Publications by authors named "Samuel G Schumacher"

56 Publications

Antigen-based rapid diagnostic testing or alternatives for diagnosis of symptomatic COVID-19: A simulation-based net benefit analysis.

Epidemiology 2021 Jul 13. Epub 2021 Jul 13.

Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, USA Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA MRC Centre for Global Infectious Disease Analysis, Imperial College, London, UK Foundation for Innovative New Diagnostics, Geneva, Switzerland.

Background: SARS-CoV-2 antigen-detection rapid diagnostic tests can diagnose COVID-19 rapidly and at low cost, but lower sensitivity compared with reverse-transcriptase polymerase chain reaction (PCR) has limited clinical adoption.

Methods: We compared antigen testing, PCR testing, and clinical judgment alone for diagnosing symptomatic COVID-19 in an outpatient setting (10% COVID-19 prevalence among the patients tested, 3-day PCR turnaround) and a hospital setting (40% prevalence, 24-hour PCR turnaround). We simulated transmission from cases and contacts, and relationships between time, viral burden, transmission, and case detection. We compared diagnostic approaches using a measure of net benefit that incorporated both clinical and public health benefits and harms of intervention.

Results: In the outpatient setting, we estimated that using antigen testing instead of PCR to test 200 individuals could be equivalent to preventing all symptomatic transmission from one person with COVID-19 (one "transmission-equivalent"). In a hospital, net benefit analysis favored PCR, and testing 25 patients with PCR instead of antigen testing achieved one transmission-equivalent of benefit. In both settings, antigen testing was preferable to PCR if PCR turnaround time exceeded 2 days. Both tests provided greater net benefit than management based on clinical judgment alone, unless intervention carried minimal harm and was provided equally regardless of diagnostic approach.

Conclusions: For diagnosis of symptomatic COVID-19, we estimated that speed of diagnosis with antigen testing is likely to outweigh its lower accuracy compared to PCR wherever PCR turnaround time is 2 days or longer. This advantage may be even greater if antigen tests are also less expensive.
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http://dx.doi.org/10.1097/EDE.0000000000001400DOI Listing
July 2021

Evaluation of the diagnostic performance of laboratory-based c-reactive protein as a triage test for active pulmonary tuberculosis.

PLoS One 2021 12;16(7):e0254002. Epub 2021 Jul 12.

Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland.

Introduction: A highly sensitive triage test that captures most symptomatic patients at increased likelihood of having pulmonary tuberculosis (PTB) would 'rule-out' lower-risk patients from expensive confirmatory testing. Although studies have assessed the diagnostic accuracy of a C-reactive protein (CRP) triage test for PTB in HIV+ patients, limited data are available from HIV- cohorts.

Materials And Methods: In this retrospective case-control study, 765 serum samples were selected from FIND's biobank. Each sample had been collected from an adult presenting with respiratory symptomatology to district hospitals in South Africa and referral hospitals in Cambodia, Peru, Georgia and Vietnam between 2007-2017. Serum CRP measurements were obtained using a laboratory-based assay. CRP cutoff-points of ≥8mg/L and ≥10mg/L were predefined as a positive triage test result. The PTB reference standard was two contemporaneously collected sputum liquid culture results.

Results: CRP demonstrated an overall sensitivity for PTB of 79.8% (95%CI 75.5-83.5) and 77.7% (95%CI 73.4-81.6) for cutoff-points of 8mg/L and 10mg/L respectively. Specificity was 62.8% (95%CI 57.8-67.6%) and 66.6% (95%CI 61.1-70.7) respectively. Area-under-the-curve using Receiver Operating Characteristic analysis was 0.77 (95%CI 0.74-0.81). Threshold analysis showed optimal CRP cutoff-points were higher in HIV+ than HIV- participants. An algorithm in which CRP triage was followed by confirmatory Xpert MTB/Rif testing achieved a sensitivity of 75.1% (95%CI 69.0-80.4%) whilst decreasing Xpert usage by 40.6%.

Discussion: CRP may not meet the challenge of a catch-all TB triage test. However, it shows promise in HIV+ individuals. Further research is required in a prospective study using point-of-care platforms to further evaluate its capabilities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254002PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274836PMC
July 2021

A novel blood-based assay for treatment monitoring of tuberculosis.

BMC Res Notes 2021 Jun 30;14(1):247. Epub 2021 Jun 30.

FIND, Chemin des Mines 9, Geneva, 1202, Switzerland.

Objectives: A novel 3-gene host transcriptional signature (GBP5, DUSP3 and KLF2) has been validated for tuberculosis (TB) treatment monitoring using laboratory-based RNA sequencing platforms. The signature was recently translated by Cepheid into a prototype cartridge-based test that can be run on the GeneXpert instrument. In this study, we prospectively evaluated the change in the expression of the cartridge-based 3-gene signature following treatment initiation among pulmonary TB patients who were microbiologically cured at the end of treatment.

Results: The 3-gene signature expression level (TB score) changed significantly over time with respect to baseline among 31 pulmonary TB patients. The greatest increase in TB score occurred within the first month of treatment (median fold-increase in TB score: 1.08 [IQR 0.54-1.52]) and plateaued after 4 months of treatment (median TB score: 1.97 [IQR: 1.03-2.33]). The rapid and substantial increase of the TB score in the first month of treatment holds promise for the early identification of patients that respond to TB treatment. The plateau in TB score at 4 months may indicate early clearance of disease and could direct treatment to be shortened. These hypotheses need to be further explored with larger prospective treatment monitoring studies.
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http://dx.doi.org/10.1186/s13104-021-05663-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243580PMC
June 2021

Analytical performance of the Xpert MTB/XDR® assay for tuberculosis and expanded resistance detection.

Diagn Microbiol Infect Dis 2021 Apr 20;101(1):115397. Epub 2021 Apr 20.

FIND, Geneva, Switzerland; Division of Tropical Medicine, Center of Infectious Diseases, University Hospital of Heidelberg, Heidelberg, Germany.

In a manufacturer-independent laboratory validation study, the Xpert MTB/XDR® assay demonstrated equivalent limit of detection to Xpert MTB/RIF®, detected 100% of tested resistance mutations and showed some utility for resistance detection in strain mixtures. The Xpert MTB/XDR assay is a reliable, sensitive assay for tuberculosis and expanded resistance detection.
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http://dx.doi.org/10.1016/j.diagmicrobio.2021.115397DOI Listing
April 2021

Impact of the diagnostic test Xpert MTB/RIF on patient outcomes for tuberculosis.

Cochrane Database Syst Rev 2021 05 6;5:CD012972. Epub 2021 May 6.

University of Basel, Basel, Switzerland.

Background: The World Health Organization (WHO) recommends Xpert MTB/RIF in place of smear microscopy to diagnose tuberculosis (TB), and many countries have adopted it into their diagnostic algorithms. However, it is not clear whether the greater accuracy of the test translates into improved health outcomes.

Objectives: To assess the impact of Xpert MTB/RIF on patient outcomes in people being investigated for tuberculosis.

Search Methods: We searched the following databases, without language restriction, from 2007 to 24 July 2020: Cochrane Infectious Disease Group (CIDG) Specialized Register; CENTRAL; MEDLINE OVID; Embase OVID; CINAHL EBSCO; LILACS BIREME; Science Citation Index Expanded (Web of Science), Social Sciences citation index (Web of Science), and Conference Proceedings Citation Index - Social Science & Humanities (Web of Science). We also searched the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and the Pan African Clinical Trials Registry for ongoing trials.

Selection Criteria: We included individual- and cluster-randomized trials, and before-after studies, in participants being investigated for tuberculosis. We analysed the randomized and non-randomized studies separately.  DATA COLLECTION AND ANALYSIS: For each study, two review authors independently extracted data, using a piloted data extraction tool. We assessed the risk of bias using Cochrane and Effective Practice and Organisation of Care (EPOC) tools. We used random effects meta-analysis to allow for heterogeneity between studies in setting and design.  The certainty of the  evidence in the randomized trials was assessed by GRADE.

