Comment
Tuberculous meningitis, a severe manifestation of extra-pulmonary tuberculosis,1,2 has a mortality of more than 60% in HIV-infected people,3 with a 54% risk of chronic neurological complications in those who survive.2 Rapid diagnosis and early initiation of treatment are needed to improve prognosis and minimise debilitating sequelae.2 However, diagnosis is difficult, because cerebrospinal fluid typically contains few Mycobacterium tuberculosis bacilli and large sample volumes cannot always be obtained.4,5 Xpert MTB/RIF (Xpert; Cepheid, Sunnyvale, CA, USA), a cartridge-based nucleic acid amplification test that is currently recommended by WHO for diagnosis of tuberculous meningitis, was a welcome advance over older diagnostic tests, including smear microscopy (which is insensitive) and culture (which takes too long to be clinically useful). Unfortunately, sensitivity of Xpert for tuberculous meningitis is relatively low (55–80%),6,7 precluding its use as a rule-out test.5,8,9 WHO have now provided guidelines for the use of the next-generation Xpert assay, Xpert MTB/RIF Ultra (Xpert Ultra), which has substantially improved analytical and clinical sensitivity, as a replacement for Xpert.10 In The Lancet Infectious Diseases, Nathan Bahr and colleagues11 report the diagnostic accuracy of Xpert Ultra for diagnosis of tuberculous meningitis. The authors tested archived cerebrospinal fluid samples from 129 HIV-infected adults in Uganda with Xpert Ultra, and evaluated accuracy by comparison with a composite microbiological reference standard, which included mycobacterial culture plus Xpert and Xpert Ultra tests. Xpert Ultra identified 21 (95%, 95% CI 77–99) of 22 microbiologically proven cases of tuberculous meningitis, which was higher than either Xpert (45% [95% CI 24–68]; 10/22; p=0·0010) or culture (45% [24–68]; 10/22; p=0·0034). Cerebrospinal fluid collection volume was an important predictor of the likelihood of a positive microbioogical test. Xpert Ultra also tests for mutations conferring resistance to rifampicin, a key drug in the antituberculosis treatment regimen. Unfortunately, because rifampicin resistance detection is not possible in samples with very low bacillary load,10 susceptibility could only be determined for 13 (62%) of the 21 Xpert Ultra-positive cases.
To account for the incorporation bias resulting from the inclusion of Xpert Ultra results in the composite reference standard, a separate comparison was done excluding Xpert Ultra results from the composite reference standard. Xpert Ultra detected 16 (70%, 95% CI 47–87) of 23 microbiologically proven or clinically probable tuberculous meningitis cases whereas culture or Xpert each identified ten (43%, 23–66). 101 (95%) of 106 cases classified as possible or non-tuberculous meningitis tested negative with Xpert Ultra. These figures might underestimate the diagnostic accuracy of Xpert Ultra, because the composite reference standard has limitations of its own (microbiological diagnosis has insufficient sensitivity and clinical diagnosis has insufficient specificity).1 Studies summarised in the WHO report have identified that Xpert Ultra has lower specificity than does Xpert in patients screened for pulmonary tuberculosis,10 with false positive results more common in patients previously treated for tuberculosis. However, specificity was good in the study by Bahr and colleagues, who point out that specificity might be less of an issue in tuberculous meningitis because prior tuberculosis is unlikely to result in residual detectable M tuberculosis DNA in cerebrospinal fluid.11 These promising findings need to be confirmed in larger cohorts, including HIV-uninfected patients and children; in the interim, the replacement of Xpert with Xpert Ultra for diagnosis of tuberculous meningitis would seem a reasonable recommendation. The clinical utility of Xpert Ultra testing for the diagnosis of tuberculous meningitis remains unclear. Given Xpert Ultra’s high positive predictive value, a positive result is a clear indication to start tuberculous meningitis treatment and information on rifampicin susceptibility, when reported by the test, is very valuable. A positive result is likely to be particularly useful in low-resource settings, where the clinical judgment of a well trained and experienced clinician is not always available. However, because most patients likely to be tested with this assay will not have tuberculous meningitis, an important question is whether a negative Xpert Ultra test can be used to rule out tuberculous meningitis.
www.thelancet.com/infection Published online September 14, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30536-4
Simon Fraser/Newcastle Hospitals Nhs Trust/Science Photo Library
Xpert MTB/RIF Ultra: a gamechanger for tuberculous meningitis?
