms,
who
wer
e en
rollin
g in
an
tiret
rovi
ral t
hera
py. T
he o
bser
ved
sens
itivi
ty m
ay h
ave
varie
d am
ong
studi
es a
s a
resu
lt of
cha
ract
erist
ics
asso
ciat
ed w
ith th
e pa
rtici
pant
s, b
ut th
ere
wer
e in
suffi
cien
t dat
a to
inve
stiga
te th
is po
ssib
ility.
Th
e qu
ality
of t
he e
vide
nce
was
dow
ngra
ded
by o
ne p
oint
.d
At a
pre
test
prob
abili
ty o
f 10%
, the
con
fiden
ce in
terv
als
for t
rue
posit
ives
and
false
neg
ativ
es w
ere
rela
tivel
y na
rrow
.e
One
unp
ublis
hed
study
was
incl
uded
in th
e an
alys
is. N
o fo
rmal
ass
essm
ent o
f pub
licat
ion
bias
was
con
duct
ed u
sing
met
hods
suc
h as
funn
el p
lots
or re
gres
sion
tests
bec
ause
suc
h te
chni
ques
hav
e no
t bee
n fo
und
to b
e he
lpfu
l in
studi
es o
f dia
gnos
tic a
ccur
acy.
How
ever
, re
porti
ng b
ias
was
con
sider
ed to
be
min
imal
sin
ce X
pert
MTB
/RI
F is
a ne
w te
st th
at h
as h
ad c
onsid
erab
le a
ttent
ion
and
scru
tiny.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 47Ta
ble
11. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
iagn
osin
g pu
lmon
ary
TB in
adu
lts li
ving
with
HIV
PIC
O q
uesti
on: W
hat i
s th
e di
agno
stic
accu
racy
of X
pert
MTB
/RI
F fo
r det
ectio
n of
pul
mon
ary
TB in
peo
ple
livin
g w
ith H
IV?
Parti
cipa
nts:
Adu
lts li
ving
with
HIV
and
sus
pect
ed o
f hav
ing
pulm
onar
y TB
Se
tting
: Mai
nly
inte
rmed
iate
-leve
l lab
orat
orie
s an
d pr
imar
y he
alth
-car
e fa
cilit
ies
Targ
et c
ondi
tion:
Pul
mon
ary
TB
Refe
renc
e sta
ndar
d: S
olid
cul
ture
or l
iqui
d cu
lture
Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
: 7 (1
789)
Pool
ed s
ensit
ivity
: 79%
(95%
CrI,
70–
86%
); po
oled
spe
cific
ity: 9
8% (9
5% C
rI, 9
6–99
%)
Out
com
eSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
Lim
itatio
nsIn
dire
ctne
ss
Inco
nsis
tenc
yIm
prec
isio
nPu
blic
atio
n bi
asPr
eval
ence
25
/100
0Pr
eval
ence
50
/100
0Pr
eval
ence
10
0/10
00
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-se
ctio
nal
Non
eaN
oneb
Serio
us (–
1)c
Non
edU
ndet
ecte
deM
oder
ate
20
(18-
22)
40(3
5-43
)79
(70-
86)
False
neg
ativ
es
(indi
vidu
als
inco
rrect
ly
clas
sified
as
not h
avin
g TB
)
Cro
ss-
sect
iona
l N
onea
Non
ebSe
rious
(–1)
cN
oned
Und
etec
tede
Mod
erat
e
5(4
-8)
11(7
-15)
21(1
4-30
)
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cl
assifi
ed a
s ha
ving
TB
Cro
ss-
sect
iona
l N
onea
Non
ebN
one
Non
eU
ndet
ecte
deH
igh
20
(10-
39)
19(1
0-38
)18
(9-3
6)
True
neg
ativ
es
(indi
vidu
als
with
out T
B)C
ross
-se
ctio
nal
Non
eaN
oneb
Non
eN
one
Und
etec
tede
Hig
h
956
(936
-965
)93
1(9
12-9
41)
882
(864
-891
)
CrI,
cre
dibl
e in
terv
al.
a Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
All
studi
es e
nrol
led
indi
vidu
als
cons
ecut
ivel
y, a
nd a
sses
sed
the
resu
lt of
the
refe
renc
e sta
ndar
d bl
inde
d to
the
resu
lt fro
m X
pert
MTB
/RI
F. Th
e Xp
ert M
TB/
RIF
resu
lt is
auto
mat
ed a
nd w
as c
onsid
ered
blin
ded
in a
ll stu
dies
.b
The
ratin
g of
the
qual
ity o
f the
evi
denc
e m
ay b
e lo
wer
ed if
ther
e ar
e im
porta
nt d
iffer
ence
s in
the
tests
stu
died
and
the
expe
rtise
of t
hose
app
lyin
g th
e te
sts in
the
studi
es c
ompa
red
with
the
setti
ngs
for w
hich
the
reco
mm
enda
tions
are
inte
nded
. The
maj
ority
of s
tudi
es (6
/7;
86%
) eva
luat
ed X
pert
MTB
/RI
F in
set
tings
whe
re it
was
inte
nded
to b
e us
ed. A
lthou
gh s
tudi
es o
f dia
gnos
tic a
ccur
acy
may
no
t pro
vide
dire
ct e
vide
nce
abou
t pat
ient
-impo
rtant
out
com
es, t
he q
ualit
y of
the
evid
ence
was
not
dow
ngra
ded.
c Th
ere
was
som
e va
riabi
lity
in s
ensit
ivity
esti
mat
es a
cros
s stu
dies
but
this
hete
roge
neity
cou
ld n
ot b
e ex
plai
ned
by s
tudy
qua
lity.
The
obs
erve
d se
nsiti
vity
may
hav
e va
ried
amon
g stu
dies
as
a re
sult
of c
hara
cter
istic
s as
soci
ated
with
the
parti
cipa
nts,
but
ther
e w
ere
insu
ffici
ent d
ata
to in
vesti
gate
this
poss
ibili
ty. T
he q
ualit
y of
evi
denc
e w
as d
owng
rade
d by
one
poi
nt.
d A
t a p
rete
st pr
obab
ility
of 1
0%, t
he c
onfid
ence
inte
rval
s fo
r tru
e po
sitiv
es a
nd fa
lse n
egat
ives
wer
e re
lativ
ely
narro
w.
e N
o fo
rmal
ass
essm
ent o
f pub
licat
ion
bias
was
con
duct
ed u
sing
met
hods
suc
h as
funn
el p
lots
or re
gres
sion
tests
bec
ause
suc
h te
chni
ques
hav
e no
t bee
n fo
und
to b
e he
lpfu
l in
studi
es o
f dia
gnos
tic
accu
racy
. How
ever
, rep
ortin
g bi
as w
as c
onsid
ered
to b
e m
inim
al s
ince
Xpe
rt M
TB/
RIF
is a
new
test
that
has
had
con
sider
able
atte
ntio
n an
d sc
rutin
y.
48 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATETa
ble
12. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
iagn
osin
g pu
lmon
ary
TB in
adu
lts w
ithou
t HIV
infe
ctio
n
PIC
O q
uesti
on: W
hat i
s th
e di
agno
stic
accu
racy
of X
pert
MTB
/RI
F fo
r det
ectio
n of
pul
mon
ary
TB in
adu
lts w
ithou
t HIV
infe
ctio
n?Pa
rtici
pant
s: A
dults
who
wer
e H
IV n
egat
ive
and
susp
ecte
d of
hav
ing
pulm
onar
y TB
Se
tting
: Mai
nly
inte
rmed
iate
-leve
l lab
orat
orie
s an
d pr
imar
y he
alth
-car
e fa
cilit
ies
Targ
et c
ondi
tion:
Pul
mon
ary
TB
Refe
renc
e sta
ndar
d: S
olid
cul
ture
or l
iqui
d cu
lture
Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
: 7 (1
470)
Pool
ed s
ensit
ivity
: 86%
(95%
CrI,
76–
92%
); po
oled
spe
cific
ity: 9
9% (9
5% C
rI, 9
8–10
0%)
Out
com
eSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
Lim
itatio
nsIn
dire
ctne
ss
Inco
nsis
tenc
yIm
prec
isio
nPu
blic
atio
n bi
asPr
eval
ence
25
/100
0Pr
eval
ence
50
/100
0Pr
eval
ence
10
0/10
00
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-se
ctio
nal
Non
eaN
oneb
Serio
us (–
1)c
Non
edU
ndet
ecte
deM
oder
ate
22
(19-
23)
43(3
8-46
)86
(76-
92)
False
neg
ativ
es
(indi
vidu
als
inco
rrect
ly
clas
sified
as
not h
avin
g TB
)
Cro
ss-
sect
iona
l N
onea
Non
ebSe
rious
(–1)
cN
oned
Und
etec
tede
Mod
erat
e
4(2
-6)
7(4
-12)
14(8
-24)
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cl
assifi
ed a
s ha
ving
TB
Cro
ss-
sect
iona
l N
onea
Non
ebN
one
Non
eU
ndet
ecte
deH
igh
10
(0-2
0)10
(0-1
9)9
(0-1
8)
True
neg
ativ
es
(indi
vidu
als
with
out T
B)C
ross
-se
ctio
nal
Non
eaN
oneb
Non
eN
one
Und
etec
tede
Hig
h
956
(956
-975
)94
1(9
31-9
50)
891
(882
-900
)
CrI,
cre
dibl
e in
terv
al.
a Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
All
studi
es e
nrol
led
indi
vidu
als
cons
ecut
ivel
y, a
nd a
sses
sed
the
resu
lt fro
m th
e re
fere
nce
stand
ard
blin
ded
to th
e re
sult
from
Xpe
rt M
TB/
RIF.
The
Xper
t MTB
/RI
F re
sult
is au
tom
ated
and
was
con
sider
ed b
linde
d in
all
studi
es.
b Th
e ra
ting
of th
e qu
ality
of t
he e
vide
nce
may
be
low
ered
if th
ere
are
impo
rtant
diff
eren
ces
in th
e te
sts s
tudi
ed a
nd th
e ex
perti
se o
f tho
se a
pply
ing
the
tests
in th
e stu
dies
com
pare
d w
ith th
e se
tting
s fo
r whi
ch th
e re
com
men
datio
ns a
re in
tend
ed. T
he m
ajor
ity o
f stu
dies
(6/
7; 8
6%) e
valu
ated
Xpe
rt M
TB/
RIF
in s
ettin
gs w
here
it w
as in
tend
ed to
be
used
. Alth
ough
stu
dies
of d
iagn
ostic
acc
urac
y m
ay
not p
rovi
de d
irect
evi
denc
e ab
out p
atie
nt-im
porta
nt o
utco
mes
, the
qua
lity
of th
e ev
iden
ce w
as n
ot d
owng
rade
d.c
Ther
e w
as s
ome
varia
bilit
y in
sen
sitiv
ity e
stim
ates
acr
oss
studi
es b
ut th
is he
tero
gene
ity c
ould
not
be
expl
aine
d by
stu
dy q
ualit
y. T
he o
bser
ved
sens
itivi
ty m
ay h
ave
varie
d am
ong
studi
es a
s a
resu
lt of
cha
ract
erist
ics
asso
ciat
ed w
ith th
e pa
rtici
pant
s, b
ut th
ere
wer
e in
suffi
cien
t dat
a to
inve
stiga
te th
is po
ssib
ility.
The
qua
lity
of th
e ev
iden
ce w
as d
owng
rade
d by
one
poi
nt.
d A
t a p
rete
st pr
obab
ility
of 1
0%, t
he c
onfid
ence
inte
rval
s fo
r tru
e po
sitiv
es a
nd fa
lse n
egat
ives
wer
e re
lativ
ely
narro
w.
e N
o fo
rmal
ass
essm
ent o
f pub
licat
ion
bias
was
con
duct
ed u
sing
met
hods
suc
h as
funn
el p
lots
or re
gres
sion
tests
bec
ause
suc
h te
chni
ques
hav
e no
t bee
n fo
und
to b
e he
lpfu
l in
studi
es o
f dia
gnos
tic
accu
racy
. How
ever
, rep
ortin
g bi
as w
as c
onsid
ered
to b
e m
inim
al s
ince
Xpe
rt M
TB/
RIF
is a
new
test
that
has
had
con
sider
able
atte
ntio
n an
d sc
rutin
y.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 49Ta
ble
13. G
RAD
E ev
iden
ce p
rofil
e: th
e in
crem
enta
l yie
ld o
f Xpe
rt M
TB/R
IF c
ompa
red
with
mic
rosc
opy
in p
atie
nts
with
cul
ture
-con
firm
ed T
B
PIC
O q
uesti
on: W
hat i
s th
e in
crem
enta
l yie
ld o
f Xpe
rt M
TB/
RIF
com
pare
d w
ith m
icro
scop
y in
pat
ient
s w
ith c
ultu
re-c
onfir
med
TB?
Parti
cipa
nts:
Adu
lts w
ith c
ultu
re-c
onfir
med
TB
Setti
ng: M
ainl
y in
term
edia
te-le
vel l
abor
ator
ies
and
prim
ary
heal
th-c
are
faci
litie
s Ta
rget
con
ditio
n: P
ulm
onar
y TB
Re
fere
nce
stand
ard:
Sol
id c
ultu
re o
r liq
uid
cultu
reN
umbe
r of s
tudi
es (n
umbe
r of p
artic
ipan
ts): 2
1 (8
880)
Pool
ed s
ensit
ivity
for s
mea
r mic
rosc
opy
: 65%
(95%
CrI,
57–
72%
); po
oled
sen
sitiv
ity fo
r Xpe
rt M
TB/
RIF:
88%
(95%
CrI,
84–
92%
)
Out
com
e
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed (9
5% C
rI)a
Qua
lity
of
ev
iden
ceb
Prev
alen
ce 2
5/10
00Pr
eval
ence
50/
1000
Prev
alen
ce 1
00/1
000
Prev
alen
ce 3
00/1
000
Smea
r
mic
rosc
opy
Xper
t M
TB/R
IFSm
ear
m
icro
scop
yXp
ert
MTB
/RIF
Smea
r
mic
rosc
opy
Xper
t M
TB/R
IFSm
ear
m
icro
scop
yXp
ert
MTB
/RIF
True
pos
itive
s (in
divi
dual
s w
ith T
B)16
(14–
18)
22(2
1–23
)33
(29–
36)
44(4
2–46
)65
(57–
72)
88(8
4–92
)19
5 (1
71–2
16)
264
(252
–276
)H
igh
True
pos
itive
s
(abs
olut
e di
ffere
nce)
6 m
ore
11 m
ore
23 m
ore
69 m
ore
False
neg
ativ
es
(indi
vidu
als
inco
rrect
ly
clas
sified
as
not h
avin
g TB
)
9(7
–11)
3(2
–4)
18(1
4–22
)6
(4–8
)35
(28–
43)
12(8
–16)
105
(84–
129)
36(2
4–48
)H
igh
False
neg
ativ
es
(abs
olut
e di
ffere
nce)
6 fe
wer
12
few
er
23 fe
wer
69 fe
wer
CrI,
cre
dibl
e in
terv
al.
a Th
e se
nsiti
vity
resu
lts w
ere
take
n fro
m b
ivar
iate
ana
lyse
s (in
clud
ing
both
sen
sitiv
ity a
nd s
peci
ficity
) to
obta
in th
e va
lues
for t
rue
posit
ives
and
false
neg
ativ
es.
b Th
e G
RAD
E fra
mew
ork
was
use
d to
ass
ess
the
qual
ity o
f the
evi
denc
e. F
or m
icro
scop
y, th
e se
nsiti
vity
esti
mat
es fo
r ind
ivid
ual s
tudi
es w
ere
varia
ble
(rang
e, 2
9–83
%),
and
the
pool
ed s
ensit
ivity
es
timat
e w
as im
prec
ise.
The
mai
n re
ason
for h
eter
ogen
eity
and
impr
ecisi
on in
the
sens
itivi
ty e
stim
ate
was
con
sider
ed to
be
the
varia
bilit
y in
sm
ear-p
ositi
ve s
tatu
s ac
ross
stu
dies
. Se
vera
l add
ition
al
fact
ors
may
hav
e co
ntrib
uted
to th
is he
tero
gene
ity, i
nclu
ding
type
of m
icro
scop
y, m
etho
d of
spe
cim
en p
roce
ssin
g an
d H
IV s
tatu
s. T
he q
ualit
y of
evi
denc
e w
as n
ot d
owng
rade
d.
50 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATETa
ble
14. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
iagn
osin
g pu
lmon
ary
TB in
adu
lts a
s an
add-
on te
st fo
llow
ing
nega
tive
sput
um-s
mea
r m
icro
scop
y
PIC
O q
uesti
on:
Wha
t is
the
diag
nosti
c ac
cura
cy o
f Xpe
rt M
TB/
RIF
for d
etec
tion
of p
ulm
onar
y TB
in a
dults
, w
here
Xpe
rt M
TB/
RIF
is us
ed a
s an
add
-on
test
follo
win
g a
nega
tive
smea
r-mic
rosc
opy
resu
lt?
Parti
cipa
nts:
Adu
lts w
ho a
re s
mea
r neg
ativ
e an
d su
spec
ted
of h
avin
g pu
lmon
ary
TB
Setti
ng: M
ainl
y in
term
edia
te-le
vel l
abor
ator
ies
and
prim
ary
heal
th-c
are
faci
litie
s Ta
rget
con
ditio
n: P
ulm
onar
y TB
Re
fere
nce
stand
ard:
Sol
id c
ultu
re o
r liq
uid
cultu
reN
umbe
r of s
tudi
es (n
umbe
r of p
artic
ipan
ts): 2
3 (7
151)
Pool
ed s
ensit
ivity
: 68%
(95%
CrI,
61–
74%
); po
oled
spe
cific
ity: 9
9% (9
5% C
rI, 9
8–99
%)
Out
com
eSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
smea
r-ne
gativ
e in
divi
dual
s te
sted
(95%
CrI)
Lim
itatio
nsIn
dire
ctne
ss
Inco
nsis
tenc
yIm
prec
isio
nPu
blic
atio
n bi
asPr
eval
ence
25
/100
0Pr
eval
ence
50
/100
0Pr
eval
ence
10
0/10
00
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-se
ctio
nal
Non
eaN
oneb
Serio
us (–
1)c
Non
edU
ndet
ecte
deM
oder
ate
17
(15-
19)
34(3
1-37
)68
(61-
74)
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cla
ssifi
ed a
s no
t ha
ving
TB)
Cro
ss-
sect
iona
l N
onea
Non
ebSe
rious
(–1)
cN
oned
Und
etec
tede
Mod
erat
e
8(7
-10)
16(1
3-20
)32
(26-
39)
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB
Cro
ss-
sect
iona
l N
onea
Non
ebN
one
Non
eU
ndet
ecte
deH
igh
10
(10-
20)
10(1
0-19
)9
(9-1
8)
True
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Cro
ss-
sect
iona
l N
onea
Non
ebN
one
Non
eU
ndet
ecte
deH
igh
96
5(9
56-9
65)
941
(931
-941
)89
1(8
82-8
91)
CrI,
cre
dibl
e in
terv
al.
a Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
The
maj
ority
of s
tudi
es e
nrol
led
indi
vidu
als
cons
ecut
ivel
y, a
nd a
sses
sed
the
resu
lt fro
m th
e re
fere
nce
stand
ard
blin
ded
to th
e re
sult
from
Xpe
rt M
TB/
RIF.