Main Results: We included 12 studies: eight were randomized controlled trials (RCTs), and four were before-and-after studies. Most included RCTs had a low risk of bias in most domains of the Cochrane 'Risk of bias' tool. There was inconclusive evidence of an effect of Xpert MTB/RIF on all-cause mortality, both overall (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.75 to 1.05; 5 RCTs, 9932 participants, moderate-certainty evidence), and restricted to studies with six-month follow-up (RR 0.98, 95% CI 0.78 to 1.22; 3 RCTs, 8143 participants; moderate-certainty evidence). There was probably a reduction in mortality in participants known to be infected with HIV (odds ratio (OR) 0.80, 95% CI 0.67 to 0.96; 5 RCTs, 5855 participants; moderate-certainty evidence). It is uncertain whether Xpert MTB/RIF has no or a modest effect on the proportion of participants starting tuberculosis treatment who had a successful treatment outcome (OR) 1.10, 95% CI 0.96 to 1.26; 3RCTs, 4802 participants; moderate-certainty evidence). There was also inconclusive evidence of an effect on the  proportion of participants who were treated for tuberculosis (RR 1.10, 95% CI 0.98 to 1.23; 5 RCTs, 8793 participants; moderate-certainty evidence). The proportion of participants treated for tuberculosis who had bacteriological confirmation was probably higher in the Xpert MTB/RIF group (RR 1.44, 95% CI 1.29 to 1.61; 6 RCTs, 2068 participants; moderate-certainty evidence). The proportion of participants with bacteriological confirmation who were lost to follow-up pre-treatment was probably reduced (RR 0.59, 95% CI 0.41 to 0.85; 3 RCTs, 1217 participants; moderate-certainty evidence).

Authors' Conclusions: We were unable to confidently rule in or rule out the effect on all-cause mortality of using Xpert MTB/RIF rather than smear microscopy. Xpert MTB/RIF probably reduces mortality among participants known to be infected with HIV. We are uncertain whether Xpert MTB/RIF has a modest effect or not on the proportion treated or, among those treated, on the proportion with a successful outcome. It probably does not have a substantial effect on these outcomes. Xpert MTB/RIF probably increases both the proportion of treated participants who had bacteriological confirmation, and the proportion with a laboratory-confirmed diagnosis who were treated. These findings may inform decisions about uptake alongside evidence on cost-effectiveness and implementation.
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http://dx.doi.org/10.1002/14651858.CD012972.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208889PMC
May 2021

A prospective multicentre diagnostic accuracy study for the Truenat tuberculosis assays.

Eur Respir J 2021 May 28. Epub 2021 May 28.

Foundation for Innovative New Diagnostics, Geneva, Switzerland.

Background: Bringing reliable and accurate tuberculosis (TB) diagnosis closer to patients is a key priority for global TB control. Molbio Diagnostics have developed the Truenat point-of-care molecular assays for detection of TB and rifampicin (RIF) resistance.

Methods: We conducted a prospective multicentre diagnostic accuracy study at 19 primary health care centres and seven reference laboratories in Peru, India, Ethiopia and Papua New Guinea to estimate the diagnostic accuracy of the point-of-care Truenat MTB, MTB Plus and MTB-RIF Dx assays for pulmonary TB using culture and phenotypic drug susceptibility testing as the reference standard, compared to Xpert MTB/RIF or Ultra.

Results: Of 1807 enrolled participants with TB signs/symptoms, 24% were culture positive for , of which 15% were RIF-resistant. In microscopy centres, the pooled sensitivity of Truenat MTB and Truenat MTB Plus was 73% [95% CI: 67, 78] and 80% [95% CI: 75, 84], respectively. Among smear-negative specimens, sensitivities were 36% [95% CI: 27, 47] and 47% [95% CI: 37, 58], respectively. Sensitivity of Truenat MTB-RIF was 84% [95% CI: 62, 95]. Truenat assays showed high specificity. Head-to-head comparison in the central reference laboratories suggested that the Truenat assays have similar performance to Xpert MTB/RIF.

Conclusion: We found performance of Molbio's Truenat MTB, MTB plus and MTB-RIF Dx assays to be comparable to that of the Xpert MTB/RIF assay. Performing the Truenat tests in primary health care centres with very limited infrastructure was feasible. These data supported the development of a WHO policy recommendation of the Molbio assays.
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http://dx.doi.org/10.1183/13993003.00526-2021DOI Listing
May 2021

Diagnostic accuracy of a novel point-of-care urine lipoarabinomannan assay for the detection of tuberculosis among adult outpatients in Zambia: a prospective cross-sectional study.

Eur Respir J 2021 Apr 29. Epub 2021 Apr 29.

Foundation for Innovative New diagnostics, Geneva, Switzerland.

Background: A novel, rapid, point-of-care urine-based lipoarabinomannan assay (Fujifilm SILVAMP TB-LAM, "FujiLAM") has previously demonstrated substantially higher sensitivity for tuberculosis (TB) compared to the commercially-available Determine TB-LAM assay using bio-banked specimens. However, FujiLAM has not been prospectively evaluated using fresh urine specimens. Therefore, we determined the diagnostic accuracy of FujiLAM among HIV-positive and HIV-negative outpatients with presumptive TB in Zambia.

Methods: Adult (≥18 years) presumptive TB patients presenting to two outpatient public health facilities in Lusaka, were included. All patients submitted sputa samples for smear-microscopy, Xpert Ultra and Mycobacterial culture and urine samples for the FujiLAM assay. Microbiologically-confirmed TB was defined by the detection of in sputum using culture; this served as the reference standard to assess the diagnostic accuracy of FujiLAM.

Results: 151 adults with paired sputum microbiologic tests and urine FujiLAM results were included; 45% were HIV-positive. Overall, 34/151 (23%) patients had culture-confirmed pulmonary TB. The overall sensitivity and specificity of FujiLAM was 77% (95% CI: 59-89) and 92% (95% CI: 86-96), respectively. FujiLAM's sensitivity among HIV-positive patients was 75% (95% CI: 43-95) compared to 75% (95% CI: 51-91) among HIV-negative patients. The sensitivity of FujiLAM in patients with smear-positive, confirmed pulmonary TB was 87% (95% CI: 60-98) compared to 68% (95%: 43-87) among patients with smear-negative, confirmed pulmonary TB.

Conclusions: FujiLAM demonstrated high sensitivity for the detection of TB among both HIV-positive and HIV-negative adults and also demonstrated good specificity despite the lack of systematic extra-pulmonary sampling to inform a comprehensive microbiological reference standard.
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http://dx.doi.org/10.1183/13993003.03999-2020DOI Listing
April 2021

Quantifying the potential value of antigen-detection rapid diagnostic tests for COVID-19: a modelling analysis.

BMC Med 2021 03 9;19(1):75. Epub 2021 Mar 9.

MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, UK.

Background: Testing plays a critical role in treatment and prevention responses to the COVID-19 pandemic. Compared to nucleic acid tests (NATs), antigen-detection rapid diagnostic tests (Ag-RDTs) can be more accessible, but typically have lower sensitivity and specificity. By quantifying these trade-offs, we aimed to inform decisions about when an Ag-RDT would offer greater public health value than reliance on NAT.

Methods: Following an expert consultation, we selected two use cases for analysis: rapid identification of people with COVID-19 amongst patients admitted with respiratory symptoms in a 'hospital' setting and early identification and isolation of people with mildly symptomatic COVID-19 in a 'community' setting. Using decision analysis, we evaluated the health system cost and health impact (deaths averted and infectious days isolated) of an Ag-RDT-led strategy, compared to a strategy based on NAT and clinical judgement. We adopted a broad range of values for 'contextual' parameters relevant to a range of settings, including the availability of NAT and the performance of clinical judgement. We performed a multivariate sensitivity analysis to all of these parameters.

Results: In a hospital setting, an Ag-RDT-led strategy would avert more deaths than a NAT-based strategy, and at lower cost per death averted, when the sensitivity of clinical judgement is less than 90%, and when NAT results are available in time to inform clinical decision-making for less than 85% of patients. The use of an Ag-RDT is robustly supported in community settings, where it would avert more transmission at lower cost than relying on NAT alone, under a wide range of assumptions.

Conclusions: Despite their imperfect sensitivity and specificity, Ag-RDTs have the potential to be simultaneously more impactful, and have a lower cost per death and infectious person-days averted, than current approaches to COVID-19 diagnostic testing.
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http://dx.doi.org/10.1186/s12916-021-01948-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939929PMC
March 2021

Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis.