Lancet Infect Dis 2017 Published Online September 14, 2017 http://dx.doi.org/10.1016/ S1473-3099(17)30536-4 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(17)30474-7
1
Comment
In Bahr and colleagues’ study,11 a negative Xpert Ultra test was correct 93% of the time (100 of 107 negative tests), when measured against a composite reference standard that included clinical diagnosis. This result might be an underestimate, but on its basis, it would take a brave clinician to rely solely on an Xpert Ultra result when deciding to withhold therapy. Empirical treatment for tuberculosis (ie, treatment in the absence of a positive microbiological test) is common and has reduced the clinical utility of the Xpert assay in patients with pulmonary tuberculosis.12,13 A similar situation for the use of Xpert Ultra in tuberculous meningitis diagnosis is likely. As the accuracy of new tuberculosis tests continues to improve incrementally, carefully designed clinical studies will need to tackle the question of when a diagnostic test can safely be used to rule out tuberculous meningitis. Margaret Khonga, *Mark Patrick Nicol Division of Medical Microbiology, Department of Pathology (MK, MPN) and Institute of Infectious Diseases and Molecular Medicine (MPN), University of Cape Town, Cape Town 7925, South Africa (MK, MPN); and National Health Laboratory Service, Cape Town, South Africa (MK, MPN) [email protected] MPN has received research funding to his institution from the National Institutes of Health of the USA and the Foundation for Innovative New Diagnostics to do studies of the accuracy of Xpert Ultra. MK declares no competing interests.
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Marais S, Thwaites G, Schoeman JF, et al. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis 2010; 10: 803–12. Chiang SS, Khan FA, Milstein MB, et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2014; 14: 947–57. Thwaites GE. Advances in the diagnosis and treatment of tuberculous meningitis. Curr Opin Neurol 2013; 26: 295–300. Ho J, Marais BJ, Gilbert GL, Ralph AP. Diagnosing tuberculous meningitis— have we made any progress? Trop Med Int Health 2013; 18: 783–93. Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J 2014; 44: 435–46. Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J 2014; 44: 435–46. Rufai SB, Singh A, Singh J, et al, for the TB Research Team. Diagnostic usefulness of Xpert MTB/RIF assay for detection of tuberculous meningitis using cerebrospinal fluid. J Infect 2017; 75: 125–31. Mai NT, Thwaites GE. Recent advances in the diagnosis and management of tuberculous meningitis. Curr Opin Infect Dis 2017; 30: 123–28. Bahr NC, Marais S, Caws M, et al. GeneXpert MTB/Rif to diagnose tuberculous meningitis: perhaps the first test but not the last. Clin Infect Dis 2016; 62: 1133–35. WHO. WHO meeting report of a technical expert consultation: non-inferiority analysis of Xpert MTF/RIF Ultra compared to Xpert MTB/RIF. Geneva: World Health Organization, 2017. Bahr NC, Nuwagira E, Evans EE, et al. Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study. Lancet Infect Dis 2017; published online Sept 14. http://dx.doi. org/10.1016/S1473-3099(17)30474-7. Theron G, Zijenah L, Chanda D, et al. Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial. Lancet 2014; 383: 424–35. Churchyard GJ, Stevens WS, Mametja LD, et al. Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis: a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIF. Lancet Glob Health 2015; 3: e450–57.