The
Xper
t MTB
/RI
F re
sult
is au
tom
ated
and
was
con
sider
ed b
linde
d in
all
studi
es.
b Th
e m
ajor
ity o
f stu
dies
(16/
23; 7
0%) e
valu
ated
Xpe
rt M
TB/
RIF
in s
ettin
gs w
here
it w
as in
tend
ed to
be
used
. Alth
ough
stu
dies
of d
iagn
ostic
acc
urac
y m
ay n
ot p
rovi
de d
irect
evi
denc
e ab
out p
atie
nt-
impo
rtant
out
com
es, t
he q
ualit
y of
the
evid
ence
was
not
dow
ngra
ded.
c Th
ere
was
som
e va
riabi
lity
in s
ensit
ivity
esti
mat
es a
cros
s stu
dies
but
this
hete
roge
neity
cou
ld n
ot b
e ex
plai
ned
by s
tudy
qua
lity
or b
y re
mov
ing
the
study
by
Law
n 20
11 fr
om th
e an
alys
is. T
he s
tudy
by
Law
n, w
hich
foun
d th
e lo
wes
t sen
sitiv
ity, e
valu
ated
the
use
of X
pert
MTB
/RI
F to
scr
een
HIV
-pos
itive
pat
ient
s w
ith a
dvan
ced
imm
unod
efici
ency
, reg
ardl
ess
of th
eir s
ympt
oms,
who
wer
e en
rollin
g in
an
tiret
rovi
ral t
hera
py. T
he o
bser
ved
sens
itivi
ty m
ay h
ave
varie
d am
ong
studi
es a
s a
resu
lt of
cha
ract
erist
ics
asso
ciat
ed w
ith th
e pa
rtici
pant
s, b
ut th
ere
wer
e in
suffi
cien
t dat
a to
inve
stiga
te th
is po
ssib
ility.
Th
e qu
ality
of t
he e
vide
nce
was
dow
ngra
ded
by o
ne p
oint
.d
At a
pre
test
prob
abili
ty o
f 10%
, the
con
fiden
ce in
terv
als
for t
rue
posit
ives
and
false
neg
ativ
es w
ere
rela
tivel
y na
rrow
.e
One
unp
ublis
hed
study
was
incl
uded
in th
e an
alys
is. N
o fo
rmal
ass
essm
ent o
f pub
licat
ion
bias
was
con
duct
ed u
sing
met
hods
suc
h as
funn
el p
lots
or re
gres
sion
tests
bec
ause
suc
h te
chni
ques
hav
e no
t be
en fo
und
to b
e he
lpfu
l in
studi
es o
f dia
gnos
tic a
ccur
acy.
How
ever
, rep
ortin
g bi
as w
as c
onsid
ered
to b
e m
inim
al s
ince
Xpe
rt M
TB/R
IF is
a ne
w te
st th
at h
as h
ad c
onsid
erab
le a
ttent
ion
and
scru
tiny.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 51
Table 15. Sensitivity of Xpert MTB/RIF in smear-negative culture-confirmed pulmonary TB in individuals, by HIV status
PICO question: What is the diagnostic accuracy of Xpert MTB/RIF for detection of pulmonary TB in adults, where Xpert MTB/RIF is used as an add-on test following a negative smear microscopy result, stratified by HIV status?Participants: Adults with smear-negative culture-confirmed pulmonary TBSetting: One intermediate-level laboratory and one primary health-care clinicReference standard: Phenotypic culture using solid media or liquid mediaNumber of studies (number of participants): 2 (91)
Study HIV-positive participants (n = 33)
HIV-negative participants (n = 58)
Sensitivity (%)(95% CI)
Sensitivity (%)(95% CI)
Theron 2011 48(27–69)
45(25–67)
Van Rie 2013 60(27–86)
67(13–98)
CI, confidence interval.
Table 16. GRADE evidence profile: additional yield of Xpert MTB/RIF over microscopy in smear-negative TB
PICO question: What is the additional yield of Xpert MTB/RIF over microscopy in smear-negative TB?Participants: Adults who are smear negative and culture positiveSetting: Mainly intermediate-level laboratories and primary health-care facilities Target condition: Pulmonary TB Reference standard: Solid culture or liquid cultureNumber of studies (number of participants): 23 (7151)Polled sensitivity for smear microscopy: 0%; pooled sensitivity for Xpert MTB/RIF : 68% (95% CrI, 61–74%)
Outcome
Number of results/1000 individuals tested (95% CrI)aQuality
of evidenceb
Prevalence 25/1000 Prevalence 50/1000 Prevalence 100/1000
Smear microscopy
Xpert MTB/RIF
Smear microscopy
Xpert MTB/RIF
Smear microscopy
Xpert MTB/RIF
True positives (individuals with TB)
0 17(15–19)
0 34(31–37)
0 68(61–74)
Moderate
True positives (absolute difference)
17 more 34 more 68 more
False negatives (individuals incorrectly classified as not having TB)
25 8(7–10)
50 16(13–20)
100 32(26–29)
Moderate
False negatives (absolute difference)
17 fewer 34 fewer 68 fewer
CrI, credible interval.a The sensitivity results were taken from the bivariate analyses (including both sensitivity and specificity) to obtain the values for true positives and false negatives. b The GRADE framework was used to assess the quality of the evidence. The quality of the evidence was downgraded one point for inconsistency/imprecision.
52 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATETa
ble
17.
GRA
DE
evid
ence
pro
file:
acc
urac
y of
Xpe
rt M
TB/R
IF in
det
ectin
g rif
ampi
cin
resi
stanc
e, w
here
Xpe
rt M
TB/R
IF r
epla
ces
phen
otyp
ic c
ultu
re-
base
d dr
ug-s
usce
ptib
ility
testi
ng a
s th
e in
itial
test
PIC
O q
uesti
on:
Wha
t is
the
diag
nosti
c ac
cura
cy o
f Xpe
rt M
TB/
RIF
for d
etec
tion
of ri
fam
pici
n re
sista
nce,
whe
re X
pert
MTB
/RI
F is
used
as
an in
itial
test
repl
acin
g ph
enot
ypic
cul
ture
-bas
ed d
rug-
susc
eptib
ility
testi
ng?
Parti
cipa
nts:
Adu
lts w
ith c
onfir
med
TB.
Set
ting:
Mai
nly
inte
rmed
iate
-leve
l lab
orat
orie
s an
d pr
imar
y he
alth
-car
e fa
cilit
ies.
Targ
et c
ondi
tion:
Rifa
mpi
cin
resis
tanc
e. R
efer
ence
sta
ndar
d: P
heno
typi
c cu
lture
-bas
ed d
rug-
susc
eptib
ility
testi
nga .
Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
poo
led
sens
itivi
ty: 1
7 (5
55).
Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
poo
led
spec
ifici
ty: 2
4 (2
414)
.Po
oled
sen
sitiv
ity: 9
5% (9
5% C
rI, 9
0–97
%);
Pool
ed s
peci
ficity
: 98%
(95%
CrI,
97–
99%
)b
Out
com
eSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
Lim
itatio
nsIn
dire
ctne
ss
Inco
nsis
tenc
yIm
prec
isio
nPu
blic
atio
n bi
asPr
eval
ence
50
/100
0cPr
eval
ence
10
0/10
00c
True
pos
itive
s (in
divi
dual
s w
ith T
B an
d rif
ampi
cin
resis
tanc
e)C
ross
-se
ctio
nal
Non
edN
onee
Non
efN
one
Und
etec
tedg
Hig
h
84(4
5-49
)14
3(1
35-1
46)
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cla
ssifi
ed
as h
avin
g TB
that
is ri
fam
pici
n su
scep
tible
)C
ross
-se
ctio
nal
Non
edN
onee
Non
efN
one
Und
etec
tedg
Hig
h
3(2
-5)
5(8
-15)
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed
as h
avin
g TB
with
rifa
mpi
cin
resis
tanc
e)C
ross
-se
ctio
nal
Non
edN
onee
Non
efN
one
Und
etec
tedg
Hig
h
19
(10-
29)
17
(9-2
6)Tr
ue n
egat
ives
(ind
ivid
uals
with
TB
that
is
rifam
pici
n su
scep
tible
)C
ross
-se
ctio
nal
Non
edN
onee
Non
efN
one
Und
etec
tedg
Hig
h
931
(922
-941
)83
3 (8
25-8
42)
CrI,
cre
dibl
e in
terv
al.
a Ph
enot
ypic
dru
g-su
scep
tibili
ty te
sting
is c
onsid
ered
an
impe
rfect
refe
renc
e sta
ndar
d bu
t its
use
shou
ld n
ot d
owng
rade
the
ratin
g of
the
qual
ity o
f evi
denc
e.
b Es
timat
es o
f sen
sitiv
ity a
nd s
peci
ficity
wer
e de
term
ined
sep
arat
ely
usin
g un
ivar
iate
ana
lyse
s.c
Prev
alen
ce e
stim
ates
wer
e pr
ovid
ed b
y th
e W
HO
Ste
erin
g G
roup
. Th
e up
per l
imit
for t
he p
reva
lenc
e of
rifa
mpi
cin
resis
tanc
e in
new
cas
es w
as e
stim
ated
to b
e 5%
(50/
1000
cas
es);
the
low
er
limit
for t
he p
reva
lenc
e of
rifa
mpi
cin
resis
tanc
e in
pre
viou
sly tr
eate
d ca
ses
was
esti
mat
ed to
be
15%
(150
/10
00 c
ases
).d
The
QU
AD
AS-
2 to
ol w
as u
sed
to a
sses
s th
e ris
k of
bia
s. T
he m
ajor
ity o
f stu
dies
enr
olle
d in
divi
dual
s co
nsec
utiv
ely,
and
ass
esse
d th
e re
sult
from
the
refe
renc
e sta
ndar
d bl
inde
d to
the
resu
lt fro
m X
pert
MTB
/RI
F. Th
e Xp
ert M
TB/
RIF
resu
lt is
auto
mat
ed a
nd w
as c
onsid
ered
blin
ded
in a
ll stu
dies
. e
The
ratin
g of
the
qual
ity o
f the
evi
denc
e m
ay b
e lo
wer
ed if
ther
e ar
e im
porta
nt d
iffer
ence
s in
the
tests
stu
died
and
the
expe
rtise
of t
hose
app
lyin
g th
e te
sts in
the
studi
es c
ompa
red
with
the
setti
ngs
for w
hich
the
reco
mm
enda
tions
are
inte
nded
. The
maj
ority
of s
tudi
es (1
2/17
, 71%
for s
ensit
ivity
; and
16/
24, 6
7% fo
r spe
cific
ity) e
valu
ated
Xpe
rt M
TB/
RIF
in s
ettin
gs w
here
it w
as in
tend
ed to
be
used
. Onl
y tw
o stu
dies
eva
luat
ed X
pert
MTB
/RI
F w
ith th
e G
4 ca
rtrid
ge. I
n 20
13, t
he G
4 ca
rtrid
ges
wer
e th
e on
ly ty
pe o
f car
tridg
e av
aila
ble.
It is
pos
sible
that
the
perfo
rman
ce o
f Xpe
rt M
TB/
RIF
usin
g th
e G
4 ca
rtrid
ge w
ill be
diff
eren
t. A
lthou
gh s
tudi
es o
f dia
gnos
tic a
ccur
acy
may
not
pro
vide
dire
ct e
vide
nce
abou
t pat
ient
-impo
rtant
out
com
es, t
he q
ualit
y of
the
evid
ence
was
not
dow
ngra
ded.
f Es
timat
es o
f se
nsiti
vity
and
spe
cific
ity w
ere
cons
isten
t. Se
vera
l stu
dies
hav
e su
gges
ted
that
det
erm
inin
g th
e sp
ecifi
city
of
a m
olec
ular
met
hod
of d
rug-
susc
eptib
ility
testi
ng,
such
as
Xper
t MTB
/RI
F, us
ing
phen
otyp
ic d
rug-
susc
eptib
ility
testi
ng a
lone
may
und
eres
timat
e th
e sp
ecifi
city
of t
he m
olec
ular
test.
Gen
e se
quen
cing
of d
iscor
dant
resu
lts o
btai
ned
usin
g Xp
ert M
TB/
RIF
and
phen
otyp
ic
drug
-susc
eptib
ility
testi
ng (d
iscre
pant
ana
lysis
) is
ofte
n re
solve
d in
favo
ur o
f Xpe
rt M
TB/
RIF,
sugg
estin
g th
at X
pert
MTB
/RI
F ha
s hi
gher
spe
cific
ity. H
owev
er, d
iscre
pant
ana
lyse
s m
ay in
trodu
ce b
ias.
g O
ne u
npub
lishe
d stu
dy w
as in
clud
ed in
the
anal
ysis.
No
form
al a
sses
smen
t of p
ublic
atio
n bi
as w
as c
ondu
cted
usin
g m
etho
ds s
uch
as fu
nnel
plo
ts or
regr
essio
n te
sts b
ecau
se s
uch
tech
niqu
es h
ave
not b
een
foun
d to
be
help
ful i
n stu
dies
of d
iagn
ostic
acc
urac
y. H
owev
er,
repo
rting
bia
s w
as c
onsid
ered
to b
e m
inim
al s
ince
Xpe
rt M
TB/
RIF
is a
new
test
that
has
had
con
sider
able
atte
ntio
n an
d sc
rutin
y.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 53Ta
ble
18. A
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
TB in
lym
ph n
ode
fluid
and
tiss
ue (A
. Evi
denc
e pr
ofile
, B. S
umm
ary
of fi
ndin
gs)
PIC
O q
uesti
on:
Wha
t is
the
diag
nosti
c ac
cura
cy o
f Xpe
rt M
TB/
RIF
for
TB d
etec
tion
in ly
mph
nod
e flu
id a
nd ti
ssue
, w
here
Xpe
rt M
TB/
RIF
is us
ed a
s a
repl
acem
ent t
est f
or u
sual
pra
ctic
e?
A. E
vide
nce
profi
le Out
com
eaSt
udy
desi
gnFa
ctor
s th
at m
ay d
ecre
ase
the
qual
ity o
f evi
denc
eQ
ualit
y of
ev
iden
ceLi
mita
tions
Indi
rect
ness
In
cons
iste
ncy
Impr
ecis
ion
Publ
icat
ion
bias
True
pos
itive
s (in
divi
dual
s w
ith T
B)M
ajor
ity
cros
s-sec
tiona
lSe
rious
(–1)
bN
onec
Serio
us (–
1)d
Serio
us (–
1)e
Und
etec
tedf
Very
low
False
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Maj
ority
cr
oss-s
ectio
nal
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Maj
ority
cr
oss-s
ectio
nal
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
False
neg
ativ
es (p
atie
nts
inco
rrect
ly c
lass
ified
as
not
hav
ing
TB)
Maj
ority
cr
oss-s
ectio
nal
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
a Fo
r eac
h ou
tcom
e, th
e ra
ting
of th
e qu
ality
of e
vide
nce
starte
d as
hig
h w
hen
the
study
des
igns
wer
e ra
ndom
ized
con
trolle
d tri
als
or h
igh-
qual
ity o
bser
vatio
nal s
tudi
es (s
uch
as c
ross
-sect
iona
l stu
dies
w
ith d
iagn
ostic
unc
erta
inty
and
dire
ct c
ompa
rison
of t
he re
sults
of t
he in
dex
test
with
a re
fere
nce
stand
ard)
, or l
ow w
hen
ther
e w
ere
case
–con
trol s
tudi
es. T
he e
vide
nce
was
dow
ngra
ded
one
poin
t w
hen
a se
rious
issu
e w
as id
entifi
ed;
it w
as d
owng
rade
d tw
o po
ints
whe
n a
very
ser
ious
issu
e w
as id
entifi
ed in
any
of t
he o
ther
five
fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce:
lim
itatio
ns,
indi
rect
ness
, inc
onsis
tenc
y, im
prec
ision
or p
ublic
atio
n bi
as.
b Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
The
maj
ority
of s
tudi
es e
nrol
led
patie
nts
cons
ecut
ivel
y, a
nd a
sses
sed
the
resu
lt fro
m th
e re
fere
nce
stand
ard
blin
ded
to th
e re
sult
from
Xpe
rt M
TB/
RIF.
The
Xper
t MTB
/RI
F re
sult
is au
tom
ated
and
was
con
sider
ed b
linde
d in
all
studi
es.
How
ever
, th
e va
riabl
e us
e of
the
com
posit
e re
fere
nce
stand
ard
acro
ss s
tudi
es w
as a
con
cern
for
its
poss
ibili
ty o
f int
rodu
cing
bia
s. T
he e
vide
nce
was
dow
ngra
ded
one
poin
t.c
The
maj
ority
of s
tudi
es u
sed
Xper
t MTB
/RI
F in
terti
ary
care
cen
tres
or re
fere
nce
labo
rato
ries.
Bec
ause
obt
aini
ng a
sam
ple
requ
ires
an in
vasiv
e pr
oced
ure,
the
test
will
likel
y be
per
form
ed a
t hig
her
leve
ls of
car
e th
an a
re fe
asib
le fo
r dia
gnos
ing
pulm
onar
y TB
. Thu
s, th
e stu
dy p
opul
atio
ns a
re p
roba
bly
repr
esen
tativ
e of
the
popu
latio
n th
at w
ill re
ceiv
e th
e te
st. T
he e
vide
nce
was
not
dow
ngra
ded.
d
Une
xpla
ined
het
erog
enei
ty in
the
findi
ngs
mig
ht o
rigin
ate
from
diff
eren
ces
in s
ampl
e pr
oces
sing,
the
cond
ition
of s
ampl
es, a
nd d
iffer
ence
s in
stu
dy p
opul
atio
ns (f
or e
xam
ple,
var
ying
pre
vale
nces
of
TB
or H
IV).
The
evid
ence
was
dow
ngra
ded
one
poin
t.e C
onfid
ence
inte
rval
s ar
e w
ide,
like
ly d
ue in
par
t to
unex
plai
ned
hete
roge
neity
as
desc
ribed
in fo
otno
te d
and
in p
art d
ue to
ver
ifica
tion
bias
bec
ause
of t
he u
se o
f an
impe
rfect
refe
renc
e sta
ndar
d.
The
evid
ence
was
dow
ngra
ded
one
poin
t.f U
npub
lishe
d stu
dies
wer
e in
clud
ed. D
ata
did
not a
llow
for f
orm
al a
sses
smen
t of p
ublic
atio
n bi
as u
sing
met
hods
suc
h as
funn
el p
lots
or re
gres
sion
tests
bec
ause
suc
h te
chni
ques
hav
e no
t bee
n fo
und
to b
e he
lpfu
l in
studi
es o
f dia
gnos
tic a
ccur
acy.
How
ever
, rep
ortin
g bi
as w
as c
onsid
ered
to b
e m
inim
al s
ince
Xpe
rt M
TB/
RIF
is a
new
test
that
has
had
con
sider
able
atte
ntio
n an
d sc
rutin
y.
54 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
B. Summary of findings
Reference standard: CultureNumber of studies (number of samples): 14 (849); 11 studies had more than 10 samplesPooled sensitivity: 85% (95% CI, 72–92); pooled specificity: 93% (95% CI, 80–97)Reference standard: Composite reference standardNumber of studies (number of samples): 5 (409)Pooled sensitivity: 84% (95% CI, 74–90%); pooled specificity: 99% (95% CI, 88–100%)
Outcome
Number of results/1000 individuals tested (95% CrI)Quality
of evidence
Prevalence 2.5% Prevalence 5% Prevalence 10%Culture CRS Culture CRS Culture CRS
True positives (individuals with TB)
21 (18–23)
21 (19–23)
43 (36–46)
42 (37–45)
85 (72–92)
84 (74–90)
Very low
True negatives (individuals without TB)
907 (780–946)
965(858–975)
884(760–922)
941 (836–950)
837(720–873)
891 (792–900)
Very low
False positives (individuals incorrectly classified as having TB)
68 (29–195)
10 (0–117)
67 (29–190)
10 (0–114)
63 (27–180)
9 (0–108)
Very low
False negatives (individuals incorrectly classified as not having TB)
4 (2–7)
3 (4–7)
8 (4–14)
8 (5–13)
15 (8–28)
16 (10–26)
Very low
CI, confidence interval; CRS, composite reference standard.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 55Ta
ble
19. A
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
TB in
ple
ural
flui
d (A
. Evi
denc
e pr
ofile
, B. S
umm
ary
of fi
ndin
gs)
PIC
O q
uesti
on:
Wha
t is
the
diag
nosti
c ac
cura
cy o
f Xpe
rt M
TB/
RIF
for T
B de
tect
ion
in p
leur
al fl
uid,
whe
re X
pert
MTB
/RI
F is
used
as
a re
plac
emen
t tes
t fo
r usu
al p
ract
ice?