Cochrane Database Syst Rev 2021 02 22;2:CD009593. Epub 2021 Feb 22.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, and Firland Northwest TB Center, University of Washington, Seattle, WA, USA.

Background: Xpert MTB/RIF and Xpert MTB/RIF Ultra (Xpert Ultra) are World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. This review builds on our recent extensive Cochrane Review of Xpert MTB/RIF accuracy.

Objectives: To compare the diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for the detection of pulmonary tuberculosis and detection of rifampicin resistance in adults with presumptive pulmonary tuberculosis. For pulmonary tuberculosis and rifampicin resistance, we also investigated potential sources of heterogeneity. We also summarized the frequency of Xpert Ultra trace-positive results, and estimated the accuracy of Xpert Ultra after repeat testing in those with trace-positive results.

Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, LILACS, Scopus, the WHO ICTRP, the ISRCTN registry, and ProQuest to 28 January 2020 with no language restriction.

Selection Criteria: We included diagnostic accuracy studies using respiratory specimens in adults with presumptive pulmonary tuberculosis that directly compared the index tests. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture-based drug susceptibility testing and line probe assays.

Data Collection And Analysis: Two review authors independently extracted data using a standardized form, including data by smear and HIV status. We assessed risk of bias using QUADAS-2 and QUADAS-C. We performed meta-analyses comparing pooled sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection, and separately by reference standard. Most analyses used a bivariate random-effects model. For tuberculosis detection, we estimated accuracy in studies in participants who were not selected based on prior microscopy testing or history of tuberculosis. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarized Xpert Ultra trace results.

Main Results: We identified nine studies (3500 participants): seven had unselected participants (2834 participants). All compared Xpert Ultra and Xpert MTB/RIF for pulmonary tuberculosis detection; seven studies used a paired comparative accuracy design, and two studies used a randomized design. Five studies compared Xpert Ultra and Xpert MTB/RIF for rifampicin resistance detection; four studies used a paired design, and one study used a randomized design. Of the nine included studies, seven (78%) were mainly or exclusively in high tuberculosis burden countries. For pulmonary tuberculosis detection, most studies had low risk of bias in all domains. Pulmonary tuberculosis detection Xpert Ultra pooled sensitivity and specificity (95% credible interval) against culture were 90.9% (86.2 to 94.7) and 95.6% (93.0 to 97.4) (7 studies, 2834 participants; high-certainty evidence) versus Xpert MTB/RIF pooled sensitivity and specificity of 84.7% (78.6 to 89.9) and 98.4% (97.0 to 99.3) (7 studies, 2835 participants; high-certainty evidence). The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at 6.3% (0.1 to 12.8) for sensitivity and -2.7% (-5.7 to -0.5) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss 9 cases, and Xpert MTB/RIF will miss 15 cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 40 with Xpert Ultra and 14 with Xpert MTB/RIF. In smear-negative, culture-positive participants, pooled sensitivity was 77.5% (67.6 to 85.6) for Xpert Ultra versus 60.6% (48.4 to 71.7) for Xpert MTB/RIF; pooled specificity was 95.8% (92.9 to 97.7) for Xpert Ultra versus 98.8% (97.7 to 99.5) for Xpert MTB/RIF (6 studies). In people living with HIV, pooled sensitivity was 87.6% (75.4 to 94.1) for Xpert Ultra versus 74.9% (58.7 to 86.2) for Xpert MTB/RIF; pooled specificity was 92.8% (82.3 to 97.0) for Xpert Ultra versus 99.7% (98.6 to 100.0) for Xpert MTB/RIF (3 studies). In participants with a history of tuberculosis, pooled sensitivity was 84.2% (72.5 to 91.7) for Xpert Ultra versus 81.8% (68.7 to 90.0) for Xpert MTB/RIF; pooled specificity was 88.2% (70.5 to 96.6) for Xpert Ultra versus 97.4% (91.7 to 99.5) for Xpert MTB/RIF (4 studies). The proportion of Ultra trace-positive results ranged from 3.0% to 30.4%. Data were insufficient to estimate the accuracy of Xpert Ultra repeat testing in individuals with initial trace-positive results. Rifampicin resistance detection Pooled sensitivity and specificity were 94.9% (88.9 to 97.9) and 99.1% (97.7 to 99.8) (5 studies, 921 participants; high-certainty evidence) for Xpert Ultra versus 95.3% (90.0 to 98.1) and 98.8% (97.2 to 99.6) (5 studies, 930 participants; high-certainty evidence) for Xpert MTB/RIF. The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at -0.3% (-6.9 to 5.7) for sensitivity and 0.3% (-1.2 to 2.0) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss 5 cases, and Xpert MTB/RIF will miss 5 cases. The number of people wrongly diagnosed with rifampicin resistance would be 8 with Xpert Ultra and 11 with Xpert MTB/RIF. We identified a higher number of rifampicin resistance indeterminate results with Xpert Ultra, pooled proportion 7.6% (2.4 to 21.0) compared to Xpert MTB/RIF pooled proportion 0.8% (0.2 to 2.4). The estimated difference in the pooled proportion of indeterminate rifampicin resistance results for Xpert Ultra versus Xpert MTB/RIF was 6.7% (1.4 to 20.1).

Authors' Conclusions: Xpert Ultra has higher sensitivity and lower specificity than Xpert MTB/RIF for pulmonary tuberculosis, especially in smear-negative participants and people living with HIV. Xpert Ultra specificity was lower than that of Xpert MTB/RIF in participants with a history of tuberculosis. The sensitivity and specificity trade-off would be expected to vary by setting. For detection of rifampicin resistance, Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity. Ultra trace-positive results were common. Xpert Ultra and Xpert MTB/RIF provide accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multidrug-resistant tuberculosis.
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http://dx.doi.org/10.1002/14651858.CD009593.pub5DOI Listing
February 2021

Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin resistance in adults.

Cochrane Database Syst Rev 2021 01 15;1:CD012768. Epub 2021 Jan 15.

Honorary Research Fellow, Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK.

Background: Xpert MTB/RIF Ultra (Xpert Ultra) and Xpert MTB/RIF are World Health Organization (WHO)-recommended rapid nucleic acid amplification tests (NAATs) widely used for simultaneous detection of Mycobacterium tuberculosis complex and rifampicin resistance in sputum. To extend our previous review on extrapulmonary tuberculosis (Kohli 2018), we performed this update to inform updated WHO policy (WHO Consolidated Guidelines (Module 3) 2020).

Objectives: To estimate diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for extrapulmonary tuberculosis and rifampicin resistance in adults with presumptive extrapulmonary tuberculosis.

Search Methods: Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, 2 August 2019 and 28 January 2020 (Xpert Ultra studies), without language restriction.

Selection Criteria: Cross-sectional and cohort studies using non-respiratory specimens. Forms of extrapulmonary tuberculosis: tuberculous meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, disseminated tuberculosis. Reference standards were culture and a study-defined composite reference standard (tuberculosis detection); phenotypic drug susceptibility testing and line probe assays (rifampicin resistance detection).

Data Collection And Analysis: Two review authors independently extracted data and assessed risk of bias and applicability using QUADAS-2. For tuberculosis detection, we performed separate analyses by specimen type and reference standard using the bivariate model to estimate pooled sensitivity and specificity with 95% credible intervals (CrIs). We applied a latent class meta-analysis model to three forms of extrapulmonary tuberculosis. We assessed certainty of evidence using GRADE.