Copyright © The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
2
www.thelancet.com/infection Published online September 14, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30536-4
Tuberculous meningitis, a severe manifestation of extra-pulmonary tuberculosis,1,2 has a mortality of more than 60% in HIV-infected people,3 with a 54% risk of chronic neurological complications in those who survive.2 Rapid diagnosis and early initiation of treatment are needed to improve prognosis and minimise debilitating sequelae.2 However, diagnosis is difficult, because cerebrospinal fluid typically contains few Mycobacterium tuberculosis bacilli and large sample volumes cannot always be obtained.4,5 Xpert MTB/RIF (Xpert; Cepheid, Sunnyvale, CA, USA), a cartridge-based nucleic acid amplification test that is currently recommended by WHO for diagnosis of tuberculous meningitis, was a welcome advance over older diagnostic tests, including smear microscopy (which is insensitive) and culture (which takes too long to be clinically useful). Unfortunately, sensitivity of Xpert for tuberculous meningitis is relatively low (55–80%),6,7 precluding its use as a rule-out test.5,8,9 WHO have now provided guidelines for the use of the next-generation Xpert assay, Xpert MTB/RIF Ultra (Xpert Ultra), which has substantially improved analytical and clinical sensitivity, as a replacement for Xpert.10 In The Lancet Infectious Diseases, Nathan Bahr and colleagues11 report the diagnostic accuracy of Xpert Ultra for diagnosis of tuberculous meningitis. The authors tested archived cerebrospinal fluid samples from 129 HIV-infected adults in Uganda with Xpert Ultra, and evaluated accuracy by comparison with a composite microbiological reference standard, which included mycobacterial culture plus Xpert and Xpert Ultra tests. Xpert Ultra identified 21 (95%, 95% CI 77–99) of 22 microbiologically proven cases of tuberculous meningitis, which was higher than either Xpert (45% [95% CI 24–68]; 10/22; p=0·0010) or culture (45% [24–68]; 10/22; p=0·0034). Cerebrospinal fluid collection volume was an important predictor of the likelihood of a positive microbioogical test. Xpert Ultra also tests for mutations conferring resistance to rifampicin, a key drug in the antituberculosis treatment regimen. Unfortunately, because rifampicin resistance detection is not possible in samples with very low bacillary load,10 susceptibility could only be determined for 13 (62%) of the 21 Xpert Ultra-positive cases.
To account for the incorporation bias resulting from the inclusion of Xpert Ultra results in the composite reference standard, a separate comparison was done excluding Xpert Ultra results from the composite reference standard. Xpert Ultra detected 16 (70%, 95% CI 47–87) of 23 microbiologically proven or clinically probable tuberculous meningitis cases whereas culture or Xpert each identified ten (43%, 23–66). 101 (95%) of 106 cases classified as possible or non-tuberculous meningitis tested negative with Xpert Ultra. These figures might underestimate the diagnostic accuracy of Xpert Ultra, because the composite reference standard has limitations of its own (microbiological diagnosis has insufficient sensitivity and clinical diagnosis has insufficient specificity).1 Studies summarised in the WHO report have identified that Xpert Ultra has lower specificity than does Xpert in patients screened for pulmonary tuberculosis,10 with false positive results more common in patients previously treated for tuberculosis. However, specificity was good in the study by Bahr and colleagues, who point out that specificity might be less of an issue in tuberculous meningitis because prior tuberculosis is unlikely to result in residual detectable M tuberculosis DNA in cerebrospinal fluid.11 These promising findings need to be confirmed in larger cohorts, including HIV-uninfected patients and children; in the interim, the replacement of Xpert with Xpert Ultra for diagnosis of tuberculous meningitis would seem a reasonable recommendation. The clinical utility of Xpert Ultra testing for the diagnosis of tuberculous meningitis remains unclear. Given Xpert Ultra’s high positive predictive value, a positive result is a clear indication to start tuberculous meningitis treatment and information on rifampicin susceptibility, when reported by the test, is very valuable. A positive result is likely to be particularly useful in low-resource settings, where the clinical judgment of a well trained and experienced clinician is not always available. However, because most patients likely to be tested with this assay will not have tuberculous meningitis, an important question is whether a negative Xpert Ultra test can be used to rule out tuberculous meningitis.
www.thelancet.com/infection Published online September 14, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30536-4
Simon Fraser/Newcastle Hospitals Nhs Trust/Science Photo Library
Xpert MTB/RIF Ultra: a gamechanger for tuberculous meningitis?
