Tuberculosis (TB) is the leading infectious cause of mortality worldwide, due in part to a limited understanding of its clinical pathogenic spectrum of infection and disease. Historically, scientific ...research, diagnostic testing, and drug treatment have focused on addressing one of two disease states: latent TB infection or active TB disease. Recent research has clearly demonstrated that human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses. This revised understanding leads us to propose two additional clinical states: incipient and subclinical TB. The recognition of incipient and subclinical TB, which helps divide latent and active TB along the clinical disease spectrum, provides opportunities for the development of diagnostic and therapeutic interventions to prevent progression to active TB disease and transmission of TB bacilli. In this report, we review the current understanding of the pathogenesis, immunology, clinical epidemiology, diagnosis, treatment, and prevention of both incipient and subclinical TB, two emerging clinical states of an ancient bacterium.
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.
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.
Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is endorsed for the detection of pulmonary tuberculosis (TB). We performed a systematic review and meta-analysis to assess the accuracy of Xpert for the ...detection of extrapulmonary TB. We searched multiple databases to October 15, 2013. We determined the accuracy of Xpert compared with culture and a composite reference standard (CRS). We grouped data by sample type and performed meta-analyses using a bivariate random-effects model. We assessed sources of heterogeneity using meta-regression for predefined covariates. We identified 18 studies involving 4461 samples. Sample processing varied greatly among the studies. Xpert sensitivity differed substantially between sample types. In lymph node tissues or aspirates, Xpert pooled sensitivity was 83.1% (95% CI 71.4-90.7%) versus culture and 81.2% (95% CI 72.4-87.7%) versus CRS. In cerebrospinal fluid, Xpert pooled sensitivity was 80.5% (95% CI 59.0-92.2%) against culture and 62.8% (95% CI 47.7-75.8%) against CRS. In pleural fluid, pooled sensitivity was 46.4% (95% CI 26.3-67.8%) against culture and 21.4% (95% CI 8.8-33.9%) against CRS. Xpert pooled specificity was consistently >98.7% against CRS across different sample types. Based on this systematic review, the World Health Organization now recommends Xpert over conventional tests for diagnosis of TB in lymph nodes and other tissues, and as the preferred initial test for diagnosis of TB meningitis.
Background
Tuberculosis (TB) is the world’s leading infectious cause of death. Extrapulmonary TB accounts for 15% of TB cases, but the proportion is increasing, and over half a million people were ...newly diagnosed with rifampicin‐resistant TB in 2016. Xpert® MTB/RIF (Xpert) is a World Health Organization (WHO)‐recommended, rapid, automated, nucleic acid amplification assay that is used widely for simultaneous detection of Mycobacterium tuberculosis complex and rifampicin resistance in sputum specimens. This Cochrane Review assessed the accuracy of Xpert in extrapulmonary specimens.
Objectives
To determine the diagnostic accuracy of Xpert a) for extrapulmonary TB by site of disease in people presumed to have extrapulmonary TB; and b) for rifampicin resistance in people presumed to have extrapulmonary TB.
Search methods
We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature (LILACS), Scopus, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number (ISRCTN) Registry, and ProQuest up to 7 August 2017 without language restriction.
Selection criteria
We included diagnostic accuracy studies of Xpert in people presumed to have extrapulmonary TB. We included TB meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, and disseminated TB. We used culture as the reference standard. For pleural TB, we also included a composite reference standard, which defined a positive result as the presence of granulomatous inflammation or a positive culture result. For rifampicin resistance, we used culture‐based drug susceptibility testing or MTBDRplus as the reference standard.
Data collection and analysis
Two review authors independently extracted data, assessed risk of bias and applicability using the QUADAS‐2 tool. We determined pooled predicted sensitivity and specificity for TB, grouped by type of extrapulmonary specimen, and for rifampicin resistance. For TB detection, we used a bivariate random‐effects model. Recognizing that use of culture may lead to misclassification of cases of extrapulmonary TB as ‘not TB' owing to the paucibacillary nature of the disease, we adjusted accuracy estimates by applying a latent class meta‐analysis model. For rifampicin resistance detection, we performed univariate meta‐analyses for sensitivity and specificity separately to include studies in which no rifampicin resistance was detected. We used theoretical populations with an assumed prevalence to provide illustrative numbers of patients with false positive and false negative results.