Main Results: 69 studies: 67 evaluated Xpert MTB/RIF and 11 evaluated Xpert Ultra, of which nine evaluated both tests. Most studies were conducted in China, India, South Africa, and Uganda. Overall, risk of bias was low for patient selection, index test, and flow and timing domains, and low (49%) or unclear (43%) for the reference standard domain. Applicability for the patient selection domain was unclear for most studies because we were unsure of the clinical settings. Cerebrospinal fluid Xpert Ultra (6 studies) Xpert Ultra pooled sensitivity and specificity (95% CrI) against culture were 89.4% (79.1 to 95.6) (89 participants; low-certainty evidence) and 91.2% (83.2 to 95.7) (386 participants; moderate-certainty evidence). Of 1000 people where 100 have tuberculous meningitis, 168 would be Xpert Ultra-positive: of these, 79 (47%) would not have tuberculosis (false-positives) and 832 would be Xpert Ultra-negative: of these, 11 (1%) would have tuberculosis (false-negatives). Xpert MTB/RIF (30 studies) Xpert MTB/RIF pooled sensitivity and specificity against culture were 71.1% (62.8 to 79.1) (571 participants; moderate-certainty evidence) and 96.9% (95.4 to 98.0) (2824 participants; high-certainty evidence). Of 1000 people where 100 have tuberculous meningitis, 99 would be Xpert MTB/RIF-positive: of these, 28 (28%) would not have tuberculosis; and 901 would be Xpert MTB/RIF-negative: of these, 29 (3%) would have tuberculosis. Pleural fluid Xpert Ultra (4 studies) Xpert Ultra pooled sensitivity and specificity against culture were 75.0% (58.0 to 86.4) (158 participants; very low-certainty evidence) and 87.0% (63.1 to 97.9) (240 participants; very low-certainty evidence). Of 1000 people where 100 have pleural tuberculosis, 192 would be Xpert Ultra-positive: of these, 117 (61%) would not have tuberculosis; and 808 would be Xpert Ultra-negative: of these, 25 (3%) would have tuberculosis. Xpert MTB/RIF (25 studies) Xpert MTB/RIF pooled sensitivity and specificity against culture were 49.5% (39.8 to 59.9) (644 participants; low-certainty evidence) and 98.9% (97.6 to 99.7) (2421 participants; high-certainty evidence). Of 1000 people where 100 have pleural tuberculosis, 60 would be Xpert MTB/RIF-positive: of these, 10 (17%) would not have tuberculosis; and 940 would be Xpert MTB/RIF-negative: of these, 50 (5%) would have tuberculosis. Lymph node aspirate Xpert Ultra (1 study) Xpert Ultra sensitivity and specificity (95% confidence interval) against composite reference standard were 70% (51 to 85) (30 participants; very low-certainty evidence) and 100% (92 to 100) (43 participants; low-certainty evidence). Of 1000 people where 100 have lymph node tuberculosis, 70 would be Xpert Ultra-positive and 0 (0%) would not have tuberculosis; 930 would be Xpert Ultra-negative and 30 (3%) would have tuberculosis. Xpert MTB/RIF (4 studies) Xpert MTB/RIF pooled sensitivity and specificity against composite reference standard were 81.6% (61.9 to 93.3) (377 participants; low-certainty evidence) and 96.4% (91.3 to 98.6) (302 participants; low-certainty evidence). Of 1000 people where 100 have lymph node tuberculosis, 118 would be Xpert MTB/RIF-positive and 37 (31%) would not have tuberculosis; 882 would be Xpert MTB/RIF-negative and 19 (2%) would have tuberculosis. In lymph node aspirate, Xpert MTB/RIF pooled specificity against culture was 86.2% (78.0 to 92.3), lower than that against a composite reference standard. Using the latent class model, Xpert MTB/RIF pooled specificity was 99.5% (99.1 to 99.7), similar to that observed with a composite reference standard. Rifampicin resistance Xpert Ultra (4 studies) Xpert Ultra pooled sensitivity and specificity were 100.0% (95.1 to 100.0), (24 participants; low-certainty evidence) and 100.0% (99.0 to 100.0) (105 participants; moderate-certainty evidence). Of 1000 people where 100 have rifampicin resistance, 100 would be Xpert Ultra-positive (resistant): of these, zero (0%) would not have rifampicin resistance; and 900 would be Xpert Ultra-negative (susceptible): of these, zero (0%) would have rifampicin resistance. Xpert MTB/RIF (19 studies) Xpert MTB/RIF pooled sensitivity and specificity were 96.5% (91.9 to 98.8) (148 participants; high-certainty evidence) and 99.1% (98.0 to 99.7) (822 participants; high-certainty evidence). Of 1000 people where 100 have rifampicin resistance, 105 would be Xpert MTB/RIF-positive (resistant): of these, 8 (8%) would not have rifampicin resistance; and 895 would be Xpert MTB/RIF-negative (susceptible): of these, 3 (0.3%) would have rifampicin resistance.

Authors' Conclusions: Xpert Ultra and Xpert MTB/RIF may be helpful in diagnosing extrapulmonary tuberculosis. Sensitivity varies across different extrapulmonary specimens: while for most specimens specificity is high, the tests rarely yield a positive result for people without tuberculosis. For tuberculous meningitis, Xpert Ultra had higher sensitivity and lower specificity than Xpert MTB/RIF against culture. Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity for rifampicin resistance. Future research should acknowledge the concern associated with culture as a reference standard in paucibacillary specimens and consider ways to address this limitation.
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http://dx.doi.org/10.1002/14651858.CD012768.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078545PMC
January 2021

Comparing accuracy of lipoarabinomannan urine tests for diagnosis of pulmonary tuberculosis in children from four African countries: a cross-sectional study.

Lancet Infect Dis 2021 03 11;21(3):376-384. Epub 2020 Dec 11.

FIND (Foundation for Innovative New Diagnostics), Geneva, Switzerland; Division of Tropical Medicine, Centre of Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany.

Background: A sensitive and specific non-sputum-based test would be groundbreaking for the diagnosis of childhood tuberculosis. We assessed side by side the diagnostic accuracy of the urine-based lipoarabinomannan assays Fujifilm SILVAMP TB LAM (FujiLAM) and Alere Determine TB LAM Ag (AlereLAM) for detection of childhood tuberculosis.

Methods: In this cross-sectional study, we tested urine samples from children younger than 15 years with presumed pulmonary tuberculosis. Children were consecutively recruited from four dedicated outpatient childhood tuberculosis clinics in The Gambia, Mali, Nigeria, and Tanzania. Biobanked urine samples were thawed and tested using FujiLAM and AlereLAM assays. We measured diagnostic performance against a microbiological reference standard (confirmed tuberculosis) and a composite reference standard (confirmed and unconfirmed tuberculosis). Sensitivity and specificity were estimated with bivariate random-effects meta-analyses.

Findings: Between July 1, 2017, and Dec 1, 2018, we obtained and stored urine samples from 415 children. 63 (15%) children had confirmed tuberculosis, 113 (27%) had unconfirmed tuberculosis, and 239 (58%) were unlikely to have tuberculosis. 61 children were HIV-positive (prevalence 15%). Using the microbiological reference standard, the sensitivity of FujiLAM was 64·9% (95% CI 43·7-85·2; positive in 40 of 63 confirmed samples) and the sensitivity of AlereLAM was 30·7% (8·6-61·6; 19 of 63). The specificity of FujiLAM was 83·8% (95% CI 76·5-89·4; negative in 297 of 352 unconfirmed and unlikely samples) and the specificity of AlereLAM was 87·8% (79·0-93·7; 312 of 352). Against the composite reference standard, both assays had decreased sensitivity; the sensitivity of FujiLAM was 32·9% (95% CI 24·6-41·9; positive in 58 of 176 confirmed and unconfirmed samples) and the sensitivity of AlereLAM was 20·2% (12·3-29·4; 36 of 176). The specificity of FujiLAM was 83·3% (95% CI 71·8-91·7; negative in 202 of 239 unlikely samples) and the specificity of AlereLAM was 90·0% (81·6-95·6; 216 of 239).

Interpretation: By comparison with AlereLAM, FujiLAM showed higher sensitivity and similar specificity. FujiLAM could potentially add value to the rapid diagnosis of tuberculosis in children.

Funding: German Federal Ministry of Education and Research, the Global Health Innovative Technology Fund, the UK Research and Innovation Global Challenges Research Fund, and the UK Medical Research Council.
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http://dx.doi.org/10.1016/S1473-3099(20)30598-3DOI Listing
March 2021

The potential impact of urine-LAM diagnostics on tuberculosis incidence and mortality: A modelling analysis.

PLoS Med 2020 12 11;17(12):e1003466. Epub 2020 Dec 11.

MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, United Kingdom.

Background: Lateral flow urine lipoarabinomannan (LAM) tests could offer important new opportunities for the early detection of tuberculosis (TB). The currently licensed LAM test, Alere Determine TB LAM Ag ('LF-LAM'), performs best in the sickest people living with HIV (PLHIV). However, the technology continues to improve, with newer LAM tests, such as Fujifilm SILVAMP TB LAM ('SILVAMP-LAM') showing improved sensitivity, including amongst HIV-negative patients. It is important to anticipate the epidemiological impact that current and future LAM tests may have on TB incidence and mortality.

