Accuracy and impact of Xpert MTB/RIF for the diagnosis of smear-negative or sputum-scarce tuberculosis using bronchoalveolar lavage fluid.
ABSTRACT: The accuracy and impact of new tuberculosis (TB) tests, such as Xpert MTB/RIF, when performed on bronchoalveolar lavage fluid (BALF) obtained from patients with sputum-scarce or smear-negative TB is unclear.South African patients with suspected pulmonary TB (n=160) who were sputum-scarce or smear-negative underwent bronchoscopy. MTB/RIF was performed on uncentrifuged BALF (1 ml) and/or a resuspended pellet of centrifuged BALF (?10 ml). Time to TB detection and anti-TB treatment initiation were compared between phase one, when MTB/RIF was performed as a research tool, and phase two, when it was used for patient management.27 of 154 patients with complete data had culture-confirmed TB. Of these, a significantly lower proportion were detected by smear microscopy compared with MTB/RIF (58%, 95% CI 39% to 75% versus 93%, 77% to 98%; p<0.001). Of the 127 patients who were culture negative, 96% (91% to 98%) were MTB/RIF negative. When phase two was compared with phase one, MTB/RIF reduced the median days to TB detection (29 (18-41) to 0 (0-0); p<0.001). However, more patients initiated empirical therapy (absence of a positive test in those commencing treatment) in phase one versus phase two (79% (11/14) versus 28% (10/25); p=0.026). Consequently, there was no detectable difference in the overall proportion of patients initiating treatment (26% (17/67; 17% to 37%) versus 36% (26/73; 26% to 47%); p=0.196) or the days to treatment initiation (10 (1-49) versus 7 (0-21); p=0.330). BALF centrifugation, HIV coinfection and a second MTB/RIF did not result in detectable changes in accuracy.MTB/RIF detected TB cases more accurately and more rapidly than smear microscopy and significantly reduced the rate of empirical treatment.
Project description:At present, tuberculosis remains a serious threat to human health. The diagnosis of pulmonary tuberculosis (PTB) is still difficult, and the prominent challenge for diagnosis is the lack of a highly sensitive and specific method. In order to explore the diagnostic value of parallel tests, this study prospectively enrolled 258 patients with smear-negative PTB from May 2, 2015 to December 31, 2016. The sputum specimens and bronchial alveolar lavage fluid (BALF) samples from all patients were assessed for MTB detection by culture, Xpert MTB/RIF, and simultaneous amplification and testing method for TB (SAT-TB). Overall, the sensitivity of any single test using culture, Xpert MTB/RIF, or SAT-TB was lower than that for parallel tests (<i>p</i> < 0.05), and the sensitivity rates for MTB detection in BALF were significantly higher than those in sputum samples. There were lower agreements in the detection results between sputum samples and BALF for all tests (<i>p</i> < 0.05). The parallel tests models of using culture plus Xpert MTB/RIF plus SAT-TB, culture plus Xpert, or culture plus SAT-TB achieved higher sensitivities compared with all three single test models (<i>p</i> < 0.05). Additionally, joint detection using sputum and BALF samples achieved a high sensitivity (0.8566, 95% CI: 0.8086-0.8941). In conclusion, the parallel tests model using culture, Xpert MTB/RIF, and SAT-TB in sputum plus BALF significantly increases the diagnostic performance of smear-negative PTB; thus, this method should be applied clinically when PTB is suspected but smear results are negative.
Project description:<h4>Rationale</h4>The clinical impact of Xpert MTB/RIF for tuberculosis (TB) diagnosis in high HIV-prevalence settings is unknown.<h4>Objective</h4>To determine the diagnostic accuracy and impact of Xpert MTB/RIF among high-risk TB suspects.<h4>Methods</h4>WE PROSPECTIVELY ENROLLED CONSECUTIVE, HOSPITALIZED, UGANDAN TB SUSPECTS IN TWO PHASES: baseline phase in which Xpert MTB/RIF results were not reported to clinicians and an implementation phase in which results were reported. We determined the diagnostic accuracy of Xpert MTB/RIF in reference to culture (solid and liquid) and compared patient outcomes by study phase.<h4>Results</h4>477 patients were included (baseline phase 287, implementation phase 190). Xpert MTB/RIF had high sensitivity (187/237, 79%, 95% CI: 73-84%) and specificity (190/199, 96%, 95% CI: 92-98%) for culture-positive TB overall, but sensitivity was lower (34/81, 42%, 95% CI: 31-54%) among smear-negative TB cases. Xpert MTB/RIF reduced median days-to-TB detection for all TB cases (1 [IQR 0-26] vs. 0 [IQR 0-1], p<0.001), and for smear-negative TB (35 [IQR 22-55] vs. 22 [IQR 0-33], p=0.001). However, median days-to-TB treatment was similar for all TB cases (1 [IQR 0-5] vs. 0 [IQR 0-2], p=0.06) and for smear-negative TB (7 [IQR 3-53] vs. 6 [IQR 1-61], p=0.78). Two-month mortality was also similar between study phases among 252 TB cases (17% vs. 14%, difference +3%, 95% CI: -21% to +27%, p=0.80), and among 87 smear-negative TB cases (28% vs. 22%, difference +6%, 95% CI: -34 to +46%, p=0.77).<h4>Conclusions</h4>Xpert MTB/RIF facilitated more accurate and earlier TB diagnosis, leading to a higher proportion of TB suspects with a confirmed TB diagnosis prior to hospital discharge in a high HIV/low MDR TB prevalence setting. However, our study did not detect a decrease in two-month mortality following implementation of Xpert MTB/RIF possibly because of insufficient powering, differences in empiric TB treatment rates, and disease severity between study phases.