Main results
We included 66 unique studies that evaluated 16,213 specimens for detection of extrapulmonary TB and rifampicin resistance. We identified only one study that evaluated the newest test version, Xpert MTB/RIF Ultra (Ultra), for TB meningitis. Fifty studies (76%) took place in low‐ or middle‐income countries. Risk of bias was low for patient selection, index test, and flow and timing domains and was high or unclear for the reference standard domain (most of these studies decontaminated sterile specimens before culture inoculation). Regarding applicability, in the patient selection domain, we scored high or unclear concern for most studies because either patients were evaluated exclusively as inpatients at tertiary care centres, or we were not sure about the clinical settings.
Pooled Xpert sensitivity (defined by culture) varied across different types of specimens (31% in pleural tissue to 97% in bone or joint fluid); Xpert sensitivity was > 80% in urine and bone or joint fluid and tissue. Pooled Xpert specificity (defined by culture) varied less than sensitivity (82% in bone or joint tissue to 99% in pleural fluid and urine). Xpert specificity was ≥ 98% in cerebrospinal fluid, pleural fluid, urine, and peritoneal fluid.
Xpert testing in cerebrospinal fluid
Xpert pooled sensitivity and specificity (95% credible interval (CrI)) against culture were 71.1% (60.9% to 80.4%) and 98.0% (97.0% to 98.8%), respectively (29 studies, 3774 specimens; moderate‐certainty evidence).
For a population of 1000 people where 100 have TB meningitis on culture, 89 would be Xpert‐positive: of these, 18 (20%) would not have TB (false‐positives); and 911 would be Xpert‐negative: of these, 29 (3%) would have TB (false‐negatives).
For TB meningitis, ultra sensitivity and specificity against culture (95% confidence interval (CI)) were 90% (55% to 100%) and 90% (83% to 95%), respectively (one study, 129 participants).
Xpert testing in pleural fluid
Xpert pooled sensitivity and specificity (95% CrI) against culture were 50.9% (39.7% to 62.8%) and 99.2% (98.2% to 99.7%), respectively (27 studies, 4006 specimens; low‐certainty evidence).
For a population of 1000 people where 150 have pleural TB on culture, 83 would be Xpert‐positive: of these, seven (8%) would not have TB (false‐positives); and 917 would be Xpert‐negative: of these, 74 (8%) would have TB (false‐negatives).
Xpert testing in urine
Xpert pooled sensitivity and specificity (95% CrI) against culture were 82.7% (69.6% to 91.1%) and 98.7% (94.8% to 99.7%), respectively (13 studies, 1199 specimens; moderate‐certainty evidence).
For a population of 1000 people where 70 have genitourinary TB on culture, 70 would be Xpert‐positive: of these, 12 (17%) would not have TB (false‐positives); and 930 would be Xpert‐negative: of these, 12 (1%) would have TB (false‐negatives).
Xpert testing for rifampicin resistance
Xpert pooled sensitivity (20 studies, 148 specimens) and specificity (39 studies, 1088 specimens) were 95.0% (89.7% to 97.9%) and 98.7% (97.8% to 99.4%), respectively (high‐certainty evidence).
For a population of 1000 people where 120 have rifampicin‐resistant TB, 125 would be positive for rifampicin‐resistant TB: of these, 11 (9%) would not have rifampicin resistance (false‐positives); and 875 would be negative for rifampicin‐resistant TB: of these, 6 (1%) would have rifampicin resistance (false‐negatives).
For lymph node TB, the accuracy of culture, the reference standard used, presented a greater concern for bias than in other forms of extrapulmonary TB.
Authors' conclusions
In people presumed to have extrapulmonary TB, Xpert may be helpful in confirming the diagnosis. Xpert sensitivity varies across different extrapulmonary specimens, while for most specimens, specificity is high, the test rarely yielding a positive result for people without TB (defined by culture). Xpert is accurate for detection of rifampicin resistance. For people with presumed TB meningitis, treatment should be based on clinical judgement, and not withheld solely on an Xpert result, as is common practice when culture results are negative.