A. E
vide
nce
profi
le Out
com
eaSt
udy
desi
gnFa
ctor
s th
at m
ay d
ecre
ase
the
qual
ity o
f evi
denc
eQ
ualit
y of
ev
iden
ceLi
mita
tions
Indi
rect
ness
In
cons
iste
ncy
Impr
ecis
ion
Publ
icat
ion
bias
True
pos
itive
s (in
divi
dual
s w
ith T
B)M
ajor
ity
cros
s-sec
tiona
lSe
rious
(–1)
bN
onec
Serio
us (–
1)d
Serio
us (–
1)e
Und
etec
tedf
Very
low
False
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Maj
ority
cr
oss-s
ectio
nal
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Maj
ority
cr
oss-s
ectio
nal
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
False
neg
ativ
es (p
atie
nts
inco
rrect
ly c
lass
ified
as
not
hav
ing
TB)
Maj
ority
cr
oss-s
ectio
nal
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
a Fo
r eac
h ou
tcom
e, th
e ra
ting
of th
e qu
ality
of e
vide
nce
starte
d as
hig
h w
hen
the
study
des
igns
wer
e ra
ndom
ized
con
trolle
d tri
als
or h
igh-
qual
ity o
bser
vatio
nal s
tudi
es (s
uch
as c
ross
-sect
iona
l stu
dies
w
ith d
iagn
ostic
unc
erta
inty
and
dire
ct c
ompa
rison
of t
he re
sults
of t
he in
dex
test
with
a re
fere
nce
stand
ard)
, or
low
whe
n th
ere
wer
e ca
se–c
ontro
l stu
dies
. The
evi
denc
e w
as d
owng
rade
d on
e po
int
whe
n a
serio
us is
sue
was
iden
tified
; it
was
dow
ngra
ded
two
poin
ts w
hen
a ve
ry s
erio
us is
sue
was
iden
tified
in a
ny o
f the
oth
er fi
ve fa
ctor
s th
at m
ay d
ecre
ase
the
qual
ity o
f evi
denc
e: li
mita
tions
, in
dire
ctne
ss, i
ncon
siste
ncy,
impr
ecisi
on o
r pub
licat
ion
bias
. b
The
QU
AD
AS-
2 to
ol w
as u
sed
to a
sses
s th
e ris
k of
bia
s. T
he m
ajor
ity o
f stu
dies
enr
olle
d pa
tient
s co
nsec
utiv
ely,
and
ass
esse
d th
e re
sult
from
the
refe
renc
e sta
ndar
d bl
inde
d to
the
resu
lt fro
m X
pert
MTB
/RI
F. Th
e Xp
ert M
TB/
RIF
resu
lt is
auto
mat
ed a
nd w
as c
onsid
ered
blin
ded
in a
ll stu
dies
. H
owev
er,
the
varia
ble
use
of th
e co
mpo
site
refe
renc
e sta
ndar
d ac
ross
stu
dies
was
a c
once
rn fo
r its
po
ssib
ility
of i
ntro
duci
ng b
ias.
The
evi
denc
e w
as d
owng
rade
d on
e po
int.
c Th
e m
ajor
ity o
f stu
dies
use
d Xp
ert M
TB/
RIF
in te
rtiar
y ca
re c
entre
s or
refe
renc
e la
bora
torie
s. B
ecau
se o
btai
ning
a s
ampl
e re
quire
s an
inva
sive
proc
edur
e, th
e te
st w
ill lik
ely
be p
erfo
rmed
at h
ighe
r le
vels
of c
are
than
are
feas
ible
for d
iagn
osin
g pu
lmon
ary
TB. T
hus,
the
study
pop
ulat
ions
are
pro
babl
y re
pres
enta
tive
of th
e po
pula
tion
that
will
rece
ive
the
test.
The
evi
denc
e w
as n
ot d
owng
rade
d.
d U
nexp
lain
ed h
eter
ogen
eity
in th
e fin
ding
s m
ight
orig
inat
e fro
m d
iffer
ence
s in
sam
ple
proc
essin
g, th
e co
nditi
on o
f the
sam
ple,
and
diff
eren
ces
in s
tudy
pop
ulat
ions
(for
exa
mpl
e, v
aryi
ng p
reva
lenc
es
of T
B or
HIV
). Th
e ev
iden
ce w
as d
owng
rade
d on
e po
int.
e C
onfid
ence
inte
rval
s ar
e w
ide,
like
ly d
ue in
par
t to
unex
plai
ned
hete
roge
neity
as
desc
ribed
in fo
otno
te d
and
in p
art d
ue to
ver
ifica
tion
bias
bec
ause
of t
he u
se o
f an
impe
rfect
refe
renc
e sta
ndar
d.
The
evid
ence
was
dow
ngra
ded
one
poin
t.f U
npub
lishe
d stu
dies
wer
e in
clud
ed. D
ata
did
not a
llow
for f
orm
al a
sses
smen
t of p
ublic
atio
n bi
as u
sing
met
hods
suc
h as
funn
el p
lots
or re
gres
sion
tests
bec
ause
suc
h te
chni
ques
hav
e no
t bee
n fo
und
to b
e he
lpfu
l in
studi
es o
f dia
gnos
tic a
ccur
acy.
How
ever
, rep
ortin
g bi
as w
as c
onsid
ered
to b
e m
inim
al s
ince
Xpe
rt M
TB/
RIF
is a
new
test
that
has
had
con
sider
able
atte
ntio
n an
d sc
rutin
y.
56 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
B. Summary of findings
Reference standard: CultureNumber of studies (number of samples): 17 (1384), 16 studies had more than 10 samples Pooled sensitivity: 44% (95% CI, 25–65%); pooled specificity: 98% (95% CI, 95–99%)Reference standard: Composite reference standardNumber of studies (number of samples): 7 (698)Pooled sensitivity: 17% (95% CI, 8–34%); pooled specificity: 100% (95% CI, 94–100%)
Outcome
Number of results/1000 individuals tested (95% CrI)Quality
of evidence
Prevalence 2.5% Prevalence 5% Prevalence 10%Culture CRS Culture CRS Culture CRS
True positives (individuals with TB)
11 (6–16)
4 (2–9)
22 (13–33)
9 (4–17)
44 (25–65)
17 (8–34)
Very low
True negatives (individuals without TB)
956(926–965)
975(917–975)
931(903–941)
950 (893–950)
882(855–891)
900 (846–900)
Low
False positives (individuals incorrectly classified as having TB)
20 (10–49)
0 (0–59)
19 (10–48)
0 (0–57)
18 (9–45)
0 (0–54)
Low
False negatives (individuals incorrectly classified as not having TB)
14 (9–19)
21 (17–23)
28 (18–38)
42 (33–46)
56 (35–75)
83 (66–92)
Very low
CI, confidence interval; CRS, composite reference standard.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 57Ta
ble
20. A
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
TB in
cer
ebro
spin
al fl
uid
(A. E
vide
nce
profi
le, B
. Sum
mar
y of
find
ings
)
PIC
O q
uesti
on: W
hat i
s th
e di
agno
stic
accu
racy
of X
pert
MTB
/RI
F fo
r TB
dete
ctio
n in
cer
ebro
spin
al fl
uid,
whe
re X
pert
MTB
/RI
F is
used
as
a re
plac
emen
t te
st fo
r usu
al p
ract
ice?
A. E
vide
nce
profi
le Out
com
eaSt
udy
desi
gnFa
ctor
s th
at m
ay d
ecre
ase
the
qual
ity o
f evi
denc
eQ
ualit
y of
ev
iden
ceLi
mita
tions
Indi
rect
ness
In
cons
iste
ncy
Impr
ecis
ion
Publ
icat
ion
bias
True
pos
itive
s (in
divi
dual
s w
ith T
B)M
ajor
ity
cros
s-sec
tiona
lSe
rious
(–1)
bN
onec
Serio
us (–
1)d
Serio
us (–
1)e
Und
etec
tedf
Very
low
False
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Maj
ority
cr
oss-s
ectio
nal
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfLo
w
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Maj
ority
cr
oss-s
ectio
nal
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfLo
w
False
neg
ativ
es (p
atie
nts
inco
rrect
ly c
lass
ified
as
not
hav
ing
TB)
Maj
ority
cr
oss-s
ectio
nal
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
a Fo
r eac
h ou
tcom
e, th
e ra
ting
of th
e qu
ality
of e
vide
nce
starte
d as
hig
h w
hen
the
study
des
igns
wer
e ra
ndom
ized
con
trolle
d tri
als
or h
igh-
qual
ity o
bser
vatio
nal s
tudi
es (s
uch
as c
ross
-sect
iona
l stu
dies
w
ith d
iagn
ostic
unc
erta
inty
and
dire
ct c
ompa
rison
of t
he re
sults
of t
he in
dex
test
with
a re
fere
nce
stand
ard)
, or l
ow w
hen
ther
e w
ere
case
–con
trol s
tudi
es. T
he e
vide
nce
was
dow
ngra
ded
one
poin
t w
hen
a se
rious
issu
e w
as id
entifi
ed;
it w
as d
owng
rade
d tw
o po
ints
whe
n a
very
ser
ious
issu
e w
as id
entifi
ed in
any
of t
he o
ther
five
fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce:
lim
itatio
ns,
indi
rect
ness
, inc
onsis
tenc
y, im
prec
ision
or p
ublic
atio
n bi
as.
b Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
The
maj
ority
of s
tudi
es e
nrol
led
patie
nts
cons
ecut
ivel
y, a
nd a
sses
sed
resu
lts fr
om th
e re
fere
nce
stand
ard
blin
ded
to th
e re
sult
from
Xpe
rt M
TB/
RIF.
The
Xper
t MTB
/RI
F re
sult
is au
tom
ated
and
was
con
sider
ed b
linde
d in
all
studi
es. H
owev
er, t
he v
aria
ble
use
of th
e co
mpo
site
refe
renc
e sta
ndar
d ac
ross
stu
dies
was
a c
once
rn fo
r its
poss
ibili
ty
of in
trodu
cing
bia
s. T
he e
vide
nce
was
dow
ngra
ded
one
poin
t.c
The
maj
ority
of s
tudi
es u
sed
Xper
t MTB
/RI
F in
terti
ary
care
cen
tres
or re
fere
nce
labo
rato
ries.
Bec
ause
obt
aini
ng a
sam
ple
requ
ires
an in
vasiv
e pr
oced
ure,
the
test
will
likel
y be
per
form
ed a
t hig
her
leve
ls of
car
e th
an a
re fe
asib
le fo
r dia
gnos
ing
pulm
onar
y TB
. Thu
s, th
e stu
dy p
opul
atio
ns a
re p
roba
bly
repr
esen
tativ
e of
the
popu
latio
n th
at w
ill re
ceiv
e th
e te
st. T
he e
vide
nce
was
not
dow
ngra
ded.
d
Une
xpla
ined
het
erog
enei
ty in
the
findi
ngs
mig
ht o
rigin
ate
from
diff
eren
ces
in s
ampl
e pr
oces
sing,
the
cond
ition
of t
he s
ampl
es, a
nd d
iffer
ence
s in
stu
dy p
opul
atio
ns (f
or e
xam
ple,
var
ying
pre
vale
nces
of
TB
or H
IV).
The
evid
ence
was
dow
ngra
ded
one
poin
t.e
Con
fiden
ce in
terv
als
are
wid
e, li
kely
due
in p
art t
o un
expl
aine
d he
tero
gene
ity a
s de
scrib
ed in
foot
note
d a
nd in
par
t due
to v
erifi
catio
n bi
as b
ecau
se o
f the
use
of a
n im
perfe
ct re
fere
nce
stand
ard.
Th
e ev
iden
ce w
as d
owng
rade
d on
e po
int.
f Unp
ublis
hed
studi
es w
ere
incl
uded
. Dat
a di
d no
t allo
w fo
r for
mal
ass
essm
ent o
f pub
licat
ion
bias
usin
g m
etho
ds s
uch
as fu
nnel
plo
ts or
regr
essio
n te
sts b
ecau
se s
uch
tech
niqu
es h
ave
not b
een
foun
d to
be
help
ful i
n stu
dies
of d
iagn
ostic
acc
urac
y. H
owev
er, r
epor
ting
bias
was
con
sider
ed to
be
min
imal
sin
ce X
pert
MTB
/RI
F is
a ne
w te
st th
at h
as h
ad c
onsid
erab
le a
ttent
ion
and
scru
tiny.
58 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
B. Summary of findings
Reference standard: CultureNumber of studies (number of samples): 16 (709); 13 studies had more than 10 samplesPooled sensitivity: 80% (95% CI, 62–90%); pooled specificity: 99% (95% CI, 96–100%)Reference standard: Composite reference standardNumber of studies (number of samples): 7 (698)Pooled sensitivity: 56% (95% CI, 44–66%); pooled specificity: 99% (95% CI, 95–100%)
Outcome
Number of results/1000 individuals tested (95% CrI)Quality
of evidence
Prevalence 2.5% Prevalence 5% Prevalence 10%Culture CRS Culture CRS Culture CRS
True positives (individuals with TB)
20 (16–23)
14 (11–17)
40 (31–45)
28 (22–33)
80 (62–90)
56 (44–66)
Very low
True negatives (individuals without TB)
965(936–975)
965(926–975)
941(912–950)
941 (903–950)
891(864–900)
891 (855–900)
Low
False positives (individuals incorrectly classified as having TB)
10 (0–39)
10 (0–49)
10 (0–38)
10 (0–48)
9 (0-36)
9 (0–45)
Low
False negatives (individuals incorrectly classified as not having TB)
5 (3-10)
9 (11-14)
10 (5-19)
22 (17-28)
20 (10-38)
56 (44-66)
Very low
CI, confidence interval; CRS, composite reference standard.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 59Ta
ble
21. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
TB in
gas
tric
fluid
PIC
O q
uesti
on:
Wha
t is
the
diag
nosti
c ac
cura
cy o
f Xpe
rt M
TB/
RIF
for T
B de
tect
ion
in g
astri
c flu
id,
whe
re X
pert
MTB
/RI
F is
used
as
a re
plac
emen
t tes
t fo
r usu
al p
ract
ice?
Refe
renc
e sta
ndar
d: C
ultu
reN
umbe
r of s
tudi
es (n
umbe
r of s
ampl
es):
12 (1
258
sam
ples
); 8
studi
es h
ad m
ore
than
10
sam
ples
Po
oled
sen
sitiv
ity: 8
4% (9
5% C
I, 66
– 93
%);
pool
ed s
peci
ficity
: 98%
(95%
CI,
92–1
00%
)
Out
com
eaSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
Lim
itatio
nsIn
dire
ctne
ss
Inco
nsis
tenc
yIm
prec
isio
nPu
blic
atio
n bi
asPr
eval
ence
2.
5%Pr
eval
ence
5%
Prev
alen
ce
10%
True
pos
itive
s (in
divi
dual
s w
ith T
B)M
ajor
ity
cros
s-se
ctio
nal
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
21(1
7-23
)42
(33-
47)
84(6
6-93
)
False
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Maj
ority
cr
oss-
sect
iona
l
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
956
(897
-975
)93
1(8
74-9
50)
882
(828
-900
)
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Maj
ority
cr
oss-
sect
iona
l
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
20(0
-78)
19(0
-76)
18(0
-72)
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cla
ssifi
ed a
s no
t ha
ving
TB)
Maj
ority
cr
oss-
sect
iona
l
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
4(2
-9)
8(4
-17)
16(7
-34)
a Fo
r eac
h ou
tcom
e, th
e ra
ting
of th
e qu
ality
of e
vide
nce
starte
d as
hig
h w
hen
the
study
des
igns
wer
e ra
ndom
ized
con
trolle
d tri
als
or h
igh-
qual
ity o
bser
vatio
nal s
tudi
es (s
uch
as c
ross
-sect
iona
l stu
dies
with
dia
gnos
tic u
ncer
tain
ty a
nd d
irect
com
paris
on o
f ind
ex te
st re
sults
with
a re
fere
nce
stand
ard)
, or l
ow w
hen
ther
e w
ere
case
–con
trol s
tudi
es. T
he
evid
ence
was
dow
ngra
ded
one
poin
t whe
n a
serio
us is
sue
was
iden
tified
; it
was
dow
ngra
ded
two
poin
ts w
hen
a ve
ry s
erio
us is
sue
was
iden
tified
in a
ny o
f the
oth
er fi
ve
fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce:
lim
itatio
ns, i
ndire
ctne
ss, i
ncon
siste
ncy,
impr
ecisi
on o
r pub
licat
ion
bias
.b
The
QU
AD
AS-
2 to
ol w
as u
sed
to a
sses
s th
e ris
k of
bia
s. T
he m
ajor
ity o
f stu
dies
enr
olle
d pa
tient
s co
nsec
utiv
ely,
and
ass
esse
d re
sults
from
the
refe
renc
e sta
ndar
d bl
inde
d to
the
resu
lts fr
om X
pert
MTB
/RI
F. Th
e Xp
ert M
TB/
RIF
resu
lt is
auto
mat
ed a
nd w
as c
onsid
ered
blin
ded
in a
ll stu
dies
. H
owev
er,
the
varia
ble
use
of th
e co
mpo
site
refe
renc
e sta
ndar
d ac
ross
stu
dies
was
a c
once
rn fo
r its
poss
ibili
ty o
f int
rodu
cing
bia
s. T
he e
vide
nce
was
dow
ngra
ded
one
poin
t.c
The
maj
ority
of s
tudi
es u
sed
Xper
t MTB
/RI
F in
terti
ary
care
cen
tres
or re
fere
nce
labo
rato
ries.
Bec
ause
obt
aini
ng a
sam
ple
requ
ires
an in
vasiv
e pr
oced
ure,
the
test
will
likel
y be
per
form
ed a
t hig
her l
evel
s of c
are
than
are
feas
ible
for d
iagn
osin
g pu
lmon
ary
TB. T
hus,
the
study
pop
ulat
ions
are
pro
babl
y re
pres
enta
tive
of th
e po
pula
tion
that
will
rece
ive
the
test.
The
evi
denc
e w
as n
ot d
owng
rade
d.
d U
nexp
lain
ed h
eter
ogen
eity
in th
e fin
ding
s m
ight
orig
inat
e fro
m d
iffer
ence
s in
sam
ple
proc
essin
g, th
e co
nditi
on o
f the
sam
ples
, an
d di
ffere
nces
in s
tudy
pop
ulat
ions
(for
ex
ampl
e, v
aryi
ng p
reva
lenc
es o
f TB
or H
IV).
The
evid
ence
was
dow
ngra
ded
one
poin
t.e C
onfid
ence
inte
rval
s ar
e w
ide,
like
ly d
ue in
par
t to
unex
plai
ned
hete
roge
neity
as
desc
ribed
in fo
otno
te d
and
in p
art d
ue to
ver
ifica
tion
bias
bec
ause
of t
he u
se o
f an
impe
rfect
refe
renc
e sta
ndar
d. T
he e
vide
nce
was
dow
ngra
ded
one
poin
t.f
Unp
ublis
hed
studi
es w
ere
incl
uded
. D
ata
did
not a
llow
for
for
mal
ass
essm
ent o
f pu
blic
atio
n bi
as u
sing
met
hods
suc
h as
fun
nel p
lots
or r
egre
ssio
n te
sts b
ecau
se s
uch
tech
niqu
es h
ave
not b
een
foun
d to
be
help
ful i
n stu
dies
of d
iagn
ostic
acc
urac
y. H
owev
er, r
epor
ting
bias
was
con
sider
ed to
be
min
imal
sin
ce X
pert
MTB
/RI
F is
a ne
w te
st th
at
has
had
cons
ider
able
atte
ntio
n an
d sc
rutin
y.