Methods And Findings: Concentrating on South Africa, we examined the impact that widening LAM test eligibility would have on TB incidence and mortality. We developed a mathematical model of TB transmission to project the impact of LAM tests, distinguishing 'current' tests (with sensitivity consistent with LF-LAM), from hypothetical 'future' tests (having sensitivity consistent with SILVAMP-LAM). We modelled the impact of both tests, assuming full adoption of the 2019 WHO guidelines for the use of these tests amongst those receiving HIV care. We also simulated the hypothetical deployment of future LAM tests for all people presenting to care with TB symptoms, not restricted to PLHIV. Our model projects that 2,700,000 (95% credible interval [CrI] 2,000,000-3,600,000) and 420,000 (95% CrI 350,000-520,000) cumulative TB incident cases and deaths, respectively, would occur between 2020 and 2035 if the status quo is maintained. Relative to this comparator, current and future LAM tests would respectively avert 54 (95% CrI 33-86) and 90 (95% CrI 55-145) TB deaths amongst inpatients between 2020 and 2035, i.e., reductions of 5% (95% CrI 4%-6%) and 9% (95% CrI 7%-11%) in inpatient TB mortality. This impact in absolute deaths averted doubles if testing is expanded to include outpatients, yet remains <1% of country-level TB deaths. Similar patterns apply to incidence results. However, deploying a future LAM test for all people presenting to care with TB symptoms would avert 470,000 (95% CrI 220,000-870,000) incident TB cases (18% reduction, 95% CrI 9%-29%) and 120,000 (95% CrI 69,000-210,000) deaths (30% reduction, 95% CrI 18%-44%) between 2020 and 2035. Notably, this increase in impact arises largely from diagnosis of TB amongst those with HIV who are not yet in HIV care, and who would thus be ineligible for a LAM test under current guidelines. Qualitatively similar results apply under an alternative comparator assuming expanded use of GeneXpert MTB/RIF ('Xpert') for TB diagnosis. Sensitivity analysis demonstrates qualitatively similar results in a setting like Kenya, which also has a generalised HIV epidemic, but a lower burden of HIV/TB coinfection. Amongst limitations of this analysis, we do not address the cost or cost-effectiveness of future tests. Our model neglects drug resistance and focuses on the country-level epidemic, thus ignoring subnational variations in HIV and TB burden.

Conclusions: These results suggest that LAM tests could have an important effect in averting TB deaths amongst PLHIV with advanced disease. However, achieving population-level impact on the TB epidemic, even in high-HIV-burden settings, will require future LAM tests to have sufficient performance to be deployed more broadly than in HIV care.
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http://dx.doi.org/10.1371/journal.pmed.1003466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732057PMC
December 2020

Diagnostic Accuracy Study of a Novel Blood-Based Assay for Identification of Tuberculosis in People Living with HIV.

J Clin Microbiol 2021 02 18;59(3). Epub 2021 Feb 18.

FIND, Geneva, Switzerland.

A nonsputum triage test to rule out tuberculosis (TB) disease is a WHO high-priority diagnostic, and a combinatory score based on a 3-gene host signature has shown promise in discriminating TB from other illnesses. We evaluated the accuracy of an early-prototype cartridge assay ("Xpert MTB Host Response" or Xpert-MTB-HR-Prototype) of this 3-gene signature on biobanked blood samples from people living with HIV (PLHIV) against a comprehensive microbiological reference standard (CMRS) and against Xpert MTB/RIF on the first sputum sample alone. We depict results based on performance targets set by the WHO in comparison with a laboratory-based C-reactive protein (CRP) assay. Of 201 patients included, 67 were culture positive for The areas under the concentration-time curve (AUCs) for Xpert-MTB-HR-Prototype were 0.89 (confidence interval [CI], 0.83 to 0.94) against the CMRS and 0.94 (CI, 0.89 to 0.98) against Xpert MTB/RIF. Considering Xpert-MTB-HR-Prototype as a triage test (at the nearest upper value of sensitivity to 90%), specificities were 55.8% (CI, 47.2 to 64.1%) compared to the CMRS and 85.9% (CI, 79.3 to 90.7%) compared to Xpert MTB/RIF as confirmatory tests. Considering Xpert-MTB-HR-Prototype as a stand-alone diagnostic test, at a specificity near 95%, the test achieved a sensitivity of 65.7% (CI, 53.7 to 75.9%), while the CRP assay achieved a sensitivity of only 13.6% (CI, 7.3 to 23.4%). In this first accuracy study of a prototype blood-based host marker assay, we show the possible value of the assay for triage and diagnosis in PLHIV.
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http://dx.doi.org/10.1128/JCM.01643-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106701PMC
February 2021

"I got tested at home, the help came to me": acceptability and feasibility of home-based TB testing of household contacts using portable molecular diagnostics in South Africa.

Trop Med Int Health 2021 03 4;26(3):343-354. Epub 2021 Jan 4.

Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA.

Objective: The effectiveness of household contact investigations is limited by low referral uptake for clinic-based TB testing by symptomatic household contacts. We qualitatively investigated the acceptability and perceived benefits of home-based TB testing using a portable GeneXpert-I instrument (GX-I) in an urban South African township.

Methods: In-depth interviews were conducted with household contacts tested and those that observed testing. Semi-structured interviews explored household contact's understanding of TB, perceptions of the GX-I device and testing procedures, confidentiality, willingness to refer others, and views on home- vs. clinic-based testing. Focus group discussions with home-based TB testing implementing staff assessed operational considerations for scale-up. Data were analysed using a constant comparison approach to qualitatively evaluate the acceptability and feasibility of home-based TB testing.

Results: Thirty in-depth interviews and two focus group discussions were conducted. Observing one's own sputum being tested resulted in an emergent trust in home-based TB testing, the GX-I device and one's test results. Home-based TB testing was considered convenient, helped to overcome apathy towards testing and mitigated barriers to clinic-based testing. Perceptions that home-based TB testing contributes to improved household and community health resulted in an emergent theme of alleviation of health insecurities. Operational concerns regarding inadvertent disclosure of one's diagnosis to household members and time spent in people's homes were identified.

Conclusions: Home-based TB testing was acceptable and feasible. Individuals expressed belief in the machine by being able to witness the testing process. Though most themes mirrored qualitative studies of home-based HIV testing, the alleviation of health insecurities theme is unique to home-based TB testing. Future research must evaluate the impact of home-based TB testing on case finding yield, time-to-treatment initiation and household outcomes.
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http://dx.doi.org/10.1111/tmi.13533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060432PMC
March 2021

Comparative Analytical Evaluation of Four Centralized Platforms for the Detection of Mycobacterium tuberculosis Complex and Resistance to Rifampicin and Isoniazid.

J Clin Microbiol 2021 02 18;59(3). Epub 2021 Feb 18.

Foundation for Innovative New Diagnostics, Geneva, Switzerland.

Failure to rapidly identify drug-resistant tuberculosis (TB) increases the risk of patient mismanagement, the amplification of drug resistance, and ongoing transmission. We generated comparative analytical data for four automated assays for the detection of TB and multidrug-resistant TB (MDR-TB): Abbott RealTie MTB and MTB RIF/INH (Abbott), Hain Lifescience FluoroType MTBDR (Hain), BD Max MDR-TB (BD), and Roche cobas MTB and MTB-RIF/INH (Roche). We included Xpert MTB/RIF (Xpert) and GenoType MTBDR as comparators for TB and drug resistance detection, respectively. We assessed analytical sensitivity for the detection of the complex using inactivated strains ( H37Rv and ) spiked into TB-negative sputa and computed the 95% limits of detection (LOD). We assessed the accuracy of rifampicin and isoniazid resistance detection using well-characterized strains with high-confidence mutations accounting for >85% of first-line resistance mechanisms globally. For H37Rv and , we measured LOD values of 3,781 and 2,926 (Xpert), 322 and 2,182 (Abbott), 826 and 4,301 (BD), 10,398 and 23,139 (Hain), and 2,416 and 2,136 (Roche) genomes/ml, respectively. Assays targeting multicopy genes or targets (Abbott, BD, and Roche) showed increased analytical sensitivity compared to Xpert. Quantification of the panel by quantitative real-time PCR prevents the determination of absolute values, and results reported here can be interpreted for comparison purposes only. All assays showed accuracy comparable to that of Genotype MTBDR for the detection of rifampicin and isoniazid resistance. The data from this analytical study suggest that the assays may have clinical performances similar to those of WHO-recommended molecular TB and MDR-TB assays.
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http://dx.doi.org/10.1128/JCM.02168-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106716PMC
February 2021

Diagnostic accuracy of centralised assays for TB detection and detection of resistance to rifampicin and isoniazid: a systematic review and meta-analysis.