2 April 2019
Up to date
All studies incorporated from most recent search
Updated review: all eligible published studies found in the last search (7 Aug, 2017) were included
Background
Xpert MTB/RIF (Xpert MTB/RIF) and Xpert MTB/RIF Ultra (Xpert Ultra), the newest version, are the only World Health Organization (WHO)‐recommended rapid tests that simultaneously detect ...tuberculosis and rifampicin resistance in persons with signs and symptoms of tuberculosis, at lower health system levels. A previous Cochrane Review found Xpert MTB/RIF sensitive and specific for tuberculosis (Steingart 2014). Since the previous review, new studies have been published. We performed a review update for an upcoming WHO policy review.
Objectives
To determine diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for tuberculosis in adults with presumptive pulmonary tuberculosis (PTB) and for rifampicin resistance in adults with presumptive rifampicin‐resistant tuberculosis.
Search methods
We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, to 11 October 2018, without language restriction.
Selection criteria
Randomized trials, cross‐sectional, and cohort studies using respiratory specimens that evaluated Xpert MTB/RIF, Xpert Ultra, or both against the reference standard, culture for tuberculosis and culture‐based drug susceptibility testing or MTBDRplus for rifampicin resistance.
Data collection and analysis
Four review authors independently extracted data using a standardized form. When possible, we also extracted data by smear and HIV status. We assessed study quality using QUADAS‐2 and performed meta‐analyses to estimate pooled sensitivity and specificity separately for tuberculosis and rifampicin resistance. We investigated potential sources of heterogeneity. Most analyses used a bivariate random‐effects model. For tuberculosis detection, we first estimated accuracy using all included studies and then only the subset of studies where participants were unselected, i.e. not selected based on prior microscopy testing.
Main results
We identified in total 95 studies (77 new studies since the previous review): 86 studies (42,091 participants) evaluated Xpert MTB/RIF for tuberculosis and 57 studies (8287 participants) for rifampicin resistance. One study compared Xpert MTB/RIF and Xpert Ultra on the same participant specimen.
Tuberculosis detection
Of the total 86 studies, 45 took place in high tuberculosis burden and 50 in high TB/HIV burden countries. Most studies had low risk of bias.
Xpert MTB/RIF pooled sensitivity and specificity (95% credible Interval (CrI)) were 85% (82% to 88%) and 98% (97% to 98%), (70 studies, 37,237 unselected participants; high‐certainty evidence). We found similar accuracy when we included all studies.
For a population of 1000 people where 100 have tuberculosis on culture, 103 would be Xpert MTB/RIF‐positive and 18 (17%) would not have tuberculosis (false‐positives); 897 would be Xpert MTB/RIF‐negative and 15 (2%) would have tuberculosis (false‐negatives).
Xpert Ultra sensitivity (95% confidence interval (CI)) was 88% (85% to 91%) versus Xpert MTB/RIF 83% (79% to 86%); Xpert Ultra specificity was 96% (94% to 97%) versus Xpert MTB/RIF 98% (97% to 99%), (1 study, 1439 participants; moderate‐certainty evidence).
Xpert MTB/RIF pooled sensitivity was 98% (97% to 98%) in smear‐positive and 67% (62% to 72%) in smear‐negative, culture‐positive participants, (45 studies). Xpert MTB/RIF pooled sensitivity was 88% (83% to 92%) in HIV‐negative and 81% (75% to 86%) in HIV‐positive participants; specificities were similar 98% (97% to 99%), (14 studies).
Rifampicin resistance detection
Xpert MTB/RIF pooled sensitivity and specificity (95% Crl) were 96% (94% to 97%) and 98% (98% to 99%), (48 studies, 8020 participants; high‐certainty evidence).
For a population of 1000 people where 100 have rifampicin‐resistant tuberculosis, 114 would be positive for rifampicin‐resistant tuberculosis and 18 (16%) would not have rifampicin resistance (false‐positives); 886 would be would be negative for rifampicin‐resistant tuberculosis and four (0.4%) would have rifampicin resistance (false‐negatives).