60 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATETa
ble
22. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
TB in
tiss
ue s
ampl
es
PIC
O q
uesti
on: W
hat i
s th
e di
agno
stic
accu
racy
of X
pert
MTB
/RI
F fo
r TB
dete
ctio
n in
tiss
ue s
ampl
es, w
here
Xpe
rt M
TB/
RIF
is us
ed a
s a
repl
acem
ent t
est
for u
sual
pra
ctic
e?Re
fere
nce
stand
ard:
Cul
ture
Num
ber o
f stu
dies
(num
ber o
f sam
ples
): 12
(699
); 10
stu
dies
had
mor
e th
an 1
0 sa
mpl
es
Pool
ed s
ensit
ivity
: 81%
(95%
CI,
68–
90%
); po
oled
spe
cific
ity: 9
8% (9
5% C
I, 87
–100
%)
Out
com
eaSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
Lim
itatio
nsIn
dire
ctne
ss
Inco
nsis
tenc
yIm
prec
isio
nPu
blic
atio
n bi
asPr
eval
ence
2.
5%Pr
eval
ence
5%
Prev
alen
ce
10%
True
pos
itive
s (in
divi
dual
s w
ith T
B)M
ajor
ity
cros
s-se
ctio
nal
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
20(1
7-23
)41
(34-
45)
81(6
8-90
)
False
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Maj
ority
cr
oss-
sect
iona
l
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
956
(848
-975
)93
1(8
27-9
50)
882
(783
-900
)
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Maj
ority
cr
oss-
sect
iona
l
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
20(0
-127
)19
(0-1
24)
18(0
-117
)
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cla
ssifi
ed a
s no
t ha
ving
TB)
Maj
ority
cr
oss-
sect
iona
l
Serio
us (–
1)b
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eU
ndet
ecte
dfVe
ry lo
w
5(3
-8)
10(5
-16)
19(1
0-32
)
CI,
confi
denc
e in
terv
al.
a Fo
r eac
h ou
tcom
e, th
e ra
ting
of th
e qu
ality
of e
vide
nce
starte
d as
hig
h w
hen
the
study
des
igns
wer
e ra
ndom
ized
con
trolle
d tri
als
or h
igh-
qual
ity o
bser
vatio
nal s
tudi
es (s
uch
as c
ross
-sect
iona
l stu
dies
w
ith d
iagn
ostic
unc
erta
inty
and
dire
ct c
ompa
rison
of i
ndex
test
resu
lts w
ith a
refe
renc
e sta
ndar
d),
or lo
w w
hen
ther
e w
ere
case
–con
trol s
tudi
es.
The
evid
ence
was
dow
ngra
ded
one
poin
t whe
n a
serio
us is
sue
was
iden
tified
; it w
as d
owng
rade
d tw
o po
ints
whe
n a
very
ser
ious
issu
e w
as id
entifi
ed in
any
of t
he o
ther
five
fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce:
lim
itatio
ns, i
ndire
ctne
ss,
inco
nsist
ency
, im
prec
ision
or p
ublic
atio
n bi
as.
b Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
The
maj
ority
of s
tudi
es e
nrol
led
patie
nts
cons
ecut
ivel
y, a
nd a
sses
sed
the
resu
lt fro
m th
e re
fere
nce
stand
ard
blin
ded
to th
e re
sult
from
Xpe
rt M
TB/
RIF.
The
Xper
t MTB
/RI
F re
sult
is au
tom
ated
and
was
con
sider
ed b
linde
d in
all
studi
es.
How
ever
, th
e va
riabl
e us
e of
the
com
posit
e re
fere
nce
stand
ard
acro
ss s
tudi
es w
as a
con
cern
for
its
poss
ibili
ty o
f int
rodu
cing
bia
s. T
he e
vide
nce
was
dow
ngra
ded
one
poin
t.c
The
maj
ority
of s
tudi
es u
sed
Xper
t MTB
/RI
F in
terti
ary
care
cen
tres
or re
fere
nce
labo
rato
ries.
Bec
ause
obt
aini
ng a
sam
ple
requ
ires
an in
vasiv
e pr
oced
ure,
the
test
will
likel
y be
per
form
ed a
t hig
her
leve
ls of
car
e th
an a
re fe
asib
le fo
r dia
gnos
ing
pulm
onar
y TB
. Thu
s, th
e stu
dy p
opul
atio
ns a
re p
roba
bly
repr
esen
tativ
e of
the
popu
latio
n th
at w
ill re
ceiv
e th
e te
st. T
he e
vide
nce
was
not
dow
ngra
ded.
d
Une
xpla
ined
het
erog
enei
ty in
the
findi
ngs
mig
ht o
rigin
ate
from
diff
eren
ces
in s
ampl
e pr
oces
sing,
the
cond
ition
of t
he s
ampl
es, a
nd d
iffer
ence
s in
stu
dy p
opul
atio
ns (f
or e
xam
ple,
var
ying
pre
vale
nces
of
TB
or H
IV).
The
evid
ence
was
dow
ngra
ded
one
poin
t.e
Con
fiden
ce in
terv
als
are
wid
e, li
kely
due
in p
art t
o un
expl
aine
d he
tero
gene
ity a
s de
scrib
ed in
foot
note
d a
nd in
par
t due
to v
erifi
catio
n bi
as b
ecau
se o
f the
use
of a
n im
perfe
ct re
fere
nce
stand
ard.
Th
e ev
iden
ce w
as d
owng
rade
d on
e po
int.
f Unp
ublis
hed
studi
es w
ere
incl
uded
. Dat
a di
d no
t allo
w fo
r for
mal
ass
essm
ent o
f pub
licat
ion
bias
usin
g m
etho
ds s
uch
as fu
nnel
plo
ts or
regr
essio
n te
sts b
ecau
se s
uch
tech
niqu
es h
ave
not b
een
foun
d to
be
help
ful i
n stu
dies
of d
iagn
ostic
acc
urac
y. H
owev
er, r
epor
ting
bias
was
con
sider
ed to
be
min
imal
sin
ce X
pert
MTB
/RI
F is
a ne
w te
st th
at h
as h
ad c
onsid
erab
le a
ttent
ion
and
scru
tiny.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 61Ta
ble
23. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
rifam
pici
n re
sista
nce
in n
onre
spira
tory
spe
cim
ens
PIC
O q
uesti
on: W
hat i
s th
e di
agno
stic
accu
racy
of X
pert
MTB
/RI
F fo
r rifa
mpi
cin-
resis
tanc
e de
tect
ion
in n
onre
spira
tory
spe
cim
ens,
whe
re X
pert
MTB
/RI
F is
used
as
an in
itial
test
repl
acin
g ph
enot
ypic
cul
ture
-bas
ed d
rug-
susc
eptib
ility
testi
ng?
Num
ber o
f stu
dies
(num
ber o
f sam
ples
): 13
(566
)
Out
com
eabSt
udy
desi
gnFa
ctor
s th
at m
ay d
ecre
ase
the
qual
ity o
f evi
denc
eQ
ualit
y of
ev
iden
ceLi
mita
tions
Indi
rect
ness
In
cons
iste
ncy
Impr
ecis
ion
Publ
icat
ion
bias
True
pos
itive
s (in
divi
dual
s w
ith T
B)M
ajor
ity
cros
s-sec
tiona
lN
onec
Serio
us (–
1)d
Serio
us (–
1)e
Serio
us (–
1)f
Und
etec
tedg
Very
low
False
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Maj
ority
cr
oss-s
ectio
nal
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eSe
rious
(–1)
fU
ndet
ecte
dgLo
w
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Maj
ority
cr
oss-s
ectio
nal
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eSe
rious
(–1)
fU
ndet
ecte
dgLo
w
False
neg
ativ
es (p
atie
nts
inco
rrect
ly c
lass
ified
as
not
hav
ing
TB)
Maj
ority
cr
oss-s
ectio
nal
Non
ecSe
rious
(–1)
dSe
rious
(–1)
eSe
rious
(–1)
fU
ndet
ecte
dgVe
ry lo
w
a G
iven
the
limite
d am
ount
of d
ata,
we
did
not c
alcu
late
sum
mar
y es
timat
es. S
ix s
tudi
es re
porte
d a
sens
itivi
ty o
f 100
% (3
4 rif
ampi
cin-
resis
tant
cas
es);
1 stu
dy h
ad 5
0% s
ensit
ivity
(2 ri
fam
pici
n-re
sista
nt
case
s); 1
stu
dy h
ad 0
% s
ensit
ivity
(1 ri
fam
pici
n-re
sista
nt c
ase)
.b
For e
ach
outc
ome,
the
ratin
g of
the
qual
ity o
f evi
denc
e sta
rted
as h
igh
whe
n th
e stu
dy d
esig
ns w
ere
rand
omiz
ed c
ontro
lled
trial
s or
hig
h-qu
ality
obs
erva
tiona
l stu
dies
(suc
h as
cro
ss-se
ctio
nal s
tudi
es
with
dia
gnos
tic u
ncer
tain
ty a
nd d
irect
com
paris
on o
f ind
ex te
st re
sults
with
a re
fere
nce
stand
ard)
, or
low
whe
n th
ere
wer
e ca
se–c
ontro
l stu
dies
. Th
e ev
iden
ce w
as d
owng
rade
d on
e po
int w
hen
a se
rious
issu
e w
as id
entifi
ed; i
t was
dow
ngra
ded
two
poin
ts w
hen
a ve
ry s
erio
us is
sue
was
iden
tified
in a
ny o
f the
oth
er fi
ve fa
ctor
s th
at m
ay d
ecre
ase
the
qual
ity o
f evi
denc
e: li
mita
tions
, ind
irect
ness
, in
cons
isten
cy, i
mpr
ecisi
on o
r pub
licat
ion
bias
. c
The
QU
AD
AS-
2 to
ol w
as u
sed
to a
sses
s th
e ris
k of
bia
s. T
he m
ajor
ity o
f stu
dies
enr
olle
d pa
tient
s co
nsec
utiv
ely,
and
ass
esse
d th
e re
sult
from
the
refe
renc
e sta
ndar
d bl
inde
d to
the
resu
lt fro
m X
pert
MTB
/RI
F. Th
e Xp
ert M
TB/
RIF
resu
lt is
auto
mat
ed a
nd w
as c
onsid
ered
blin
ded
in a
ll stu
dies
. The
refe
renc
e sta
ndar
d of
phe
noty
pic
drug
-susc
eptib
ility
testi
ng w
as u
sed
in a
ll stu
dies
. The
evi
denc
e w
as
not d
owng
rade
d. H
owev
er,
ther
e ar
e co
ncer
ns th
at p
heno
typi
c dr
ug-su
scep
tibili
ty te
sting
is n
ot a
per
fect
refe
renc
e sta
ndar
d fo
r det
ectin
g rif
ampi
cin
resis
tanc
e sin
ce s
eque
ncin
g da
ta h
ave
show
n th
at X
pert
MTB
/RI
F m
ight
cor
rect
ly id
entif
y re
sista
nce
that
is n
ot id
entifi
ed b
y ph
enot
ypic
dru
g-su
scep
tibili
ty te
sting
. Acr
oss
all s
tudi
es in
clud
ed h
ere,
six
false
-pos
itive
resu
lts fr
om X
pert
MTB
/RI
F te
sting
w
ere
iden
tified
. Of t
hose
, five
wer
e te
sted
with
seq
uenc
ing,
and
four
out
of fi
ve w
ere
foun
d to
hav
e a
mut
atio
n in
cod
on 5
33.
d Th
e m
ajor
ity o
f stu
dies
use
d Xp
ert M
TB/
RIF
in te
rtiar
y ca
re c
entre
s or
refe
renc
e la
bora
torie
s. B
ecau
se o
btai
ning
a s
ampl
e re
quire
s an
inva
sive
proc
edur
e, th
e te
st w
ill lik
ely
be p
erfo
rmed
at h
ighe
r le
vels
of c
are
than
are
feas
ible
for d
iagn
osin
g pu
lmon
ary
TB. T
hus,
the
study
pop
ulat
ions
are
pro
babl
y re
pres
enta
tive
of th
e po
pula
tion
that
will
rece
ive
the
test.
The
evi
denc
e w
as n
ot d
owng
rade
d.
e U
nexp
lain
ed h
eter
ogen
eity
in th
e fin
ding
s m
ight
orig
inat
e fro
m d
iffer
ence
s in
the
type
s of
spe
cim
en te
sted
and
in s
ampl
e pr
oces
sing.
The
evi
denc
e w
as d
owng
rade
d on
e po
int.
6 Th
ere
wer
e in
suffi
cien
t dat
a to
obt
ain
a su
mm
ary
estim
ate
for r
ifam
pici
n re
sista
nce.
The
resu
lts fr
om in
divi
dual
stu
dies
var
ied
wid
ely;
ther
efor
e, th
e ev
iden
ce w
as d
owng
rade
d on
e po
int.
f Unp
ublis
hed
studi
es w
ere
not i
nclu
ded
in th
e as
sess
men
t of u
sing
Xper
t MTB
/RI
F to
det
ect r
ifam
pici
n re
sista
nce
beca
use
data
col
lect
ion
on d
rug-
susc
eptib
ility
testi
ng w
as n
ot c
ompl
ete
for s
ome
of
the
studi
es. H
owev
er, r
epor
ting
bias
was
con
sider
ed to
be
min
imal
sin
ce X
pert
MTB
/RI
F is
a ne
w te
st th
at h
as h
ad c
onsid
erab
le a
ttent
ion
and
scru
tiny.
62 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATETa
ble
24. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
TB in
chi
ldre
n co
mpa
red
with
cul
ture
as a
refe
renc
e sta
ndar
d (A
. Exp
ecto
rate
d sp
utum
and
indu
ced
sput
um, B
. Gas
tric
lava
ge o
r as
pira
te, C
. Sum
mar
y of
find
ings
)
PIC
O q
uesti
on:
Wha
t is
the
diag
nosti
c ac
cura
cy o
f Xpe
rt M
TB/
RIF
for t
he d
etec
tion
of T
B in
chi
ldre
n ag
ains
t cul
ture
, w
here
Xpe
rt M
TB/
RIF
is us
ed a
s a
repl
acem
ent t
est f
or u
sual
pra
ctic
e?
A. E
xpec
tora
ted
sput
um a
nd in
duce
d sp
utum
Parti
cipa
nts:
Chi
ldre
n ag
ed 0
–15
year
s su
spec
ted
of h
avin
g TB
. Set
ting:
Mai
nly
terti
ary
care
refe
rral h
ospi
tals
and
univ
ersit
y ho
spita
lsTa
rget
con
ditio
n: P
ulm
onar
y TB
. Ref
eren
ce te
st: S
olid
cul
ture
or l
iqui
d cu
lture
. Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
: 10
(154
6)a .
Pool
ed s
ensit
ivity
: 66%
(95%
CrI,
52–
77%
); po
oled
spe
cific
ity: 9
8% (9
5% C
rI, 9
6–99
%)
Out
com
eSt
udy
desi
gnFa
ctor
s th
at m
ay d
ecre
ase
the
qual
ity o
f evi
denc
eQ
ualit
y of
ev
iden
ceLi
mita
tions
Indi
rect
ness
In
cons
iste
ncy
Impr
ecis
ion
Publ
icat
ion
bias
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-sect
iona
l N
oneb
Serio
us (–
1)c
Serio
us (–
1)d
Non
eeU
ndet
ecte
dfLo
w
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cla
ssifi
ed
as n
ot h
avin
g TB
)C
ross
-sect
iona
l N
oneb
Serio
us (–
1)c
Serio
us (–
1)d
Non
eeU
ndet
ecte
dfLo
w
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Cro
ss-se
ctio
nal
Non
ebSe
rious
(–1)
cSe
rious
(–1)
dN
onee
Und
etec
tedf
Mod
erat
e
True
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Cro
ss-se
ctio
nal
Non
ebSe
rious
(–1)
cSe
rious
(–1)
dN
onee
Und
etec
tedf
Mod
erat
e
Tim
e to
dia
gnos
isgO
nly
desc
riptiv
e da
ta a
vaila
ble
Not
rate
d
CrI,
cre
dibl
e in
terv
al.
a Ra
chow
201
2 re
porte
d te
sting
one
coh
ort u
sing
expe
ctor
ated
spu
tum
and
one
usin
g in
duce
d sp
utum
; thi
s w
as c
ount
ed a
s tw
o stu
dies
.b
The
QU
AD
AS-
2 to
ol w
as u
sed
to a
sses
s the
risk
of b
ias.
The
maj
ority
of s
tudi
es e
nrol
led
patie
nts c
onse
cutiv
ely.
Res
ults
from
Xpe
rt M
TB/
RIF
are
auto
mat
ed a
nd w
ere
cons
ider
ed b
linde
d in
all
studi
es. T
he e
xclu
sion
of e
nrol
led
patie
nts
from
ana
lyse
s w
ere
wel
l exp
lain
ed in
mos
t stu
dies
; how
ever
, in
one
study
(LaC
ours
e, u
npub
lishe
d) 9
9/30
0 ch
ildre
n w
ere
excl
uded
bec
ause
they
wer
e lo
st to
follo
w u
p. A
noth
er s
tudy
(Bat
es 2
013)
enr
olle
d a
num
ber o
f chi
ldre
n w
ho
had
alre
ady
initi
ated
ant
i-TB
treat
men
t (77
/10
37 w
ith sa
mpl
es o
f exp
ecto
rate
d or
indu
ced
sput
um, o
r gas
tric
lava
ge o
r asp
irate
): 6
6 of
thes
e ch
ildre
n w
ere
cultu
re n
egat
ive
and
wer
e ex
clud
ed fr
om th
e an
alys
is; 1
1 w
ere
cultu
re p
ositi
ve
and
wer
e in
clud
ed. A
dditi
onal
ly, th
e fo
llow
ing
cons
ider
atio
ns w
ere
not t
aken
into
acc
ount
in ju
dgem
ents
abou
t the
lim
itatio
ns o
f the
stud
ies b
ut th
ey a
re im
porta
nt: c
ultu
re is
an
impe
rfect
refe
renc
e sta
ndar
d. In
chi
ldre
n, c
ultu
re se
nsiti
vity
va
ries f
rom
20%
to 7
0%, d
epen
ding
on
fact
ors s
uch
as th
e ch
ild’s
smea
r sta
tus,
seve
rity
of d
iseas
e, th
e ch
ild’s
age,
the
cultu
re m
etho
d us
ed, a
nd sp
ecim
en ty
pe. I
n or
der t
o im
prov
e th
e di
agno
stic
yiel
d, 9
/10
stud
ies p
erfo
rmed
at l
east
two
cultu
res f
or e
ach
child
, but
som
e pe
rform
ed a
s man
y as
six
cultu
res p
er c
hild
. The
sens
itivi
ty o
f Xpe
rt M
TB/
RIF
may
be
unde
resti
mat
ed w
hen
it is
com
pare
d ag
ains
t cul
ture
as a
refe
renc
e sta
ndar
d. T
he e
vide
nce
was
not
dow
ngra
ded.
c T
he ra
ting
of th
e qua
lity o
f evi
denc
e may
be l
ower
ed if t
here
are
impo
rtant
diff
eren
ces i
n the
pop
ulat
ions
stud
ied
and
the t
ests
studi
ed, a
nd in
the e
xper
tise o
f thos
e usin
g th
e tes
ts in
stud
ies c
ompa
red
with
the s
ettin
gs fo
r whi
ch th
e rec
omm
enda
tions
are
in
tend
ed. A
ll stu
dies
wer
e pe
rform
ed a
t hig
her le
vels
of ca
re –
that
is, h
ighe
r-lev
el re
ferra
l hos
pita
ls an
d un
iver
sity h
ospi
tals.