Eur Respir J 2021 02 4;57(2). Epub 2021 Feb 4.

Foundation for Innovative New Diagnostics, Geneva, Switzerland.

Various diagnostic companies have developed high throughput molecular assays for tuberculosis (TB) and resistance detection for rifampicin and isoniazid. We performed a systematic review and meta-analyses to assess the diagnostic accuracy of five of these tests for pulmonary specimens. The tests included were Abbott RealTime MTB, Abbott RealTime RIF/INH, FluoroType MTB, FluoroType MTDBR and BD Max MDR-TB assay.A comprehensive search of six databases for relevant citations was performed. Cross-sectional, case-control, cohort studies, and randomised controlled trials of any of the index tests were included. Respiratory specimens (such as sputum, bronchoalveolar lavage, tracheal aspirate, ) or their culture isolates.A total of 21 included studies contributed 26 datasets. We could only meta-analyse data for three of the five assays identified, as data were limited for the remaining two. For TB detection, the included assays had a sensitivity of 91% or more and the specificity ranged from 97% to 100%. For rifampicin resistance detection, all the included assays had a sensitivity of more than 92%, with a specificity of 99-100%. Sensitivity for isoniazid resistance detection varied from 70 to 91%, with higher specificity of 99-100% across all index tests. Studies that included head-to-head comparisons of these assays with Xpert MTB/RIF for detection of TB and rifampicin resistance suggested comparable diagnostic accuracy.In people with symptoms of pulmonary TB, the centralised molecular assays demonstrate comparable diagnostic accuracy for detection of TB, rifampicin and isoniazid resistance to Xpert MTB/RIF assay, a WHO recommended molecular test.
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http://dx.doi.org/10.1183/13993003.00747-2020DOI Listing
February 2021

Accuracy of a Novel Urine Test, Fujifilm SILVAMP Tuberculosis Lipoarabinomannan, for the Diagnosis of Pulmonary Tuberculosis in Children.

Clin Infect Dis 2021 05;72(9):e280-e288

Foundation for Innovative New Diagnostics, Geneva, Switzerland.

Background: An accurate point-of-care test for tuberculosis (TB) in children remains an elusive goal. Recent evaluation of a novel point-of-care urinary lipoarabinomannan test, Fujifilm SILVAMP Tuberculosis Lipoarabinomannan (FujiLAM), in adults living with human immunodeficiency virus (HIV) showed significantly superior sensitivity than the current Alere Determine Tuberculosis Lipoarabinomannan test (AlereLAM). We therefore compared the accuracy of FujiLAM and AlereLAM in children with suspected TB.

Methods: Children hospitalized with suspected TB in Cape Town, South Africa, were enrolled (consecutive admissions plus enrichment for a group of children living with HIV and with TB), their urine was collected and biobanked, and their sputum was tested with mycobacterial culture and Xpert MTB/RIF or Xpert MTB/RIF Ultra. Biobanked urine was subsequently batch tested with FujiLAM and AlereLAM. Children were categorized as having microbiologically confirmed TB, unconfirmed TB (clinically diagnosed), or unlikely TB.

Results: A total of 204 children were enrolled and had valid results from both index tests, as well as sputum microbiological testing. Compared to a microbiological reference standard, the sensitivity of FujiLAM and AlereLAM was similar (42% and 50%, respectively), but lower than that of Xpert MTB/RIF of sputum (74%). The sensitivity of FujiLAM was higher in children living with HIV (60%) and malnourished children (62%). The specificity of FujiLAM was substantially higher than that of AlereLAM (92% vs 66%, respectively). The specificity of both tests was higher in children 2 years or older (FujiLAM, 96%; AlereLAM, 72%).

Conclusions: The high specificity of FujiLAM suggests utility as a "rule-in" test for children with a high pretest probability of TB, including hospitalized children living with HIV or with malnutrition.
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http://dx.doi.org/10.1093/cid/ciaa1052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096212PMC
May 2021

Advances in Molecular Diagnosis of Tuberculosis.

J Clin Microbiol 2020 09 22;58(10). Epub 2020 Sep 22.

Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada

Molecular tests for tuberculosis (TB) have the potential to help reach the three million people with TB who are undiagnosed or not reported each year and to improve the quality of care TB patients receive by providing accurate, quick results, including rapid drug-susceptibility testing. The World Health Organization (WHO) has recommended the use of molecular nucleic acid amplification tests (NAATs) tests for TB detection instead of smear microscopy, as they are able to detect TB more accurately, particularly in patients with paucibacillary disease and in people living with HIV. Importantly, some of these WHO-endorsed tests can detect mycobacterial gene mutations associated with anti-TB drug resistance, allowing clinicians to tailor effective TB treatment. Currently, a wide array of molecular tests for TB detection is being developed and evaluated, and while some tests are intended for reference laboratory use, others are being aimed at the point-of-care and peripheral health care settings. Notably, there is an emergence of molecular tests designed, manufactured, and rolled out in countries with high TB burden, of which some are explicitly aimed for near-patient placement. These developments should increase access to molecular TB testing for larger patient populations. With respect to drug susceptibility testing, NAATs and next-generation sequencing can provide results substantially faster than traditional phenotypic culture. Here, we review recent advances and developments in molecular tests for detecting TB as well as anti-TB drug resistance.
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http://dx.doi.org/10.1128/JCM.01582-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512154PMC
September 2020

Diagnostic accuracy of 3 urine lipoarabinomannan tuberculosis assays in HIV-negative outpatients.

J Clin Invest 2020 11;130(11):5756-5764

FIND, Geneva, Switzerland.

BACKGROUNDInadequate tuberculosis (TB) diagnostics are a major hurdle in the reduction of disease burden, and accurate point-of-care tests (POCTs) are urgently needed. We assessed the diagnostic accuracy of Fujifilm SILVAMP TB lipoarabinomannan (FujiLAM) POCT for TB diagnosis in HIV-negative outpatients and compared it with Alere Determine TB LAM Ag (AlereLAM) POCT and a laboratory-based ultrasensitive electrochemiluminescence LAM research assay (EclLAM).METHODSIn this multicenter diagnostic test accuracy study, we recruited HIV-negative adults with symptoms suggestive of pulmonary TB presenting to outpatient health care centers in Peru and South Africa. Urine samples were tested using FujiLAM, AlereLAM, and EclLAM, and the diagnostic accuracy was assessed against a microbiological reference standard (MRS) and a composite reference standard.RESULTSThree hundred seventy-two HIV-negative participants were included and the prevalence of microbiologically confirmed TB was 30%. Compared with the MRS, the sensitivities of AlereLAM, FujiLAM, and EclLAM were 10.8% (95% confidence interval [CI] 6.3%-18.0%), 53.2% (95% CI 43.9%-62.1%), and 66.7% (95% CI 57.5%-74.7%), respectively. The specificities of AlereLAM, FujiLAM, and EclLAM were 92.3% (95% CI 88.5%-95.0%), 98.9% (95% CI 96.7%-99.6%), and 98.1% (95% CI 95.6%-99.2%), respectively. Positive likelihood ratios of AlereLAM, FujiLAM, and EclLAM were 1.4, 46.2, and 34.8, respectively, and positive predictive values were 37.5%, 95.2%, and 93.7%, respectively.CONCLUSIONCompared with AlereLAM, FujiLAM detected 5 times more patients with TB in HIV-negative participants, had a high positive predictive value, and has the potential to improve rapid diagnosis of TB at the point-of-care. EclLAM demonstrated that additional sensitivity gains are possible, which highlights LAM's potential as a biomarker. Additional research is required to assess FujiLAM's performance in prospective cohorts, its cost-effectiveness, and its impact in real-world clinical settings.FUNDINGGlobal Health Innovative Technology Fund, the UK Department for International Development, the Dutch Ministry of Foreign Affairs, the Bill and Melinda Gates Foundation, the Australian Department of Foreign Affairs and Trade, the German Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, and the NIH and National Institute of Allergy and Infectious Diseases.
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http://dx.doi.org/10.1172/JCI140461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598043PMC
November 2020

Effect of history of tuberculosis on specificity of Xpert MTB/RIF.