Xpert Ultra sensitivity (95% CI) was 95% (90% to 98%) versus Xpert MTB/RIF 95% (91% to 98%); Xpert Ultra specificity was 98% (97% to 99%) versus Xpert MTB/RIF 98% (96% to 99%), (1 study, 551 participants; moderate‐certainty evidence).
Authors' conclusions
We found Xpert MTB/RIF to be sensitive and specific for diagnosing PTB and rifampicin resistance, consistent with findings reported previously. Xpert MTB/RIF was more sensitive for tuberculosis in smear‐positive than smear‐negative participants and HIV‐negative than HIV‐positive participants. Compared with Xpert MTB/RIF, Xpert Ultra had higher sensitivity and lower specificity for tuberculosis and similar sensitivity and specificity for rifampicin resistance (1 study). Xpert MTB/RIF and Xpert Ultra provide accurate results and can allow rapid initiation of treatment for multidrug‐resistant tuberculosis.
29 October 2019
Update pending
Authors currently updating
The update is due to be published in 2020.
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.
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Xpert MTB/RIF (Xpert) assay offers rapid and accurate diagnosis of tuberculosis (TB) but still suffers from imperfect sensitivity. The newer Xpert MTB/RIF Ultra cartridge has shown improved ...sensitivity in recent field trials, but at the expense of reduced specificity. The clinical implications of switching from the existing Xpert cartridge to the Xpert Ultra cartridge in different populations remain uncertain.
We developed a Markov microsimulation model of hypothetical cohorts of 100,000 individuals undergoing diagnostic sputum evaluation with Xpert for suspected pulmonary TB, in each of 3 emblematic settings: an HIV clinic in South Africa, a public TB center in India, and an adult primary care setting in China. In each setting, we used existing data to project likely diagnostic results, treatment decisions, and ultimate clinical outcomes, assuming use of the standard Xpert versus Xpert Ultra cartridge. Our primary outcomes were the projected number of additional unnecessary treatments generated, the projected number of TB deaths averted, and the projected number of unnecessary treatments generated per TB death averted, if standard Xpert were switched to Xpert Ultra. We also simulated alternative approaches to interpreting positive results of the Ultra cartridge's semi-quantitative trace call. Extensive sensitivity and uncertainty analyses were performed to evaluate the drivers and generalizability of projected results. In the Indian TB center setting, replacing the standard Xpert cartridge with the Xpert Ultra cartridge was projected to avert 0.5 TB deaths (95% uncertainty range UR: 0, 1.3) and generate 18 unnecessary treatments (95% UR: 10, 29) per 1,000 individuals evaluated-resulting in a median ratio of 38 incremental unnecessary treatments added by Ultra per incremental death averted by Ultra compared to outcomes using standard Xpert (95% UR: 12, indefinite upper bound). In the South African HIV care setting-where TB mortality rates are higher and Ultra's improved sensitivity has greater absolute benefit-this ratio improved to 7 unnecessary treatments per TB death averted (95% UR: 2, 43). By contrast, in the Chinese primary care setting, this ratio was much less favorable, at 372 unnecessary treatments per TB death averted (95% UR: 75, indefinite upper bound), although the projected number of unnecessary treatments using Xpert Ultra was lower (with a possibility of no increased overtreatment) when using specificity data only from lower-burden settings. Alternative interpretations of the trace call had little effect on these ratios. Limitations include uncertainty in key parameters (including the clinical implications of false-negative results), the exclusion of transmission effects, and restriction of this analysis to adult pulmonary TB.
Switching from the standard Xpert cartridge to the Xpert Ultra cartridge for diagnosis of adult pulmonary TB may have different consequences in different clinical settings. In settings with high TB and HIV prevalence, Xpert Ultra is likely to offer considerable mortality benefit, whereas in lower-prevalence settings, Xpert Ultra will likely result in considerable overtreatment unless the possibility of higher specificity of Ultra in lower-prevalence settings in confirmed. The ideal use of the Ultra cartridge may therefore involve a more nuanced, setting-specific approach to implementation, with priority given to populations in which the anticipated prevalence of TB (and HIV) is the highest.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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