Six
of th
e 10
stud
ies (
60%
) incl
uded
onl
y inp
atie
nts;
4/
10 st
udie
s inc
lude
d in
patie
nts a
nd o
utpa
tient
s. In
the
paed
iatri
c po
pula
tion,
inpa
tient
s may
pre
sent
with
mor
e se
vere
dise
ase
and
have
a h
ighe
r lik
elih
ood
of b
eing
smea
r pos
itive
; the
y ar
e on
e gr
oup
that
mig
ht b
enefi
t fro
m X
pert
MTB
/RI
F. O
utpa
tient
s may
pre
sent
diff
eren
tly, w
ith le
ss se
vere
dise
ase
and
so b
e le
ss lik
ely t
o be
smea
r pos
itive
or c
ultu
re p
ositi
ve. O
utpa
tient
s are
not
repr
esen
ted
by th
e stu
dies
incl
uded
in th
is re
view
. Onl
y one
stud
y (Ra
chow
201
2) in
clud
ed a
bro
ader
gro
up o
f chi
ldre
n: a
ppro
xim
atel
y 20%
of c
hild
ren
susp
ecte
d of
ha
ving
TB
had
been
iden
tified
thro
ugh
cont
act tr
acin
g. Tw
o un
publ
ished
stud
ies (
Chi
sti a
nd La
Cou
rse)
incl
uded
chi
ldre
n w
ho w
ere
seve
rely
mal
nour
ished
, and
TB
was
one
diff
eren
tial d
iagn
osis.
(Chi
ldre
n in
the
Chi
sti st
udy
addi
tiona
lly h
ad
to h
ave
coug
h la
sting
long
er th
an 2
wee
ks o
r pne
umon
ia o
n X-
ray,
or b
oth.
) The
re w
ere
serio
us c
once
rns a
bout
indi
rect
ness
in th
e m
ajor
ity o
f stu
dies
per
form
ed in
hig
her-l
evel
refe
rral h
ospi
tals.
The
evi
denc
e w
as d
owng
rade
d by
one
poi
nt.
d The
poin
t esti
mat
es fo
r sen
sitiv
ity ra
nged
from
25%
to 1
00%
, ind
icat
ing
a hi
gh le
vel o
f het
erog
enei
ty. H
owev
er, t
he 9
5% c
onfid
ence
inte
rval
s ov
erla
pped
. Sub
grou
p an
alys
es s
ugge
sted
that
ther
e w
as a
n ef
fect
of s
mea
r sta
tus
on
over
all s
ensit
ivity
, w
ith a
poo
led
estim
ate
for s
ensit
ivity
am
ong
smea
r-pos
itive
chi
ldre
n of
96%
(95%
CrI,
90–
99%
) and
for s
mea
r-neg
ativ
e ch
ildre
n of
55%
(95%
CrI,
41–
69%
). Th
ere
was
no
rele
vant
het
erog
enei
ty a
mon
g sm
ear-
posit
ive
child
ren
(poo
led
estim
ates
of s
ensit
ivity
rang
e, 9
2–10
0%),
but t
here
was
con
sider
able
het
erog
enei
ty a
mon
g sm
ear-n
egat
ive
child
ren
(rang
e, 2
5–10
0%).
Subg
roup
ana
lyse
s by
age
gro
up (f
or th
ose
aged
0–4
yea
rs th
e po
oled
sen
sitiv
ity e
stim
ate
was
57%
with
95%
CrI,
36–
74%
; fo
r chi
ldre
n ag
ed 5
–15
year
s th
e po
oled
sen
sitiv
ity e
stim
ate
was
83%
with
95%
CrI,
68–
92%
) and
HIV
sta
tus
(for H
IV-p
ositi
ve c
hild
ren
the
pool
ed s
ensit
ivity
esti
mat
e w
as 7
5% w
ith 9
5% C
rI, 5
7–88
%;
for H
IV-n
egat
ive
child
ren
the
pool
ed s
ensit
ivity
esti
mat
e w
as 5
7% w
ith 9
5% C
rI, 4
1–71
%) i
ndic
ated
that
ther
e w
ere
diffe
renc
es a
mon
g th
ese
grou
ps,
but t
hese
esti
mat
es a
re h
eter
ogen
eous
and
se
em to
be
affe
cted
by
smea
r sta
tus.
Ove
rall,
het
erog
enei
ty c
anno
t be
fully
exp
lain
ed b
y th
e su
bgro
up a
naly
ses;
ther
efor
e, in
cons
isten
cy is
rate
d as
a s
erio
us c
once
rn fo
r the
sen
sitiv
ity e
stim
ates
. The
evi
denc
e w
as d
owng
rade
d by
on
e po
int.
Estim
ates
of s
peci
ficity
did
not
sho
w s
erio
us h
eter
ogen
eity
: poi
nt e
stim
ates
rang
ed fr
om 9
3% to
100
%. T
here
was
no
conc
ern
abou
t spe
cific
ity.
e Five
of t
he 1
0 stu
dies
incl
uded
mor
e th
an 1
00 c
hild
ren,
and
the
yiel
d of
cul
ture
am
ong
all s
tudi
es v
arie
d fro
m 2
% to
52%
. The
con
fiden
ce in
terv
al fo
r sen
sitiv
ity w
as w
ide
(cro
ssin
g +/
– 10
%),
whi
ch is
of c
once
rn. T
he e
vide
nce
was
not
dow
ngra
ded
furth
er g
iven
the
dow
ngra
ding
for i
ncon
siste
ncy.
The
re w
as n
o co
ncer
n ab
out s
peci
ficity
.f T
hree
unpu
blish
ed st
udie
s wer
e inc
lude
d. A
few
othe
r stu
dies
wer
e in p
rogr
ess,
but d
ata w
ere n
ot av
aila
ble f
or an
alys
is. Th
e dat
a tha
t wer
e inc
lude
d in t
he re
view
did n
ot al
low
for fo
rmal
asse
ssm
ent o
f pub
licat
ion b
ias u
sing m
etho
ds su
ch as
funn
el pl
ots
or re
gres
sion t
ests;
such
tech
niqu
es ha
ve no
t bee
n fou
nd to
be he
lpfu
l in st
udie
s eva
luat
ing d
iagn
ostic
accu
racy
. How
ever
, rep
ortin
g bia
s was
cons
ider
ed to
be m
inim
al si
nce X
pert M
TB/
RIF i
s a ne
w te
st th
at ha
s had
cons
ider
able
atte
ntio
n and
scru
tiny.
g Th
e time
to d
iagn
osis
was
mai
nly
repo
rted
for t
he tu
rnar
ound
tim
e in
the
labo
rato
ry ra
ther
than
from
the
day
of s
peci
men
col
lect
ion:
it ra
nged
from
6 d
ays
to 7
wee
ks fo
r cul
ture
(7 s
tudi
es) a
nd fr
om 2
hou
rs to
2.5
hou
rs fo
r Xpe
rt M
TB/
RIF.
Thre
e stu
dies
des
crib
ed th
e tim
e fro
m e
nrol
men
t or s
peci
men
col
lect
ion
to d
iagn
osis
usin
g Xp
ert M
TB/
RIF
(1 d
ay) a
nd c
ultu
re (2
1 da
ys u
sing
the
BAC
TEC
MG
IT 9
60, a
nd 3
0 da
ys u
sing
Löw
enste
in–J
ense
n m
ediu
m).
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 63B.
Gas
tric
lava
ge o
r as
pira
te
Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
: 7 (1
319)
Pool
ed s
ensit
ivity
: 66%
(95%
CrI,
51–
81%
); po
oled
spe
cific
ity: 9
8% (9
5% C
rI, 9
6–99
%)
Out
com
eSt
udy
desi
gnFa
ctor
s th
at m
ay d
ecre
ase
the
qual
ity o
f evi
denc
eQ
ualit
y of
ev
iden
ceLi
mita
tions
Indi
rect
ness
In
cons
iste
ncy
Impr
ecis
ion
Publ
icat
ion
bias
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-sect
iona
l N
onea
Serio
us (–
1)b
Serio
us (–
1)c
Non
e (se
rious
)dU
ndet
ecte
deLo
w
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cla
ssifi
ed
as n
ot h
avin
g TB
)C
ross
-sect
iona
l N
onea
Serio
us (–
1)b
Serio
us (–
1)c
Non
e (se
rious
)dU
ndet
ecte
deLo
w
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Cro
ss-se
ctio
nal
Non
eaSe
rious
(–1)
bSe
rious
(–1)
cN
oned
Und
etec
tede
Mod
erat
e
True
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Cro
ss-se
ctio
nal
Non
eaSe
rious
(–1)
bSe
rious
(–1)
cN
oned
Und
etec
tede
Mod
erat
e
CrI,
cre
dibl
e in
terv
al.
a Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
Thr
ee o
f se
ven
studi
es e
nrol
led
indi
vidu
als
cons
ecut
ivel
y. R
esul
ts fro
m X
pert
MTB
/RI
F ar
e au
tom
ated
and
wer
e co
nsid
ered
blin
ded
in a
ll stu
dies
. Th
e ex
clus
ion
of e
nrol
led
patie
nts
from
ana
lyse
s w
ere
wel
l exp
lain
ed i
n m
ost
studi
es;
how
ever
in
one
study
(Ba
tes
2013
) a
num
ber
of c
hild
ren
who
had
alre
ady
initi
ated
ant
i-TB
tre
atm
ent
wer
e en
rolle
d (7
7/10
37,
for
spec
imen
s fro
m e
xpec
tora
ted
or i
nduc
ed s
putu
m a
nd o
f ga
stric
lav
age
and
aspi
rate
).
A t
otal
of
66 o
f th
ese
child
ren
wer
e cu
lture
neg
ativ
e an
d w
ere
excl
uded
; 11
wer
e cu
lture
pos
itive
and
wer
e in
clud
ed i
n th
e an
alys
is. A
dditi
onal
ly, t
he f
ollo
win
g co
nsid
erat
ions
wer
e no
t ta
ken
into
acc
ount
in
judg
emen
ts ab
out
the
limita
tions
of
the
studi
es b
ut t
hey
are
impo
rtant
: cu
lture
is
an i
mpe
rfect
ref
eren
ce s
tand
ard.
In
child
ren,
cul
ture
sen
sitiv
ity v
arie
s fro
m 2
0% t
o 70
%,
depe
ndin
g on
fac
tors
suc
h as
the
sev
erity
of
dise
ase,
the
ag
e of
the
chi
ld,
the
cultu
re m
etho
ds u
sed,
and
spe
cim
en t
ypes
. In
ord
er t
o im
prov
e th
e di
agno
stic
yiel
d, 9
/10
stu
dies
per
form
ed a
t le
ast
two
cultu
res
for
each
chi
ld,
but
som
e pe
rform
ed
as m
any
as s
ix c
ultu
res
per
child
. Th
e se
nsiti
vity
of
Xper
t MTB
/RI
F m
ay b
e un
dere
stim
ated
whe
n it
is co
mpa
red
agai
nst c
ultu
re a
s a
refe
renc
e sta
ndar
d. T
he e
vide
nce
was
not
dow
ngra
ded.
b
The
ratin
g of
the
qual
ity o
f evi
denc
e m
ay b
e lo
wer
ed if
ther
e ar
e im
porta
nt d
iffer
ence
s in
the
popu
latio
ns st
udie
d an
d th
e te
sts st
udie
d, a
nd in
the
expe
rtise
of t
hose
usin
g th
e te
sts in
the
studi
es c
ompa
red
with
the
setti
ngs f
or w
hich
the
reco
mm
enda
tions
are
inte
nded
. All
studi
es w
ere
perfo
rmed
at h
ighe
r lev
els o
f car
e –
that
is, h
ighe
r-lev
el re
ferra
l hos
pita
ls an
d un
iver
sity
hosp
itals.
Fou
r of t
he se
ven
studi
es
incl
uded
onl
y in
patie
nts;
one
incl
uded
inpa
tient
s and
out
patie
nts;
two
wer
e la
bora
tory
stud
ies t
hat d
id n
ot p
rovi
de in
form
atio
n on
the
patie
nt c
ohor
t. In
the
paed
iatri
c po
pula
tion,
inpa
tient
s may
pre
sent
w
ith m
ore
seve
re d
iseas
e an
d ha
ve a
hig
her l
ikel
ihoo
d of
bei
ng sm
ear p
ositi
ve; t
hey
are
one
grou
p th
at m
ight
ben
efit f
rom
Xpe
rt M
TB/
RIF.
Out
patie
nts m
ay p
rese
nt d
iffer
ently
, with
less
seve
re d
iseas
e an
d so
be
less
like
ly to
be
smea
r pos
itive
or c
ultu
re p
ositi
ve. O
utpa
tient
s are
not
repr
esen
ted
by th
e stu
dies
incl
uded
in th
is re
view
. One
unp
ublis
hed
study
(Chi
sti) i
nclu
ded
seve
rely
mal
nour
ished
chi
ldre
n w
ho
had
coug
h la
sting
long
er th
an 2
wee
ks o
r pne
umon
ia o
n X-
ray,
or b
oth;
TB
was
one
diff
eren
tial d
iagn
osis.
The
re w
ere
serio
us c
once
rns a
bout
indi
rect
ness
. The
evi
denc
e w
as d
owng
rade
d by
one
poi
nt.
c The
poin
t esti
mat
es fo
r sen
sitiv
ity ra
nged
from
40%
to 1
00%
, ind
icat
ing
a hi
gh le
vel o
f het
erog
enei
ty. H
owev
er, t
he 9
5% c
onfid
ence
inte
rval
s ov
erla
pped
. Sub
grou
p an
alys
es s
ugge
sted
that
ther
e w
as a
n ef
fect
of s
mea
r sta
tus
on o
vera
ll se
nsiti
vity,
with
a p
oole
d es
timat
e fo
r sen
sitiv
ity a
mon
g sm
ear-p
ositi
ve c
hild
ren
of 9
5% (9
5% C
rI, 8
3–99
%) a
nd fo
r sm
ear-n
egat
ive
child
ren
of 6
2% (9
%%
CrI,
44
– 80
%).
Ther
e w
as n
o re
leva
nt h
eter
ogen
eity
am
ong
smea
r–po
sitiv
e ch
ildre
n (p
oole
d es
timat
es o
f sen
sitiv
ity ra
nge,
92–
100%
), bu
t the
re w
as c
onsid
erab
le h
eter
ogen
eity
am
ong
smea
r-neg
ativ
e ch
ildre
n (ra
nge,
36–
100%
). A
naly
ses
of s
ubgr
oups
by
age
was
pos
sible
onl
y fo
r chi
ldre
n ag
ed 0
–4 y
ears
(poo
led
estim
ate
of s
ensit
ivity
was
57%
with
95%
CrI,
38–
75%
). Th
ree
studi
es in
clud
ed
only
chi
ldre
n ag
ed 0
–5 y
ears
; the
num
ber o
f gas
tric
lava
ge a
nd a
spira
tions
per
form
ed in
chi
ldre
n ag
ed 5
–15
in th
e re
mai
ning
stu
dies
was
sm
all.
Subg
roup
ana
lysis
for H
IV s
tatu
s w
as n
ot p
ossib
le
for s
peci
men
s fro
m g
astri
c la
vage
or a
spira
tion.
Ove
rall,
het
erog
enei
ty c
ould
not
be
fully
exp
lain
ed b
y th
e su
bgro
up a
naly
ses;
ther
efor
e, in
cons
isten
cy w
as ra
ted
as a
ser
ious
con
cern
for t
he s
ensit
ivity
es
timat
es. T
he e
vide
nce
was
dow
ngra
ded
by o
ne p
oint
. Esti
mat
es o
f spe
cific
ity d
id n
ot sh
ow se
rious
het
erog
enei
ty: p
oint
esti
mat
es ra
nged
from
93%
to 1
00%
. The
re w
as n
o co
ncer
n ab
out s
peci
ficity
. d
Thre
e of
7
studi
es
incl
uded
m
ore
than
10
0 ch
ildre
n,
and
the
yiel
d of
cu
lture
am
ong
all
studi
es
varie
d fro
m
2.8%
to
32
.7%
. Th
e co
nfide
nce
inte
rval
fo
r se
nsiti
vity
w
as
wid
e (c
ross
ing
+/–
10%
), w
hich
is
of
conc
ern.
Th
e ev
iden
ce
was
no
t do
wng
rade
d fu
rther
gi
ven
the
dow
ngra
ding
fo
r in
cons
isten
cy.
Ther
e w
as
no
conc
ern
abou
t sp
ecifi
city.
e Tw
o un
publ
ished
stu
dies
wer
e in
clud
ed. A
few
oth
er s
tudi
es w
ere
in p
rogr
ess,
but
dat
a w
ere
not a
vaila
ble
for a
naly
sis. T
he d
ata
that
wer
e in
clud
ed d
id n
ot a
llow
for f
orm
al a
sses
smen
t of p
ublic
atio
n bi
as u
sing
met
hods
suc
h as
funn
el p
lots
or re
gres
sion
tests
; suc
h te
chni
ques
hav
e no
t bee
n fo
und
to b
e he
lpfu
l in
studi
es e
valu
atin
g di
agno
stic
accu
racy
. How
ever
, rep
ortin
g bi
as w
as c
onsid
ered
to
be m
inim
al s
ince
Xpe
rt M
TB/
RIF
is a
new
test
that
has
had
con
sider
able
atte
ntio
n an
d sc
rutin
y.
64 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATEC.
Sum
mar
y of
find
ings
Out
com
e
Xper
t MTB
/RIF
usi
ng s
peci
men
s of
exp
ecto
rate
or
indu
ced
sput
umXp
ert M
TB/R
IF u
sing
spe
cim
ens
of g
astr
ic la
vage
or
asp
irate
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
aQ
ualit
y
of
evid
ence
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
aQ
ualit
y
of
evid
ence
Prev
alen
ce
10/1
000b
Prev
alen
ce
50/1
000b
Prev
alen
ce
100/
1000
bPr
eval
ence
10
/100
0bPr
eval
ence
50
/100
0bPr
eval
ence
10
0/10
00b
True
pos
itive
s (in
divi
dual
s w
ith T
B)7
(5-8
)33
(26-
39)
66(5
2-77
)Lo
w
7(5
-8)
33(2
6-41
)66
(51-
81)
Low
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cl
assifi
ed a
s no
t hav
ing
TB)
3(2
-5)
17(1
2-24
)34
(23-
48)
Low
3
(2-5
)17
(10-
25)
34(1
9-49
)Lo
w
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cl
assifi
ed a
s ha
ving
TB)
20(1
0-40
)19
(10-
38)
18(9
-36)
Very
low
20
(10-
40)
19(1
0-38
)18
(9-3
6)M
oder
ate
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cl
assifi
ed a
s no
t hav
ing
TB)
970
(950
-980
)93
1(9
12-9
41)
882
(864
-891
)Ve
ry lo
w
970
(950
-980
)93
1(9
12-9
41)
882
(864
-891
)M
oder
ate
CrI,
cre
dibl
e in
terv
al.
a The
expe
cted
num
ber o
f Xpe
rt M
TB/
RIF
resu
lts w
as b
ased
on
the
sens
itivi
ty a
nd s
peci
ficity
esti
mat
es c
alcu
late
d fro
m a
com
paris
on w
ith c
ultu
re fo
r diff
eren
t pre
vale
nces
of T
B.
b The
estim
ates
of T
B pr
eval
ence
wer
e pr
ovid
ed b
y th
e W
HO
Ste
erin
g G
roup
.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 65Ta
ble
25. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
TB in
chi
ldre
n co
mpa
red
with
a c
linic
al re
fere
nce
stand
ard
(A. E
xpec
tora
ted
sput
um a
nd in
duce
d sp
utum
, and
gas
tric
lava
ge a
nd a
spira
te, B
. Sum
mar
y of
find
ings
)PI
CO
que
stion
: Wha
t is
the
diag
nosti
c ac
cura
cy o
f Xpe
rt M
TB/
RIF
for d
etec
tion
of T
B in
chi
ldre
n co
mpa
red
with
a c
linic
al re
fere
nce
stand
ard,
whe
re X
pert
MTB
/RI
F is
used
as
a re
plac
emen
t tes
t for
usu
al p
ract
ice?