Eur Respir J 2020 09 24;56(3). Epub 2020 Sep 24.

Foundation for Innovative New Diagnostics, Geneva, Switzerland.

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http://dx.doi.org/10.1183/13993003.00343-2020DOI Listing
September 2020

Diagnostic accuracy of a novel tuberculosis point-of-care urine lipoarabinomannan assay for people living with HIV: A meta-analysis of individual in- and outpatient data.

PLoS Med 2020 05 1;17(5):e1003113. Epub 2020 May 1.

FIND, Geneva, Switzerland.

Background: Tuberculosis (TB) is the most common cause of death in people living with HIV (PLHIV), yet TB often goes undiagnosed since many patients are not able to produce a sputum specimen, and traditional diagnostics are costly or unavailable. A novel, rapid lateral flow assay, Fujifilm SILVAMP TB LAM (SILVAMP-LAM), detects the presence of TB lipoarabinomannan (LAM) in urine, and is substantially more sensitive for diagnosing TB in PLHIV than an earlier LAM assay (Alere Determine TB LAM lateral flow assay [LF-LAM]). Here, we present an individual participant data meta-analysis of the diagnostic accuracy of SILVAMP-LAM in adult PLHIV, including both published and unpublished data.

Methods And Findings: Adult PLHIV (≥18 years) were assessed in 5 prospective cohort studies in South Africa (3 cohorts), Vietnam, and Ghana, carried out during 2012 to 2017. Of the 1,595 PLHIV who met eligibility criteria, the majority (61%) were inpatients, median age was 37 years (IQR 30-43), 43% had a CD4 count ≤ 100 cells/μl, and 35% were receiving antiretroviral therapy. Most participants (94%) had a positive WHO symptom screen for TB on enrollment, and 45% were diagnosed with microbiologically confirmed TB, using mycobacterial culture or Xpert MTB/RIF testing of sputum, urine, or blood. Previously published data from inpatients were combined with unpublished data from outpatients. Biobanked urine samples were tested, using blinded double reading, with SILVAMP-LAM and LF-LAM. Applying a microbiological reference standard for assessment of sensitivity, the overall sensitivity for TB detection was 70.7% (95% CI 59.0%-80.8%) for SILVAMP-LAM compared to 34.9% (95% CI 19.5%-50.9%) for LF-LAM. Using a composite reference standard (which included patients with both microbiologically confirmed as well as clinically diagnosed TB), SILVAMP-LAM sensitivity was 65.8% (95% CI 55.9%-74.6%), and that of LF-LAM 31.4% (95% CI 19.1%-43.7%). In patients with CD4 count ≤ 100 cells/μl, SILVAMP-LAM sensitivity was 87.1% (95% CI 79.3%-93.6%), compared to 56.0% (95% CI 43.9%-64.9%) for LF-LAM. In patients with CD4 count 101-200 cells/μl, SILVAMP-LAM sensitivity was 62.7% (95% CI 52.4%-71.9%), compared to 25.3% (95% CI 15.8%-34.9%) for LF-LAM. In those with CD4 count > 200 cells/μl, SILVAMP-LAM sensitivity was 43.9% (95% CI 34.3%-53.9%), compared to 10.9% (95% CI 5.2%-18.4%) for LF-LAM. Using a microbiological reference standard, the specificity of SILVAMP-LAM was 90.9% (95% CI 87.2%-93.7%), and that of LF-LAM 95.3% (95% CI 92.2%-97.7%). Limitations of this study include the use of biobanked, rather than fresh urine samples, and testing by skilled laboratory technicians in research laboratories, rather than at the point of care.

Conclusions: In this study, we found that SILVAMP-LAM identified a substantially higher proportion of TB patients in PLHIV than LF-LAM. The sensitivity of SILVAMP-LAM was highest in patients with CD4 count ≤ 100 cells/μl. Further work is needed to demonstrate accuracy when implemented as a point-of-care test.
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http://dx.doi.org/10.1371/journal.pmed.1003113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194366PMC
May 2020

Xpert MTB/RIF Ultra and Xpert MTB/RIF for diagnosis of tuberculosis in an HIV-endemic setting with a high burden of previous tuberculosis: a two-cohort diagnostic accuracy study.

Lancet Respir Med 2020 04 14;8(4):368-382. Epub 2020 Feb 14.

NRF-DST Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa. Electronic address:

Background: Xpert MTB/RIF Ultra (Ultra) is a new test for tuberculosis undergoing global roll-out. We assessed the performance of Ultra compared with Xpert MTB/RIF (Xpert) in an HIV-endemic setting where previous tuberculosis is frequent and current test performance is suboptimal.

Methods: In this two-cohort diagnostic accuracy study, we used sputum samples from patients in South Africa to evaluate the accuracy of Ultra and Xpert against a single culture reference standard. For the first cohort (cohort A), we recruited adults (aged ≥18 years) with symptoms of presumptive tuberculosis at Scottsdene clinic in Cape Town, South Africa. We collected three sputum samples from each patient in cohort A, two at the first visit of which one was tested using Xpert and the other was tested using culture, and one sample the next morning which was tested using Ultra. In a separate cohort of patients with presumptive tuberculosis and recent previous tuberculosis (≤2 years) who had submitted sputum samples to the National Health Laboratory Services (cohort B), decontaminated sediments were, after processing, randomly allocated (1:1) for testing with Ultra or Xpert. For both cohorts we calculated the sensitivity and specificity of Ultra and Xpert and evaluated the effects of different methods of interpreting Ultra trace results.

Findings: Between Feb 6, 2016, and Feb 2, 2018, we recruited 302 people into cohort A, all of whom provided sputum samples and 239 were included in the head-to-head analyses of Ultra and Xpert. For cohort B, we collected sputum samples from eligible patients who had submitted samples between Dec 6, 2016, and Dec 21, 2017, to give a cohort of 831 samples, of which 352 were eligible for inclusion in analyses and randomly assigned to Ultra (n=173) or Xpert (n=179). In cohort A, Ultra gave more non-actionable results (not positive or negative) than did Xpert (28 [10%] 275 vs 14 [5%] 301; p=0·011). In the head-to-head analysis, in smear-negative patients, sensitivity of Ultra was 80% (95% CI 64-90) and of Xpert was 73% (57-85; p=0·45). Overall, specificity of Ultra was lower than that of Xpert (90% [84-94] vs 99% [95-100]; p=0·001). In cohort B, overall sensitivity was 92% (81-98) for Xpert versus 86% (73-95; p=0·36) for Ultra and overall specificity was 69% (60-77) for Ultra versus 84% (78-91; p=0·005) for Xpert. Ultra specificity estimates improved after reclassification of results with the lowest Ultra-positive semiquantitation category (trace) to negative (15% [8-22]). In cohort A, the positive predictive value (PPV) for Ultra was 78% (67-87) and for Xpert was 96% (87-99; p=0·004); in cohort B, the PPV for Ultra was 50% (43-57) and for Xpert was 70% (61-78; p=0·014). Ultra PPV estimates in previously treated patients were low: at 15% tuberculosis prevalence, half of Ultra-positive patients with presumptive tuberculosis would be culture negative, increasing to approximately 70% in patients with recent previous tuberculosis. In cohort B, 21 (28%) of 76 samples that were Ultra positive were rifampicin indeterminate (all trace) and, like cohort A, most were culture negative (19 [90%] of 21).

Interpretation: In a setting with a high burden of previous tuberculosis, Ultra generated more non-actionable results and had diminished specificity compared with Xpert. In patients with recent previous tuberculosis, a quarter of Ultra-positive samples were indeterminate for rifampicin resistance and culture negative, suggesting that additional drug-resistance testing will probably be unsuccessful. Our data have implications for the handling of Ultra-positive results in patients with previous tuberculosis in high burden settings.