Lancet Infect Dis 2017 Published Online September 14, 2017 http://dx.doi.org/10.1016/ S1473-3099(17)30536-4 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(17)30474-7
1
Comment
In Bahr and colleagues’ study,11 a negative Xpert Ultra test was correct 93% of the time (100 of 107 negative tests), when measured against a composite reference standard that included clinical diagnosis. This result might be an underestimate, but on its basis, it would take a brave clinician to rely solely on an Xpert Ultra result when deciding to withhold therapy. Empirical treatment for tuberculosis (ie, treatment in the absence of a positive microbiological test) is common and has reduced the clinical utility of the Xpert assay in patients with pulmonary tuberculosis.12,13 A similar situation for the use of Xpert Ultra in tuberculous meningitis diagnosis is likely. As the accuracy of new tuberculosis tests continues to improve incrementally, carefully designed clinical studies will need to tackle the question of when a diagnostic test can safely be used to rule out tuberculous meningitis. Margaret Khonga, *Mark Patrick Nicol Division of Medical Microbiology, Department of Pathology (MK, MPN) and Institute of Infectious Diseases and Molecular Medicine (MPN), University of Cape Town, Cape Town 7925, South Africa (MK, MPN); and National Health Laboratory Service, Cape Town, South Africa (MK, MPN) [email protected] MPN has received research funding to his institution from the National Institutes of Health of the USA and the Foundation for Innovative New Diagnostics to do studies of the accuracy of Xpert Ultra. MK declares no competing interests.
1 2 3 4 5
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Marais S, Thwaites G, Schoeman JF, et al. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis 2010; 10: 803–12. Chiang SS, Khan FA, Milstein MB, et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2014; 14: 947–57. Thwaites GE. Advances in the diagnosis and treatment of tuberculous meningitis. Curr Opin Neurol 2013; 26: 295–300. Ho J, Marais BJ, Gilbert GL, Ralph AP. Diagnosing tuberculous meningitis— have we made any progress? Trop Med Int Health 2013; 18: 783–93. Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J 2014; 44: 435–46. Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J 2014; 44: 435–46. Rufai SB, Singh A, Singh J, et al, for the TB Research Team. Diagnostic usefulness of Xpert MTB/RIF assay for detection of tuberculous meningitis using cerebrospinal fluid. J Infect 2017; 75: 125–31. Mai NT, Thwaites GE. Recent advances in the diagnosis and management of tuberculous meningitis. Curr Opin Infect Dis 2017; 30: 123–28. Bahr NC, Marais S, Caws M, et al. GeneXpert MTB/Rif to diagnose tuberculous meningitis: perhaps the first test but not the last. Clin Infect Dis 2016; 62: 1133–35. WHO. WHO meeting report of a technical expert consultation: non-inferiority analysis of Xpert MTF/RIF Ultra compared to Xpert MTB/RIF. Geneva: World Health Organization, 2017. Bahr NC, Nuwagira E, Evans EE, et al. Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study. Lancet Infect Dis 2017; published online Sept 14. http://dx.doi. org/10.1016/S1473-3099(17)30474-7. Theron G, Zijenah L, Chanda D, et al. Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial. Lancet 2014; 383: 424–35. Churchyard GJ, Stevens WS, Mametja LD, et al. Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis: a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIF. Lancet Glob Health 2015; 3: e450–57.
Copyright © The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
2
www.thelancet.com/infection Published online September 14, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30536-4