A. E
xpec
tora
ted
and
indu
ced
sput
um, a
nd g
astr
ic la
vage
and
asp
irate
Parti
cipa
nts:
Cul
ture
neg
ativ
e ch
ildre
n ag
ed 0
-15
year
s su
spec
ted
of h
avin
g TB
. Set
ting:
Mai
nly
terti
ary
care
refe
rral h
ospi
tals,
uni
vers
ity h
ospi
tals.
Targ
et c
ondi
tion:
Pul
mon
ary
TB. R
efer
ence
test:
Clin
ical
TB.
Exp
ecto
rate
d sp
utum
and
indu
ced
sput
um c
ombi
ned.
Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
: 8 (9
95)a .
Pool
ed s
ensit
ivity
: 4%
(95%
CrI,
1–1
2%);
pool
ed s
peci
ficity
100
% (9
5% C
rI, 9
9–10
0%).
Gas
tric
lava
ge a
nd a
spira
te.
Num
ber
of s
tudi
es (n
umbe
r of
par
ticip
ants)
: 3
(269
). Po
oled
sen
sitiv
ity:
15%
(95%
CrI,
5–3
1%);
pool
ed s
peci
ficity
: 99
%
(95%
CrI,
96–
100%
)
Out
com
eSt
udy
desi
gnFa
ctor
s th
at m
ay d
ecre
ase
the
qual
ity o
f evi
denc
eQ
ualit
y of
ev
iden
ceLi
mita
tions
Indi
rect
ness
In
cons
iste
ncy
Impr
ecis
ion
Publ
icat
ion
bias
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-sect
iona
l Se
rious
(–1)
bSe
rious
(–1)
cSe
rious
(–1)
dN
onee
Und
etec
tedf
Very
low
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cla
ssifi
ed
as n
ot h
avin
g TB
)C
ross
-sect
iona
l Se
rious
(–1)
bSe
rious
(–1)
cSe
rious
(–1)
dN
onee
Und
etec
tedf
Very
low
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Cro
ss-se
ctio
nal
Serio
us (–
1)b
Serio
us (–
1)c
Serio
us (–
1)d
Non
eeU
ndet
ecte
dfLo
w
True
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Cro
ss-se
ctio
nal
Serio
us (–
1)b
Serio
us (–
1)c
Serio
us (–
1)d
Non
eeU
ndet
ecte
dfLo
w
CrI,
cre
dibl
e in
terv
al.
a Ra
chow
201
2 re
porte
d te
sting
one
coh
ort u
sing
expe
ctor
ated
spu
tum
and
one
usin
g in
duce
d sp
utum
; thi
s w
as c
ount
ed a
s tw
o stu
dies
.b
The
QU
ADAS
-2 to
ol w
as u
sed
to a
sses
s the
risk
of b
ias.
Six
of s
even
stud
ies i
nclud
ed in
the
met
a-an
alys
is en
rolle
d in
divid
uals
cons
ecut
ively
(seve
n stu
dies
use
d sp
ecim
ens o
f exp
ecto
rate
d or
indu
ced
sput
um; t
hree
use
d sp
ecim
ens f
rom
gas
tric
lava
ge o
r asp
iratio
n). R
esult
s fro
m X
pert
MTB
/RIF
are
auto
mat
ed a
nd w
ere
cons
ider
ed b
linde
d in
all s
tudi
es. C
linic
al T
B is
an im
perfe
ct re
fere
nce
stand
ard.
In th
is re
view
it w
as d
efine
d on
the
basis
of w
heth
er c
ultur
e-ne
gativ
e ch
ildre
n su
spec
ted
of h
avin
g TB
wer
e in
itiate
d on
ant
i-TB
treat
men
t. Da
ta a
re la
ckin
g on
how
wel
l thi
s cli
nica
l ref
eren
ce s
tand
ard
iden
tifies
true
cas
es, b
oth
in te
rms
of o
verd
iagn
osis
and
unde
rdia
gnos
is. T
he ri
sk o
f bia
s fo
r the
refe
renc
e sta
ndar
d w
as ra
ted
as
uncle
ar fo
r all
studi
es. T
here
wer
e ve
ry s
erio
us c
once
rns
abou
t the
lim
itatio
ns o
f the
stu
dies
. The
evid
ence
was
dow
ngra
ded
by o
ne p
oint
.c
The
ratin
g of
the
qual
ity o
f evid
ence
may
be
low
ered
if th
ere
are
impo
rtant
diff
eren
ces
in th
e te
sts s
tudi
ed a
nd th
e ex
perti
se o
f tho
se u
sing
the
tests
in th
e stu
dies
com
pare
d w
ith th
e se
ttings
for w
hich
the
reco
mm
enda
tions
are
inte
nded
. All
studi
es w
ere
perfo
rmed
at h
ighe
r lev
els
of c
are
– th
at is
, hig
her-le
vel r
efer
ral h
ospi
tals
and
unive
rsity
hosp
itals.
Five
of t
he s
even
stu
dies
(71%
) stu
dies
inclu
ded
only
inpa
tient
s; tw
o stu
dies
inclu
ded
inpa
tient
s an
d ou
tpat
ient
s. In
the
paed
iatri
c po
pula
tion,
inpa
tient
s m
ay p
rese
nt w
ith m
ore
seve
re d
iseas
e an
d ha
ve a
hig
her
likel
ihoo
d of
bei
ng s
mea
r po
sitive
. In
one
stu
dy (R
acho
w 2
012)
, ap
prox
imat
ely
20%
of c
hild
ren
susp
ecte
d of
hav
ing
TB w
ere
iden
tified
thro
ugh
cont
act
traci
ng;
this
study
is m
ost r
epre
sent
ative
of t
he p
aedi
atric
pop
ulatio
n th
at m
ight
ben
efit f
rom
Xpe
rt M
TB/R
IF Tw
o un
publ
ished
stu
dies
(Chi
sti a
nd L
aCou
rse) i
nclud
ed c
hild
ren
who
wer
e se
vere
ly m
alno
urish
ed,
and
TB w
as o
ne d
iffer
entia
l di
agno
sis.
Addi
tiona
lly,
child
ren
in th
e C
histi
stu
dy h
ad to
hav
e ha
d co
ugh
lasti
ng lo
nger
than
2 w
eeks
or
pneu
mon
ia o
n X-
ray,
or
both
. Th
ere
wer
e se
rious
con
cern
s ab
out i
ndire
ctne
ss.
The
evid
ence
was
dow
ngra
ded
by o
ne p
oint
. d
The
poin
t es
timat
es
for
sens
itivity
ra
nged
fro
m
0%
to
35%
fo
r te
sting
sp
ecim
ens
of
expe
ctor
ated
or
in
duce
d sp
utum
; fo
r te
sting
sp
ecim
ens
from
ga
stric
la
vage
or
as
pira
tion,
th
e po
int
estim
ates
ra
nged
fro
m
0%
to
20%
; th
ese
resu
lts
indi
cate
m
oder
ate
hete
roge
neity
. H
owev
er,
the
95%
co
nfide
nce
inte
rval
s ov
erla
pped
. N
o su
bgro
up
anal
ysis
was
pe
rform
ed
for
Xper
t M
TB/R
IF co
mpa
red
agai
nst
a cli
nica
l re
fere
nce
stand
ard.
H
eter
ogen
eity
may
pa
rtly
be
the
resu
lt of
di
ffere
nces
in
pa
tient
po
pula
tions
(fo
r ex
ampl
e,
caus
ed
by
the
use
of
diffe
rent
in
clusio
n cr
iteria
). In
cons
isten
cy
was
ra
ted
as
a se
rious
co
ncer
n fo
r th
e es
timat
es
of
sens
itivity
.
The
evid
ence
w
as
dow
ngra
ded
by
one
poin
t. Th
e es
timat
es
of
spec
ifici
ty di
d no
t sh
ow
hete
roge
neity
: po
int
estim
ates
ra
nged
fro
m
99%
to
10
0%.
Ther
e w
as
no
conc
ern
abou
t sp
ecifi
city.
e
The
maj
ority
of
coho
rts i
nclud
ed i
n th
e re
view
had
a s
ampl
e siz
e gr
eate
r th
an 6
0 (5
/8 s
tudi
es u
sing
expe
ctor
ated
or
indu
ced
sput
um,
and
2/3
usin
g ga
stric
lava
ge o
r as
pira
te )
; th
e yi
eld
of c
ultur
e am
ong
all c
ohor
ts va
ried
from
2.4
% t
o 54
.2%
. Th
e co
nfide
nce
inte
rval
for
sen
sitivi
ty fo
r ex
pect
orat
ed o
r in
duce
d sp
utum
was
with
in t
he +
/-10
% m
argi
n; h
owev
er,
for
gastr
ic la
vage
and
asp
irate
it
was
wid
e. T
here
wer
e no
con
cern
s fo
r ex
pect
orat
ed o
r in
duce
d sp
utum
; th
ere
wer
e se
rious
con
cern
s ab
out
gastr
ic l
avag
e an
d as
pira
te.
The
evid
ence
was
not
dow
ngra
ded
furth
er g
iven
the
dow
ngra
ding
for
inc
onsis
tenc
y. T
here
was
no
conc
ern
abou
t th
e ev
iden
ce f
or s
peci
ficity
. f T
wo
unpu
blish
ed s
tudi
es w
ere
inclu
ded.
A fe
w o
ther
stu
dies
wer
e in
pro
gres
s bu
t dat
a w
ere
not a
vaila
ble
for a
nalys
is. T
he d
ata
that
wer
e in
clude
d do
not
allo
w fo
r for
mal
ass
essm
ent o
f pub
licat
ion
bias
usin
g m
etho
ds s
uch
as fu
nnel
plo
ts or
regr
essio
n te
sts; s
uch
tech
niqu
es h
ave
not b
een
foun
d to
be
help
ful i
n stu
dies
eva
luatin
g di
agno
stic
accu
racy
. How
ever
, rep
ortin
g bi
as w
as c
onsid
ered
to b
e m
inim
al s
ince
Xpe
rt M
TB/R
IF is
a ne
w te
st th
at h
as h
ad c
onsid
erab
le a
ttent
ion
and
scru
tiny.
66 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATEB.
Sum
mar
y of
find
ings
Out
com
e
Xper
t MTB
/RIF
usi
ng s
peci
men
s of
exp
ecto
rate
or
indu
ced
sput
umXp
ert M
TB/R
IF u
sing
spe
cim
ens
of g
astr
ic la
vage
or
asp
irate
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
aQ
ualit
y
of
evid
ence
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
aQ
ualit
y
of
evid
ence
Prev
alen
ce
10/1
000b
Prev
alen
ce
50/1
000b
Prev
alen
ce
100/
1000
bPr
eval
ence
10
/100
0bPr
eval
ence
50
/100
0bPr
eval
ence
10
0/10
00b
True
pos
itive
s (in
divi
dual
s w
ith T
B)0
(0-1
)2
(1-6
)4
(1-1
2)Lo
w
4(1
-8)
8(3
-16)
15(5
-31)
Very
low
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cl
assifi
ed a
s no
t hav
ing
TB)
10(9
-10)
48(4
4-50
)96
(88-
99)
Low
21
(17-
24)
43(3
5-48
)85
(69-
95)
Very
low
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cl
assifi
ed a
s ha
ving
TB)
0(1
-10)
0(0
-10)
0(1
-9)
Mod
erat
e
10(0
-39)
10(0
-38)
9(0
-9)
Mod
erat
e
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cl
assifi
ed a
s no
t hav
ing
TB)
0(0
-1)
2(1
-6)
4(1
-12)
Mod
erat
e
965
(936
-975
)94
1(9
12-9
50)
891
(864
-900
)M
oder
ate
CrI,
cre
dibl
e in
terv
al.
a The
expe
cted
num
ber o
f Xpe
rt M
TB/
RIF
resu
lts w
as b
ased
on
the
sens
itivi
ty a
nd s
peci
ficity
esti
mat
es c
alcu
late
d fro
m a
com
paris
on w
ith c
ultu
re fo
r diff
eren
t pre
vale
nces
of T
B.
b The
estim
ates
of T
B pr
eval
ence
wer
e pr
ovid
ed b
y th
e W
HO
Ste
erin
g G
roup
.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 67Ta
ble
26. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
TB in
chi
ldre
n fo
llow
ing
nega
tive
smea
r mic
rosc
opy
(A. E
vide
nce
profi
le, B
. Su
mm
ary
of fi
ndin
gs, C
. Add
ition
al y
ield
of X
pert
MTB
/RIF
ove
r m
icro
scop
y)
PIC
O q
uesti
on: W
hat i
s th
e di
agno
stic
accu
racy
of X
pert
MTB
/RI
F fo
r det
ectio
n of
TB
in c
hild
ren,
whe
re X
pert
MTB
/RI
F is
used
as
an a
dd-o
n te
st fo
llow
ing
a ne
gativ
e sm
ear-m
icro
scop
y re
sult?
A. E
vide
nce
profi
lePa
rtici
pant
s: S
mea
r neg
ativ
e ch
ildre
n ag
ed 0
-15
year
s su
spec
ted
of h
avin
g TB
. Set
ting:
Mai
nly
terti
ary
care
refe
rral h
ospi
tals
and
univ
ersit
y ho
spita
ls.Ta
rget
con
ditio
n: P
ulm
onar
y TB
. Ref
eren
ce te
st: S
olid
cul
ture
or l
iqui
d cu
lture
. Exp
ecto
rate
d sp
utum
and
indu
ced
sput
um c
ombi
ned.
Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
: 7 (1
008)
. Poo
led
sens
itivi
ty 4
4% (9
5% C
rI, 4
1–69
%);
pool
ed s
peci
ficity
: 98%
(95%
CrI,
96–
99%
).G
astri
c la
vage
or a
spira
te.
Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
: 6
(120
4).
Pool
ed s
ensit
ivity
: 62
% (9
5% C
rI, 4
4–80
%);
pool
ed s
peci
ficity
: 99
%
(95%
CrI,
97–
99%
)
Out
com
eSt
udy
desi
gnFa
ctor
s th
at m
ay d
ecre
ase
the
qual
ity o
f evi
denc
eQ
ualit
y of
ev
iden
ceLi
mita
tions
Indi
rect
ness
In
cons
iste
ncy
Impr
ecis
ion
Publ
icat
ion
bias
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-sect
iona
l N
onea
Serio
us (–
1)b
Serio
us (–
1)c
Expe
ctor
ated
or i
nduc
ed
sput
um: n
oned
Gas
tric
lava
ge o
r as
pira
te: s
erio
us (–
1)d
Und
etec
tede
Expe
ctor
ated
or i
nduc
ed
sput
um:
Low
G
astri
c la
vage
or
aspi
rate
: Ve
ry lo
w
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cla
ssifi
ed a
s no
t hav
ing
TB)
Cro
ss-se
ctio
nal
Non
eaSe
rious
(–1)
bSe
rious
(–1)
cEx
pect
orat
ed o
r ind
uced
sp
utum
: non
ed
Gas
tric
lava
ge o
r as
pira
te: s
erio
us (–
1)d
Und
etec
tede
Expe
ctor
ated
or i
nduc
ed
sput
um:
Low
G
astri
c la
vage
or
aspi
rate
: Ve
ry lo
w
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Cro
ss-se
ctio
nal
Non
eaSe
rious
(–1)
bN
onec
Non
edU
ndet
ecte
deM
oder
ate
True
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB
)C
ross
-sect
iona
l N
onea
Serio
us (–
1)b
Non
ecN
oned
Und
etec
tede
Mod
erat
e
CrI,
cre
dibl
e in
terv
al.
a Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess t
he ri
sk o
f bia
s for
all 1
1 stu
dies
that
wer
e in
clud
ed in
this
estim
ate
(7 c
ohor
ts co
ntrib
utin
g sa
mpl
es o
f exp
ecto
rate
d or
indu
ced
sput
um; 4
coh
orts
with
spec
imen
s fro
m g
astri
c la
vage
or a
spira
tion)
. The
maj
ority
of s
tudi
es e
nrol
led
indi
vidu
als
cons
ecut
ivel
y. R
esul
ts fro
m X
pert
MTB
/RI
F re
sult
are
auto
mat
ed a
nd w
ere
cons
ider
ed b
linde
d in
all
studi
es. T
he e
xclu
sion
of e
nrol
led
patie
nts f
rom
ana
lyse
s wer
e w
ell e
xpla
ined
in m
ost s
tudi
es; h
owev
er in
one
stud
y (B
ates
201
3) th
at u
sed
spec
imen
s fro
m g
astri
c la
vage
or a
spira
tion,
a n
umbe
r of c
hild
ren
who
had
alre
ady
initi
ated
ant
i-TB
treat
men
t wer
e en
rolle
d (7
7/10
37 s
ampl
es o
f exp
ecto
rate
d or
indu
ced
sput
um, a
nd s
ampl
es fr
om g
astri
c la
vage
or a
spira
tion)
; 66
of th
ese
child
ren
wer
e cu
lture
neg
ativ
e an
d w
ere
excl
uded
from
the
anal
ysis;
11 w
ere
cultu
re p
ositi
ve a
nd w
ere
incl
uded
. Add
ition
ally,
the
follo
win
g co
nsid
erat
ions
wer
e no
t tak
en in
to a
ccou
nt in
judg
emen
ts ab
out t
he li
mita
tions
of t
he s
tudi
es b
ut th
ey
are
impo
rtant
: cul
ture
is a
n im
perfe
ct re
fere
nce
stand
ard.
In c
hild
ren,
cul
ture
sen
sitiv
ity v
arie
s fro
m 2
0% to
70%
, dep
endi
ng o
n fa
ctor
s su
ch a
s th
e se
verit
y of
dise
ase,
the
age
of th
e ch
ild, t
he c
ultu
re
68 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATEm
etho
ds u
sed,
and
spec
imen
type
s. In
ord
er to
impr
ove
the
diag
nosti
c yi
eld,
2/
11 st
udie
s (bo
th u
sing
spec
imen
s fro
m g
astri
c la
vage
or a
spira
tion
perfo
rmed
at le
ast t
wo
cultu
res f
or e
ach
child
, but
som
e pe
rform
ed a
s m
any
as s
ix c
ultu
res
per c
hild
. The
sen
sitiv
ity o
f Xpe
rt M
TB/
RIF
may
be
unde
resti
mat
ed w
hen
it is
com
pare
d ag
ains
t cul
ture
as
a re
fere
nce
stand
ard.
The
evi
denc
e w
as n
ot d
owng
rade
d.
b A
ll stu
dies
wer
e pe
rform
ed a
t hig
her l
evel
s of c
are
– th
at is
, at h
ighe
r-lev
el re
ferra
l hos
pita
ls an
d un
iver
sity
hosp
itals.
Eig
ht st
udie
s inc
lude
d on
ly in
patie
nts;
two
studi
es in
clud
ed in
patie
nts a
nd o
utpa
tient
s (tw
o stu
dies
teste
d sp
ecim
ens o
f exp
ecto
rate
d or
indu
ced
sput
um; o
ne st
udy
teste
d sp
ecim
ens f
rom
gas
tric
lava
ge o
r asp
iratio
n); t
wo
studi
es w
ere
labo
rato
ry-b
ased
and
pro
vide
d lit
tle c
linic
al in
form
atio
n (th
ese
teste
d sp
ecim
ens f
rom
gas
tric
lava
ge o
r asp
iratio
n). I
n th
e pa
edia
tric
popu
latio
n, in
patie
nts m
ay p
rese
nt w
ith m
ore
seve
re d
iseas
e an
d ha
ve a
hig
her l
ikel
ihoo
d of
bei
ng sm
ear p
ositi
ve; t
hey
are
one
grou
p th
at m
ight
ben
efit f
rom
Xpe
rt M
TB/
RIF.