Funding: South African Medical Research Council, the EDCTP2 program, and the Faculty of Medicine and Health Sciences, Stellenbosch University.
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http://dx.doi.org/10.1016/S2213-2600(19)30370-4DOI Listing
April 2020

Diagnostic Accuracy of a Novel and Rapid Lipoarabinomannan Test for Diagnosing Tuberculosis Among People With Human Immunodeficiency Virus.

Open Forum Infect Dis 2020 Jan 21;7(1):ofz530. Epub 2019 Dec 21.

FIND, Geneva, Switzerland.

Background: The novel Fujifilm SILVAMP TB-LAM (FujiLAM) assay detects mycobacterial lipoarabinomannan in urine and has demonstrated superior sensitivity to the Alere Determine TB-LAM Ag (AlereLAM) assay for detection of tuberculosis among hospitalized people with human immunodeficiency virus (PWH). This is the first study to evaluate the assay among a broad population referred for antiretroviral therapy including both outpatients (mainly) and inpatients.

Methods: We assessed diagnostic accuracy of FujiLAM and AlereLAM assays in biobanked urine samples from a cohort of adults referred for antiretroviral therapy in Ghana against a microbiological and a composite (including clinical judgement) reference standard, and we assessed the association of FujiLAM test positivity with mortality.

Results: We evaluated urine samples from 532 PWH (462 outpatients, 70 inpatients). Against a microbiological reference standard, the sensitivity of FujiLAM was 74.2% (95% confidence interval [CI], 62.0-84.2) compared to 53.0% (95% CI, 40.3-65.4) for AlereLAM, a difference of 21.2% (CI, 13.1-32.5). Specificity was 89.3% (95% CI, 85.8-92.2) versus 95.6% (95% CI, 93.0-97.4) for FujiLAM and AlereLAM, a difference of -6.3% (95% CI -9.6 to -3.3). Specificity estimates for FujiLAM increased markedly to 98.8% (95% CI, 96.6-99.8) in patients with CD4 >100 cells/µL and when using a composite reference standard. FujiLAM test positivity was associated with increased cumulative risk of mortality at 6 months (hazard ratio, 4.80; 95% CI, 3.01-7.64).

Conclusions: FujiLAM offers significantly increased diagnostic sensitivity in comparison to AlereLAM. Specificity estimates for FujiLAM were lower than for AlereLAM but were affected by the limited ability of the reference standard to correctly diagnose tuberculosis in individuals with low CD4 counts.
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http://dx.doi.org/10.1093/ofid/ofz530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966242PMC
January 2020

"SILVAMP TB LAM" Rapid Urine Tuberculosis Test Predicts Mortality in Patients Hospitalized With Human Immunodeficiency Virus in South Africa.

Clin Infect Dis 2020 11;71(8):1973-1976

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa.

Reducing diagnostic delay is key toward decreasing tuberculosis-associated deaths in people living with human immunodeficiency virus. In tuberculosis patients with retrospective urine testing, the point-of-care Fujifilm SILVAMP TB LAM (FujiLAM) could have rapidly diagnosed tuberculosis in up to 89% who died. In FujiLAM negative patients, the probability of 12-week survival was 86-97%.
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http://dx.doi.org/10.1093/cid/ciaa024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240995PMC
November 2020

Guidance for Studies Evaluating the Accuracy of Tuberculosis Triage Tests.

J Infect Dis 2019 10;220(220 Suppl 3):S116-S125

University Hospital Heidelberg, Division of Tropical Medicine, Centre of Infectious Diseases, Germany.

Approximately 3.6 million cases of active tuberculosis (TB) go potentially undiagnosed annually, partly due to limited access to confirmatory diagnostic tests, such as molecular assays or mycobacterial culture, in community and primary healthcare settings. This article provides guidance for TB triage test evaluations. A TB triage test is designed for use in people with TB symptoms and/or significant risk factors for TB. Triage tests are simple and low-cost tests aiming to improve ease of access and implementation (compared with confirmatory tests) and decrease the proportion of patients requiring more expensive confirmatory testing. Evaluation of triage tests should occur in settings of intended use, such as community and primary healthcare centers. Important considerations for triage test evaluation include study design, population, sample type, test throughput, use of thresholds, reference standard (ideally culture), and specimen flow. The impact of a triage test will depend heavily on issues beyond accuracy, primarily centered on implementation.
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http://dx.doi.org/10.1093/infdis/jiz243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6782021PMC
October 2019

Guidance for Studies Evaluating the Accuracy of Rapid Tuberculosis Drug-Susceptibility Tests.

J Infect Dis 2019 10;220(220 Suppl 3):S126-S135

FIND, Geneva, Switzerland.

The development and implementation of rapid molecular diagnostics for tuberculosis (TB) drug-susceptibility testing is critical to inform treatment of patients and to prevent the emergence and spread of resistance. Optimal trial planning for existing tests and those in development will be critical to rapidly gather the evidence necessary to inform World Health Organization review and to support potential policy recommendations. The evidence necessary includes an assessment of the performance for TB and resistance detection as well as an assessment of the operational characteristics of these platforms. The performance assessment should include analytical studies to confirm the limit of detection and assay ability to detect mutations conferring resistance across globally representative strains. The analytical evaluation is typically followed by multisite clinical evaluation studies to confirm diagnostic performance in sites and populations of intended use. This paper summarizes the considerations for the design of these analytical and clinical studies.
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http://dx.doi.org/10.1093/infdis/jiz106DOI Listing
October 2019

Guidance for Studies Evaluating the Accuracy of Biomarker-Based Nonsputum Tests to Diagnose Tuberculosis.

J Infect Dis 2019 10;220(220 Suppl 3):S108-S115

Foundation for Innovative New Diagnostics, Geneva.

The World Health Organization's (WHO) "End TB" strategy calls for development and implementation of novel tuberculosis (TB) diagnostics. Sputum-based diagnostics are challenging to implement and often less sensitive in high-priority populations. Nonsputum, biomarker-based tests may facilitate TB testing at lower levels of the healthcare system, accelerate treatment initiation, and improve outcomes. We provide guidance on the design of diagnostic accuracy studies evaluating nonsputum, biomarker-based tests within the context of WHO's target product profile for such tests. Study designs should account for the intended use when choosing the study population, setting, and reference standards. Although adults with respiratory symptoms may be an initial target population, other high-priority populations regardless of symptoms-including people living with human immunodeficiency virus, those unable to produce sputum samples or with extrapulmonary TB, household contacts, and children-should be considered. Studies beyond diagnostic accuracy that evaluate feasibility and population-level impacts are also needed. A biomarker-based diagnostic may be critical to ending the TB epidemic, but requires appropriate validation before implementation.
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http://dx.doi.org/10.1093/infdis/jiz356DOI Listing
October 2019

Guidance for Studies Evaluating the Accuracy of Sputum-Based Tests to Diagnose Tuberculosis.

J Infect Dis 2019 10;220(220 Suppl 3):S99-S107

World Health Organization, Geneva, Switzerland.

Tests that can replace sputum smear microscopy have been identified as a top priority diagnostic need for tuberculosis by the World Health Organization. High-quality evidence on diagnostic accuracy for tests that may meet this need is an essential requirement to inform decisions about policy and scale-up. However, test accuracy studies are often of low and inconsistent quality and poorly reported, leading to uncertainty about true test performance. Here we provide guidance for the design of diagnostic test accuracy studies of sputum smear-replacement tests. Such studies should have a cross-sectional or cohort design, enrolling either a consecutive series or a random sample of patients who require evaluation for tuberculosis. Adults with respiratory symptoms are the target population. The reference standard should at a minimum be a single, automated, liquid culture, but additional cultures, follow-up, clinical case definition, and specific measures to understand discordant results should also be included. Inclusion of smear microscopy and Xpert MTB/RIF (or MTB/RIF Ultra) as comparators is critical to allow broader comparability and generalizability of results, because disease spectrum can vary between studies and affects relative test performance. Given the complex nature of sputum (the primary specimen type used for pulmonary TB), careful design and reporting of the specimen flow is essential. Test characteristics other than accuracy (such as feasibility, implementation considerations, and data on impact on patient, population and health systems outcomes) are also important aspects.
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http://dx.doi.org/10.1093/infdis/jiz258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6782025PMC
October 2019
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