Out
patie
nts m
ay p
rese
nt d
iffer
ently
, with
less
seve
re d
iseas
e an
d so
be
less
likel
y to
be
smea
r pos
itive
or c
ultu
re p
ositi
ve. O
utpa
tient
s are
not
repr
esen
ted
by th
e stu
dies
incl
uded
in th
is re
view
. Onl
y on
e stu
dy (R
acho
w 2
012,
usin
g sp
ecim
ens f
rom
exp
ecto
rate
d sp
utum
) rep
rese
nted
a b
road
er g
roup
of c
hild
ren:
app
roxi
mat
ely
20%
of c
hild
ren
susp
ecte
d of
hav
ing
TB h
ad b
een
iden
tified
thro
ugh
cont
act t
raci
ng. O
ne u
npub
lishe
d stu
dy (C
histi
) inc
lude
d se
vere
ly m
alno
urish
ed c
hild
ren
with
cou
gh la
sting
long
er th
an 2
wee
ks o
r pne
umon
ia o
n X-
ray,
or b
oth;
in th
ese
case
s, T
B w
as o
ne d
iffer
entia
l dia
gnos
is. T
here
wer
e se
rious
con
cern
s abo
ut in
dire
ctne
ss in
the
maj
ority
of s
tudi
es p
erfo
rmed
in h
ighe
r-lev
el re
ferra
l hos
pita
ls. T
he e
vide
nce
was
dow
ngra
ded
by o
ne p
oint
.
c No
study
dire
ctly
add
ress
ed th
e que
stion
of in
cons
isten
cy b
y per
form
ing
prio
r testi
ng w
ith m
icro
scop
y and
then
subs
eque
ntly
per
form
ing
Xper
t MTB
/RI
F. Es
timat
es o
f sen
sitiv
ity w
ere v
aria
ble a
cros
s stu
dies
and
sp
ecim
en ty
pes,
and
rang
ed fr
om 3
6% to
86%
for e
xpec
tora
ted
sput
um, f
rom
43%
to 7
0% fo
r ind
uced
sput
um, a
nd fr
om 4
0% to
100
% fo
r spe
cim
ens f
rom
gas
tric l
avag
e or
asp
iratio
n. Th
e he
tero
gene
ity co
uld
not b
e exp
lain
ed; th
e evi
denc
e was
ther
efor
e dow
ngra
ded b
y one
poin
t. Esti
mat
es of
spec
ifici
ty di
d not
show
serio
us he
tero
gene
ity: p
oint
estim
ates
rang
ed fro
m 9
3% to
100
%. T
here
was
no co
ncer
n abo
ut sp
ecifi
city.
d
The
pool
ed e
stim
ate
of s
ensit
ivity
for
spe
cim
ens
from
exp
ecto
rate
d or
ind
uced
spu
tum
had
a w
ide
95%
con
fiden
ce i
nter
val
(gre
ater
tha
n +/
-10%
of
the
poin
t es
timat
e);
the
estim
ate
for
gastr
ic l
avag
e or
asp
iratio
n ha
d a
wid
e 95
% c
onfid
ence
int
erva
l +/
-20%
of
the
poin
t es
timat
e).
The
conc
erns
abo
ut e
xpec
tora
ted
or i
nduc
ed s
putu
m w
ere
serio
us;
the
conc
erns
abo
ut
sam
ples
fro
m g
astri
c la
vage
or
aspi
ratio
n w
ere
very
ser
ious
. Th
e ev
iden
ce w
as n
ot d
owng
rade
d fu
rther
giv
en t
he d
owng
radi
ng f
or i
ncon
siste
ncy.
The
re w
as n
o co
ncer
n ab
out
spec
ifici
ty.
e Tw
o un
publ
ished
stu
dies
wer
e in
clud
ed.
The
data
that
wer
e in
clud
ed in
the
revi
ew d
id n
ot a
llow
for f
orm
al a
sses
smen
t of p
ublic
atio
n bi
as u
sing
met
hods
suc
h as
funn
el p
lots
or re
gres
sion
tests
; su
ch te
chni
ques
hav
e no
t bee
n fo
und
to b
e he
lpfu
l in
studi
es e
valu
atin
g di
agno
stic
accu
racy
. How
ever
, rep
ortin
g bi
as w
as c
onsid
ered
to b
e m
inim
al s
ince
Xpe
rt M
TB/
RIF
is a
new
test
that
has
had
co
nsid
erab
le a
ttent
ion
and
scru
tiny.
B. S
umm
ary
of fi
ndin
gs
Out
com
e
Xper
t MTB
/RIF
usi
ng s
peci
men
s of
exp
ecto
rate
or
indu
ced
sput
umXp
ert M
TB/R
IF u
sing
spe
cim
ens
of g
astr
ic la
vage
or
asp
irate
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
aQ
ualit
y
of
evid
ence
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
aQ
ualit
y
of
evid
ence
Prev
alen
ce
10/1
000b
Prev
alen
ce
50/1
000b
Prev
alen
ce
100/
1000
bPr
eval
ence
10
/100
0bPr
eval
ence
50
/100
0bPr
eval
ence
10
0/10
00b
True
pos
itive
s (in
divi
dual
s w
ith T
B)6
(4-7
)28
(21-
35)
55(4
1-69
)Lo
w
6(4
-8)
31(2
2-40
)62
(44-
80)
Very
low
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cl
assifi
ed a
s no
t hav
ing
TB)
5(3
-6)
23(1
6-30
)45
(31-
59)
Low
4
(2-6
)19
(10-
28)
38(2
0-56
)Ve
ry lo
w
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cl
assifi
ed a
s ha
ving
TB)
20(1
0-40
)19
(10-
38)
18(9
-36)
Mod
erat
e
10(1
0-30
)10
(10-
29)
9(9
-27)
Mod
erat
e
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cl
assifi
ed a
s no
t hav
ing
TB)
970
(950
-980
)93
1(9
12-9
41)
882
(864
-891
)M
oder
ate
98
0(9
60-9
41)
941
(922
-941
)89
1(8
73-8
91)
Mod
erat
e
CrI,
cre
dibl
e in
terv
al.
a The
expe
cted
num
ber o
f Xpe
rt M
TB/
RIF
resu
lts w
as b
ased
on
the
sens
itivi
ty a
nd s
peci
ficity
esti
mat
es c
alcu
late
d fro
m a
com
paris
on w
ith c
ultu
re fo
r diff
eren
t pre
vale
nces
of T
B.
b The
estim
ates
of T
B pr
eval
ence
wer
e pr
ovid
ed b
y th
e W
HO
Ste
erin
g G
roup
.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 69
C. What is the additional yield of Xpert MTB/RIF compared with microscopy in children with smear-negative culture-positive TB?
Outcome
Number of results/1000 smear-negative culture-positive children tested (95% CrI) Quality
of evidence
Prevalence 10/1000 Prevalence 50/1000 Prevalence 100/1000
Smear microscopy
Xpert MTB/RIF
Smear microscopy
Xpert MTB/RIF
Smear microscopy
Xpert MTB/RIF
Specimens from expectorated or induced sputumTrue positives (patients with TB)
0 6(4–7)
0 28(21–35)
0 55(41–69)
Low
True positives (absolute difference)
6 more 28 more 55 more
False negatives (patients incorrectly classified as not having TB)
10 5(3–6)
50 23(16–30)
100 45(31–59)
Low
False negatives (absolute difference)
5 fewer 27 fewer 55 fewer
Specimens from gastric lavage or aspirationTrue positives (patients with TB)
0 6(4–8)
0 31(22–40)
0 62(44–80)
Low
True positives (absolute difference)
6 more 31 more 62 more
False negatives (patients incorrectly classified as not having TB)
10 4(2–6)
50 19(10–28)
100 38(20–56)
Low
False negatives (absolute difference)
6 fewer 31 fewer 62 fewer
CrI, credible interval.
70 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Table 27. Incremental yield of Xpert MTB/RIF compared with smear microscopy in children with culture-confirmed TB (A. Expectorated sputum and induced sputum, B. Gastric lavage or aspirate)PICO question: What is the incremental yield of Xpert MTB/RIF compared with smear microscopy in children with culture-confirmed TB?A. Expectorated sputum and induced sputumParticipants: Children aged 0-15 years with culture-confirmed TBSetting: Mainly tertiary care referral hospitals and university hospitalsTarget condition: Pulmonary TB. Reference standard: Solid culture or liquid culture.Number of studies (number of participants): 10 (1546)aMicroscopyPooled sensitivity: 29% (95% CrI, 16–42%); pooled specificity: 100% (95% CrI, 99–100%)Xpert MTB/RIFPooled sensitivity: 66% (95% CrI, 52–77%); pooled specificity: 98% (95% CrI, 96–99%)
Outcome
Number of results/1000 culture-positive children tested (95% CrI)aQuality
of evidence
Prevalence 10/1000 Prevalence 50/1000 Prevalence 100/1000
Smear microscopy
Xpert MTB/RIF
Smear microscopy
Xpert MTB/RIF
Smear microscopy
Xpert MTB/RIF
True positives (patients with TB)
3 (2–4)
7(5–8)
15 (8–21)
33(26–39)
29 (16–42)
66(52–77)
Low
True positives (absolute difference)
4 more 18 more 37 more
False negatives (patients incorrectly classified as not having TB)
7 (6–8)
3(2–5)
36 (29–42)
17 (12–24)
71 (58–84)
34 (23–48)
Low
False negatives (absolute difference)
4 fewer 19 fewer 37 fewer
CrI, credible interval.a These are the same studies as those assessed in Table 24 A. Rachow 2012 reported testing one cohort using expectorated sputum and one using induced sputum; this was counted as two studies.
B. Gastric lavage or aspirateNumber of studies (number of participants): 7 (1319)Microscopy Pooled sensitivity: 11% (95% CrI, 12–35%); pooled specificity: 99% (95% CrI, 97–100%)Xpert MTB/RIFPooled sensitivity: 66% (95% CrI, 51–81%); pooled specificity: 98% (95% CrI, 96–99%)
Outcome
Number of results/1000 culture-positive children tested (95% CrI)aQuality
of evidence
Prevalence 10/1000 Prevalence 50/1000 Prevalence 100/1000
Smear microscopy
Xpert MTB/RIF
Smear microscopy
Xpert MTB/RIF
Smear microscopy
Xpert MTB/RIF
True positives (patients with TB)
2 (1–4)
7(5–8)
11 (6–18)
33(26–41)
22 (12–35)
66(51–81)
Low
True positives (absolute difference)
5 more 22 more 44 more
False negatives (patients incorrectly classified as not having TB)
8 (7–9)
3(2–5)
39 (33–44)
17 (10–25)
78 (65–88)
34 (19–49)
Low
False negatives (absolute difference)
5 fewer 22 fewer 44 fewer
CrI, credible interval.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 71Ta
ble
28. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
rifam
pici
n re
sista
nce
in r
espi
rato
ry s
peci
men
s fro
m c
hild
ren
PIC
O q
uesti
on: W
hat i
s th
e di
agno
stic
accu
racy
of X
pert
MTB
/RI
F fo
r det
ectio
n of
rifa
mpi
cin
resis
tanc
e in
resp
irato
ry s
peci
men
s fro
m c
hild
ren?
Parti
cipa
nts:
Chi
ldre
n ag
ed 0
–15
year
s su
spec
ted
of h
avin
g TB
or m
ultid
rug-
resis
tant
TB
Setti
ng: M
ainl
y te
rtiar
y ca
re re
ferra
l hos
pita
ls an
d un
iver
sity
hosp
itals
Targ
et c
ondi
tion:
Rifa
mpi
cin
resis
tanc
eRe
fere
nce
test:
Cul
ture
and
cul
ture
-bas
ed p
heno
typi
c dr
ug-su
scep
tibili
ty te
sting
(1 s
tudy
) or H
ain
Lifes
cien
ce’s
Gen
otyp
e M
TBD
Rplu
s (2
stu
dies
)N
umbe
r of s
tudi
es (n
umbe
r of p
artic
ipan
ts): 3
(176
) Po
oled
sen
sitiv
ity: 8
6% (9
5% C
rI, 5
3–98
%);
pool
ed s
peci
ficity
: 98%
(95%
CrI,
94–
100%
)
Out
com
eSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
Lim
itatio
nsIn
dire
ctne
ss
Inco
nsis
tenc
yIm
prec
isio
nPu
blic
atio
n bi
asPr
eval
ence
50
/100
0Pr
eval
ence
10
0/10
00
True
pos
itive
s (in
divi
dual
s w
ith T
B an
d rif
ampi
cin
resis
tanc
e)C
ross
-se
ctio
nal
Non
eaN
oneb
Non
ecVe
ry s
erio
us
(–2)
dU
ndet
ecte
deLo
w
43(2
7-49
)12
9(8
0-14
7)Fa
lse n
egat
ives
(ind
ivid
uals
inco
rrect
ly c
lass
ified
as
hav
ing
TB th
at is
rifa
mpi
cin
susc
eptib
le)
Cro
ss-
sect
iona
l N
onea
Non
ebN
onec
Very
ser
ious
(–
2)d
Und
etec
tede
Low
7
(1-2
4)21
(3-7
1)Fa
lse p
ositi
ves
(indi
vidu
als
inco
rrect
ly c
lass
ified
as
hav
ing
TB w
ith ri
fam
pici
n re
sista
nce)
Cro
ss-
sect
iona
l N
onea
Non
ebN
onec
Non
eU
ndet
ecte
deH
igh
19
(0
-57)
17
(0-5
1)Tr
ue n
egat
ives
(ind
ivid
uals
with
TB
that
is
rifam
pici
n su
scep
tible
)C
ross
-se
ctio
nal
Non
eaN
oneb
Non
ecN
one
Und
etec
tede
Hig
h
931
(893
-950
)83
3 (7
99-8
50)
CrI,
cre
dibl
e in
terv
al; D
ST, d
rug-
susc
eptib
ility
testi
ng.
a Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
All
thre
e stu
dies
enr
olle
d in
divi
dual
s co
nsec
utiv
ely.
The
resu
lt fro
m X
pert
MTB
/RI
F is
auto
mat
ed a
nd w
as c
onsid
ered
blin
ded
in a
ll stu
dies
. Th
ere
wer
e no
con
cern
s ab
out r
isk o
f bia
s.b
The
ratin
g of
the
qual
ity o
f evi
denc
e m
ay b
e lo
wer
ed if
ther
e ar
e im
porta
nt d
iffer
ence
s in
the
popu
latio
ns a
nd te
sts s
tudi
ed, a
nd in
the
expe
rtise
of t
hose
usin
g th
e te
sts in
the
studi
es c
ompa
red
with
th
e se
tting
s fo
r whi
ch th
e re
com
men
datio
ns a
re in
tend
ed. A
ll stu
dies
wer
e pe
rform
ed a
t ter
tiary
car
e re
ferra
l hos
pita
ls or
uni
vers
ity h
ospi
tals,
and
all
child
ren
incl
uded
in th
e stu
dies
wer
e in
patie
nts.
c
For
the
3 stu
dies
, th
e po
int
estim
ates
fo
r se
nsiti
vity
w
ere
67%
, 83
%
and
100%
, in
dica
ting
som
e he
tero
gene
ity.
The
95%
co
nfide
nce
inte
rval
s w
ere
wid
e an
d ov
erla
ppin
g.
The
estim
ates
of
sp
ecifi
city
di
d no
t sh
ow
serio
us
hete
roge
neity
: th
e po
int
estim
ates
ra
nged
fro
m
94%
to
10
0%.
Ther
e w
ere
no
conc
erns
ab
out
spec
ifici
ty.
d O
nly
3 stu
dies
with
a to
tal o
f 176
chi
ldre
n w
ere
incl
uded
in th
e re
view
; 121
chi
ldre
n w
ere
enro
lled
in o
ne s
tudy
. The
con
fiden
ce in
terv
al fo
r sen
sitiv
ity w
as w
ide
(cro
ssin
g +/
– 20
%).
Ther
e w
ere
very
ser
ious
con
cern
s ab
out t
his
evid
ence
. The
evi
denc
e w
as d
owng
rade
d by
two
poin
ts. T
here
wer
e no
con
cern
s ab
out s
peci
ficity
.e
One
unp
ublis
hed
study
was
incl
uded
in th
e re
view
. A
few
add
ition
al s
tudi
es w
ere
in p
rogr
ess
but d
ata
wer
e no
t ava
ilabl
e fo
r ana
lysis
. Th
e da
ta in
clud
ed in
the
revi
ew d
id n
ot a
llow
for f
orm
al
asse
ssm
ent o
f pub
licat
ion
bias
usin
g m
etho
ds s
uch
as fu
nnel
plo
ts or
regr
essio
n te
sts; s
uch
tech
niqu
es h
ave
not b
een
foun
d to
be
help
ful i
n stu
dies
eva
luat
ing
diag
nosti
c ac
cura
cy. H
owev
er, r
epor
ting
bias
was
con
sider
ed to
be
min
imal
sin
ce X
pert
MTB
/RI
F is
a ne
w te
st th
at h
as h
ad c
onsid
erab
le a
ttent
ion
and
scru
tiny.
72 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATETa
ble
29. G
RAD
E ev
iden
ce p
rofil
e: a
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
perip
hera
l lym
ph n
ode
TB in
chi
ldre
n
PIC
O q
uesti
on:
Wha
t is
the
diag
nosti
c ac
cura
cy o
f Xpe
rt M
TB/
RIF
for d
etec
tion
of p
erip
hera
l lym
ph n
ode
TB in
chi
ldre
n, w
here
Xpe
rt M
TB/
RIF
is us
ed
as a
repl
acem
ent t
est f
or u
sual
pra
ctic
e?Pa
rtici
pant
s: C
hild
ren
aged
0–1
5 ye
ars
susp
ecte
d of
hav
ing
perip
hera
l lym
ph n
ode
TBSe
tting
: Mai
nly
terti
ary
care
refe
rral h
ospi
tals
and
univ
ersit
y ho
spita
lsTa
rget
con
ditio
n: P
erip
hera
l lym
ph n
ode
TBRe
fere
nce
test:
Sol
id c
ultu
re o
r liq
uid
cultu
re o
f sam
ples
from
fine
nee
dle
aspi
ratio
n or
bio
psy
Num
ber o
f stu
dies
(num
ber o
f par
ticip
ants)
: 3 (1
72)
Pool
ed s
ensit
ivity
: 86%
(95%
CrI,
65–
96%
); po
oled
spe
cific
ity: 8
1% (9
5% C
rI, 5
4–93
%)
Out
com
eSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
Lim
itatio
nsIn
dire
ctne
ss
Inco
nsis
tenc
yIm
prec
isio
nPu
blic
atio
n bi
asPr
eval
ence
10
/100
0Pr
eval
ence
50
/100
0Pr
eval
ence
10
0/10
00
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-se
ctio
nal
Non
eaN
oneb
Serio
us (–
1)c
Serio
us (–
1)d
Und
etec
tede
Very
low
22
(16-
24)
43(3
3-48
)86
(65-
96)
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cla
ssifi
ed a
s no
t ha
ving
TB)
Cro
ss-
sect
iona
lN
onea
Non
ebSe
rious
(–1)
cSe
rious
(–1)
dU
ndet
ecte
deVe
ry lo
w
4(1
-9)
7(2
-18)
14(4
-35)
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Cro
ss-
sect
iona
lN
onea
Non
ebSe
rious
(–1)
cSe
rious
(–1)
dU
ndet
ecte
deVe
ry lo
w
185
(68-
449)
181
(67-
437)
171
(63-
414)
True
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Cro
ss-
sect
iona
lN
onea
Non
ebSe
rious
(–1)
cSe
rious
(–1)
dU
ndet
ecte
deVe
ry lo
w
790
(527
-907
)77
0(5
13-8
84)
729
(486
-837
)
CrI,
cre
dibl
e in
terv
al.
a Th
e Q
UA
DA
S-2
tool
was
use
d to
ass
ess
the
risk
of b
ias.
Tw
o of
thre
e stu
dies
enr
olle
d ch
ildre
n co
nsec
utiv
ely;
one
was
a la
bora
tory
-bas
ed s
tudy
and
pro
vide
d no
clin
ical
info
rmat
ion.
The
resu
lt fro
m
Xper
t MTB
/RI
F is
auto
mat
ed a
nd w
as c
onsid
ered
blin
ded
in a
ll stu
dies
. Cul
ture
is a
n im
perfe
ct re
fere
nce
stand
ard.
The
re w
ere
no c
once
rns
abou
t lim
itatio
ns.
b Th
e ra
ting
of th
e qu
ality
of e
vide
nce
may
be
low
ered
if th
ere
are
impo
rtant
diff
eren
ces
in th
e po
pula
tions
and
tests
stu
died
, and
in th
e ex
perti
se o
f tho
se u
sing
the
tests
in th
e stu
dies
com
pare
d w
ith
the
setti
ngs
for w
hich
the
reco
mm
enda
tions
are
inte
nded
. All
studi
es w
ere
perfo
rmed
at h
ighe
r-lev
el c
are
faci
litie
s. T
he p
atie
nt p
opul
atio
n th
at re
ceiv
ed th
e in
dex
test
prob
ably
refle
cts
the
popu
latio
n of
inte
nded
use
. The
re w
ere
no c
once
rns
abou
t ind
irect
ness
.c
For t
he 3
stu
dies
, the
poi
nt e
stim
ates
for s
ensit
ivity
wer
e 77
%, 1
00%
and
100
%, i
ndic
atin
g so
me
hete
roge
neity
. The
95%
con
fiden
ce in
terv
als
over
lapp
ed. T
he e
stim
ates
for s
peci
ficity
wer
e 50
%,
71%
and
96%
. The
re is
no
expl
anat
ion
for t
he h
eter
ogen
eity.
The
re w
ere
serio
us c
once
rns
abou
t thi
s ev
iden
ce. T
he e
vide
nce
was
dow
ngra
ded
by o
ne p
oint
.d
Onl
y 3
studi
es w
ith a
tota
l of 1
72 c
hild
ren
wer
e in
clud
ed; 1
stu
dy h
ad o
nly
5 pa
rtici
pant
s. T
he c
onfid
ence
inte
rval
s fo
r bot
h se
nsiti
vity
and
spe
cific
ity w
ere
wid
e (c
ross
ing
+/–
20%
). Th
ere
wer
e ve
ry s
erio
us c
once
rns
abou
t thi
s ev
iden
ce. H
owev
er, t
he e
vide
nce
was
not
dow
ngra
ded
furth
er g
iven
the
dow
ngra
ding
for i
ncon
siste
ncy.
e O
ne u
npub
lishe
d stu
dy w
as in
clud
ed. A
few
oth
er st
udie
s wer
e in
pro
gres
s but
dat
a w
ere
not a
vaila
ble
for a
naly
sis. T
he d
ata
incl
uded
in th
e re
view
did
not
allo
w fo
r for
mal
ass
essm
ent o
f pub
licat
ion
bias
usin
g m
etho
ds s
uch
as fu
nnel
plo
ts or
regr
essio
n te
sts; s
uch
tech
niqu
es h
ave
not b
een
foun
d to
be
help
ful i
n stu
dies
eva
luat
ing
diag
nosti
c ac
cura
cy. H
owev
er, r
epor
ting
bias
was
con
sider
ed to
be
min
imal
sin
ce X
pert
MTB
/RI
F is
a ne
w te
st th
at h
as h
ad c
onsid
erab
le a
ttent
ion
and
scru
tiny.
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 73Ta
ble
30. G
RAD
E ev
iden
ce p
rofil
e an
d su
mm
ary
of fi
ndin
gs: a
ccur
acy
of X
pert
MTB
/RIF
in d
etec
ting
TB m
enin
gitis
in c
hild
ren
PIC
O q
uesti
on: W
hat i
s the
dia
gnos
tic a
ccur
acy
of X
pert
MTB
/RI
F fo
r det
ectio
n of
TB
men
ingi
tis in
chi
ldre
n, w
here
Xpe
rt M
TB/
RIF
is us
ed a
s a re
plac
emen
t te
st fo
r usu
al p
ract
ice?
Parti
cipa
nts:
Chi
ldre
n ag
ed 0
–15
year
s su
spec
ted
of h
avin
g TB
men
ingi
tisSe
tting
: Mai
nly
terti
ary
care
refe
rral h
ospi
tals
and
univ
ersit
y ho
spita
lsTa
rget
con
ditio
n: T
B m
enin
gitis
Refe
renc
e te
st: S
olid
cul
ture
or l
iqui
d cu
lture
of c
ereb
rosp
inal
flui
dN
umbe
r of s
tudi
es (n
umbe
r of p
artic
ipan
ts): 3
(51)
Pool
ed s
ensit
ivity
: not
eno
ugh
data
; poo
led
spec
ifici
ty: 9
5% (9
5% C
rI, 8
1–99
%)
Out
com
eSt
udy
desi
gn
Fact
ors
that
may
dec
reas
e th
e qu
ality
of e
vide
nce
Qua
lity
of
ev
iden
ce
Num
ber
of r
esul
ts/1
000
indi
vidu
als
test
ed
(95%
CrI)
Lim
itatio
nsIn
dire
ctne
ss
Inco
nsis
tenc
yIm
prec
isio
nPu
blic
atio
n bi
asPr
eval
ence
10
/100
0Pr
eval
ence
50
/100
0Pr
eval
ence
10
0/10
00
True
pos
itive
s (in
divi
dual
s w
ith T
B)C
ross
-se
ctio
nal
Insu
ffici
ent d
ataa
No
data
No
data
No
data
False
neg
ativ
es (i
ndiv
idua
ls in
corre
ctly
cla
ssifi
ed a
s no
t ha
ving
TB)
Cro
ss-
sect
iona
lIn
suffi
cien
t dat
aaN
o da
taN
o da
taN
o da
ta
False
pos
itive
s (in
divi
dual
s in
corre
ctly
cla
ssifi
ed a
s ha
ving
TB)
Cro
ss-
sect
iona
lN
onea
Non
ebN
onec
Serio
us (–
1)d
Und
etec
tede
Mod
erat
e
True
neg
ativ
es (i
ndiv
idua
ls w
ithou
t TB)
Cro
ss-
sect
iona
lN
onea
Non
ebN
onec
Serio
us (–
1)d
Und
etec
tede
Mod
erat
e
CrI,
cre
dibl
e in
terv
al.
a Th
ree
studi
es p
rovi
ded
data
abo
ut u
sing
Xper
t M
TB/
RIF
on c
ereb
rosp
inal
flui
d to
dia
gnos
e TB
men
ingi
tis.
Ther
e w
ere
insu
ffici
ent
data
to
calc
ulat
e th
e se
nsiti
vity
of
Xper
t M
TB/
RIF.
In t
wo
studi
es,
two
out
of s
ix c
ultu
re-p
ositi
ve c
hild
ren
wer
e al
so f
ound
to
be p
ositi
ve u
sing
Xper
t M
TB/
RIF.
One
stu
dy d
id n
ot h
ave
any
posit
ive
resu
lts f
or c
ultu
re o
r Xp
ert
MTB
/RI
F. b
The
studi
es w
ere
all p
erfo
rmed
at h
ighe
r lev
els
of c
are
(such
as
refe
rral h
ospi
tals)
, whi
ch re
flect
s th
e po
pula
tion
that
wou
ld b
enefi
t fro
m u
sing
Xper
t MTB
/RI
F on
cer
ebro
spin
al fl
uid.
The
re w
ere
no
conc
ern
for i
ndire
ctne
ss.
c Fo
r the
3 s
tudi
es, t
he p
oint
esti
mat
es fo
r spe
cific
ity w
ere
86%
, 97%
and
100
%, i
ndic
atin
g lit
tle h
eter
ogen
eity.
The
95%
con
fiden
ce in
terv
als
over
lapp
ed. T
here
was
no
conc
ern
abou
t inc
onsis
tenc
y.
d O
nly
3 stu
dies
with
a to
tal o
f 51
child
ren
wer
e in
clud
ed in
the
revi
ew. T
he c
onfid
ence
inte
rval
s fo
r bot
h se
nsiti
vity
and
spe
cific
ity w
ere
wid
e (c
ross
ing
+/–
20%
). Th
ere
wer
e ve
ry s
erio
us c
once
rns
abou
t im
prec
ision
. The
evi
denc
e w
as n
ot d
owng
rade
d fu
rther
giv
en th
e do
wng
radi
ng fo
r inc
onsis
tenc
y.e
One
unp
ublis
hed
study
was
incl
uded
. A fe
w o
ther
stud
ies w
ere
in p
rogr
ess b
ut d
ata
wer
e no
t ava
ilabl
e fo
r ana
lysis
. The
dat
a in
clud
ed in
the
revi
ew d
id n
ot a
llow
for f
orm
al a
sses
smen
t of p
ublic
atio
n bi
as u
sing
met
hods
suc
h as
funn
el p
lots
or re
gres
sion
tests
; suc
h te
chni
ques
hav
e no
t bee
n fo
und
to b
e he
lpfu
l in
studi
es e
valu
atin
g di
agno
stic
accu
racy
. How
ever
, rep
ortin
g bi
as w
as c
onsid
ered
to
be m
inim
al s
ince
Xpe
rt M
TB/
RIF
is a
new
test
that
has
had
con
sider
able
atte
ntio
n an
d sc
rutin
y.
74 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Annexes
Annex 1. Members of the Expert Group
Sevim Ahmedov (Observer)Senior Tuberculosis Technical AdvisorUnited States Agency for International Development 1300 Pennsylvania Ave NWWashington, DC 20523E-mail: [email protected]
Lucia BarreraServicio Micobacterias (Mycobacteria Laboratory)Velez Sarsfield 5631281 Buenos AiresArgentinaE-mail [email protected]
Catharina BoehmeSenior Medical OfficerFoundation for Innovative New DiagnosticsAvenue de Budé 161202 GenevaSwitzerlandE-Mail: [email protected]
Lucy Cheshire Tuberculosis Advocacy Consortium Adalyn CourtSuite C6Ngong RoadNairobi KenyaE-mail: [email protected]
Gavin Churchyard (Observer)The Aurum Institute NPCThe Ridge29 Queens RoadParktownJohannesburgSouth AfricaE-mail: [email protected]
Daniela Maria Cirillo HeadEmerging Bacterial Pathogens Unit San Raffaele Scientific Institute Via Olgettina 58 20132 Milan ItalyE-mail: [email protected]
Frank Cobelens (Observer)Amsterdam Institute of Global Health and Development &Department of Global HealthAcademic Medical CenterAmsterdam The NetherlandsE-mail: [email protected]
Bill Coggin (Observer)Department of State/PEPFAROffice of the US Global AIDS Coordinator2100 Pennsylvania Ave NWWashington, DC 20522United StatesE-mail: [email protected]
Colleen DanielsDirector TB/HIVTreatment Action GroupNew York, NY 10016United StatesE-mail: [email protected]
Claudia Denkinger (systematic reviewer)McGill University4075 Rue CartierMontreal, QuebecCanadaE-mail: [email protected]
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 75
Anne Detjen (systematic reviewer)Technical Consultant North America Office The International Union Against Tuberculosis and Lung Disease 61 Broadway, Suite 1720New York, NY 10006 United States E-mail: [email protected]
Mildred FernandoManagement Sciences for Health, Inc. 181 Floro Subdivision Malhacan, MeycauayanBulacan PhilippinesE-mail: [email protected]
Nazir Ismail (Observer)Head of Centre for Tuberculosis National Institute for Communicable Diseases1 Modderfontein RoadSandringhamJohannesburgSouth AfricaE-mail: [email protected]
Moses JolobaDepartment of Medical MicrobiologyMakerere University College of Health Sciences2nd Floor Pathology/Microbiology BLRoom C31, Upper Mulago Hill Road256 KampalaUgandaE-mail: [email protected]
Anna Mandalakas (systematic reviewer)DirectorGlobal Tuberculosis and Mycobacteriology ProgramThe Tuberculosis InitiativeTexas Children’s Hospital1102 Bates St, FC-630 Houston, Texas 77030United StatesE-mail: [email protected]
Andrea Pantoja (systematic reviewer)ConsultantAnkenhofstrasse 23 Oberengstringen 8102 SwitzerlandE-mail: [email protected]
Holger Schünemann ChairDepartment of Clinical Epidemiology & BiostatisticsMcMaster University Health Sciences CentreRoom 2C10B1200 Main Street WestHamilton, Ontario ON L8N 3Z5CanadaE-mail: [email protected]
Moorine Penniah SekaddeNational Tuberculosis and Leprosy ProgrammeKampalaUgandaE-mail: [email protected]
Thomas M ShinnickAssociate Director for Global Laboratory ActivitiesCenters for Disease Control and Prevention1600 Clifton RoadMS-G35, NEAtlanta, GA 30333United StatesE-mail: [email protected]
Karen Steingart (systematic reviewer)EditorCochrane Infectious Diseases Group United StatesE-mail: [email protected]
Sabira TahseenNational coordinatorNational TB Control Programme IslamabadPakistanE-mail: [email protected]
76 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Maarten van CleeffKNCV Tuberculosis FoundationParkstraat 172514 JD The HagueThe NetherlandsE-mail: [email protected]
Francis VaraineMédecins sans Frontières8 rue St Sabin75011 ParisFranceE-mail: [email protected]
Annex 2. WHO staff members
Haileyesus Getahun E-mail: [email protected]
Christopher Gilpin E-mail: [email protected]
Jean Iragena E-mail: [email protected]
Knut Lönnroth Email: [email protected]
Lisa Nelson Email: [email protected]
Fuad Mirzayev E-mail: [email protected]
Wayne van Gemert Email: [email protected]
Karin Weyer E-mail: [email protected]
Matteo Zignol E-mail: [email protected]
Annex 3. Members of the Strategic and Technical Advisory Group for Tuberculosis (STAG-TB)
Dr Draurio BarreiraHeadNational TB Control Program Ministry of HealthBrasilia-DFBrazil
Dr Amy BloomSenior Technical AdviserUS Agency for International Development (USAID)Washington, DCUnited States
Prof. Gavin ChurchyardChief Executive OfficerThe Aurum Institute NPCParktown, Johannesburg South Africa
Dr Daniela M CirilloHeadEmerging Bacterial Pathogens UnitSan Raffaele del Monte Tabor Foundation San Raffaele Scientific InstituteMilanItaly
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 77
Professor Elizabeth CorbettTropical EpidemiologyLondon School of Hygiene & Tropical Medicine and Malawi Liverpool Wellcome Trust Clinical Research ProgrammeBlantyre Malawi
Dr Charles L DaleyChiefDivision of Mycobacterial and Respiratory InfectionsNational Jewish Medical and Research CenterDenver, COUnited States
Professor Stephen GrahamInternational Child HealthUniversity of MelbourneDepartment of PaediatricsRoyal Children’s HospitalParkville, MelbourneAustralia
Dr Akramul IslamAssociate DirectorHealth, Nutrition and Population ProgramBangladesh Rural Advancement Committee CentreDhakaBangladesh
Dr Michael KimerlingSenior Program Officer, TBGlobal Health ProgramBill and Melinda Gates FoundationSeattle, WAUnited States
Dr Jaime LagahidNational Center for Disease, Prevention and ControlDepartment of HealthManilaThe Philippines
Dr Chakaya J Muhwa(STAG-TB Chair)Chief Research OfficerCentre for Respiratory Diseases ResearchKenya Medical Research InstituteNairobiKenya
Dr A PrakashJoint SecretaryDisease ControlMinistry of Health and Family WelfareNew DelhiIndia
Dr Ejaz Qadeer ManagerNational TB Control ProgrammeFederal Ministry of HealthIslamabadPakistan
Dr Joseph Sitienei National TB Programme ManagerDivision of Leprosy, Tuberculosis and Lung DiseaseMinistry of HealthNairobiKenya
Dr Alena SkrahinaScientific DirectorRepublican Research and Practical Centre for Pulmonology and TuberculosisMinskBelarus
Dr Soumya SwaminathanDirector National Institute for Research in TuberculosisIndian Council for Medical ResearchChennaiIndia
78 XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE
Dr Francis VaraineCoordinator of MSF Working Group on TuberculosisMédecins Sans FrontièresParisFrance
Dr Maarten van CleeffProgram Director TB Care KNCV Tuberculosis FoundationThe HagueThe Netherlands
Dr Dalene von DelftMedical DoctorTB PROOFSomerset WestCape TownSouth Africa
Annex 4. Declarations of Interests
None declaredLucia Barrera, Lucy Cheshire, Colleen Daniels, Holger Schünemann (Chairperson), Moorine Penniah Sekadde, Sabira Tahseen, Maarten van Cleeff
Declared, insignificantDaniela Maria Cirillo: meeting participation sponsored by Cepheid; research grant support from FIND and ST microelectronics.
Mildred Fernando: Management Sciences for Health contributed approximately US$ 80 to enable her to participate in the Expert Group meeting; the Xpert MTB/RIF assay may have been used to determine if her TB had relapsed.
Thomas M Shinnick: received funding from the United States Government to participate in the meeting.
Francis Varaine: leader of the Médecins sans Frontières working group on TB; required to defend positions related to TB diagnostics.
Declared, significant (observer status)Sevim Ahmedov: United States government employee; the US government has contributed funds to enable reductions in the end-user price of cartridges used for the Xpert MTB/RIF test.
Catharina Boehme: employed by FIND, which had a cofunding agreement with Cepheid supporting the development of Xpert MTB/RIF.
Gavin Churchyard: employed by the Aurum Institute, which received funding from the Bill and Melinda Gates Foundation for trials using the Xpert MTB/RIF assay to diagnose TB in South Africa, and to evaluate the impact of the test and its cost effectiveness during routine roll-out of the test.
Frank Cobelens: consultant to the Bill and Melinda Gates Foundation for research on rolling out and scaling up the use of Xpert MTB/RIF; also conducted a cost-effectiveness analysis of Xpert MTB/RIF for FIND.
Bill Coggin: United States government employee; the US government has contributed funds to enable reductions in the end-user price of cartridges used in the Xpert MTB/RIB test.
Claudia Denkinger: conducted the systematic review of using Xpert MTB/RIF to diagnose extrapulmonary TB
Anne Detjen: conducted the systematic review of using Xpert MTB/RIF to diagnose paediatric TB
XPERT MTB/RIF FOR THE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TB – POLICY UPDATE 79
Nazir Ismail: employed by the National Health Laboratory Service of South Africa and involved in the roll out of Xpert MTB/RIF testing in South Africa; South Africa purchased more than 1 million cartridges; Nazir Ismail received no financial gain from this process.
Moses Joloba: laboratory manger of the National TB Reference Laboratory in Kampala which was used by FIND as one testing site for the initial Xpert MTB/RIF demonstration studies.
Anna Mandalakas: conducted the systematic review of using Xpert MTB/RIF to diagnose paediatric TB.
Andrea Pantoja: conducted the review of the affordability and cost effectiveness of Xpert MTB/RIF.
Karen Steingart: conducted the systematic review of using Xpert MTB/RIF to diagnose pulmonary TB.
Automated real-time nucleic acid amplification technology for rapid
and simultaneous detection of tuberculosis and rifampicin resistance:
Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB
in adults and children
Global TB ProgrammeWorld Health OrganizationAvenue Appia 20, CH-1211 Geneva-27, Switzerland
Information Resource Centre HTM/GTB:Email: [email protected]: www.who.int/tb
ISBN 978 92 4 150633 5
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