Project description:Introduction:The World Health Organization endorsed (2010) the use of Xpert MTB/RIF and countries are shifting from smear microscopy (smear)-based to Xpert MTB/RIF-based tuberculosis (TB) diagnostic algorithms. As with smear, sputum quality may predict the likelihood of obtaining a bacteriologically-confirmed TB when using Xpert MTB/RIF. Methods:From 08/12-11/2014, all people living with HIV were recruited at 22 clinics. For patients screened positive using the four TB symptoms their sputa were tested by Xpert MTB/RIF and smear. Laboratorians assessed and recorded sputum appearance and volume. The yield of bacteriologically-positive sputum evaluated using Xpert MTB/RIF and smear, likelihood-ratios were calculated. Results:Among 6,041 patients enrolled 2,296 were presumptive TB, 1,305 (56.8%) had > 1 sputa collected and 644/1,305 (49.3%) had both Xpert MTB/RIF and smear results. Since >1 sputa collected from 644 patients 954 sputa were tested by Xpert MTB/RIF and smear. Bacteriologically-positive sputum was two-fold higher with Xpert MTB/RIF 11.4% versus smear 5.3%, p < 0.001. Sputum appearance and quantity were not predictive of bacteriologically-positive results, except volume of 2ml to < 3ml, tested by Xpert MTB/RIF LR+= 1.26 (95% CI, 1.05-1.50). Conclusion:Xpert MTB/RIF test yield to bacteriologically-positive sputum was superior to smear. Sputum quality and quantity, however, were not consistently predictive of bacteriologically-positive results by Xpert MTB/RIF or smear.
Project description:Performance of the Xpert MTB/RIF assay, designed to simultaneously detect Mycobacterium tuberculosis complex (MTBC) and rifampin (RIF) resistance, has been well documented in low-resource settings with high TB-incidence. However, few studies have assessed its accuracy in low TB incidence settings. We evaluated the performance of Xpert MTB/RIF using clinical sputum specimens routinely collected from suspect pulmonary TB patients over a 4-year time period in San Diego County, California. Xpert MTB/RIF results were compared to acid-fast bacilli (AFB) smear microscopy, mycobacterial culture, and phenotypic drug susceptibility testing (DST). Of 751 sputum specimens, 134 (17.8%) were MTBC culture-positive and 2 (1.5%) were multidrug-resistant (MDR). For the detection of MTBC, Xpert MTB/RIF sensitivity was 89.6% (97.7% and 74.5% in smear-positive and -negative sputa, respectively) and specificity was 97.2%; while AFB smear sensitivity and specificity were 64.9% and 77.8%, respectively. Xpert MTB/RIF detected 35 of 47 smear-negative culture-positive specimens, and excluded 124 of 137 smear-positive culture-negative specimens. Xpert MTB/RIF also correctly excluded 99.2% (121/122) of nontuberculous mycobacteria (NTM) specimens, including all 33 NTM false-positives by smear microscopy. For the detection of RIF resistance, Xpert MTB/RIF sensitivity and specificity were 100% and 98.3%, respectively. Our findings demonstrate that Xpert MTB/RIF is able to accurately detect MTBC and RIF resistance in routinely collected respiratory specimens in a low TB-incidence setting, with comparable performance to that achieved in high-incidence settings; and suggest that under these conditions the assay has particular utility in detecting smear-negative TB cases, excluding smear-positive patients without MTBC disease, and differentiating MTBC from NTM.
Project description:The diagnosis of active pulmonary tuberculosis (TB) remains a challenge in clinic, especially for sputum negative pulmonary TB. Bronchoalveolar lavage fluid (BALF) has higher sensitivity than sputum for detection of Mycobacterium tuberculosis (Mtb). However, bronchoscopy is invasive and costly, and not suitable for all patients. In order to make TB patients get more benefit from BALF for diagnosis, we explore which indicator might be used to optimize the choice of bronchoscopy.A total of 1539 sputum-smear-negative pulmonary TB suspects who underwent bronchoscopy were recruited for evaluation. The sensitivity, specificity and accuracy of Mtb detection in sputum and BALF were compared. Odds ratios and 95% confidence intervals were used to assess variables that associated with positive acid-fast bacilli (AFB) smear, Mtb culture and nucleic acid amplification test (NAAT) of BALF in sputum-negative and non-sputum-producing pulmonary TB suspects.BALF has significantly higher sensitivity (63.4%) than sputum (43.5%) for Mtb detection by culture and NAAT. 19.7% (122/620) sputum-negative and 40.0% (163/408) non-sputum-producing suspects had positive bacteriological results in BALF. Among sputum-negative and non-sputum-producing pulmonary TB suspects, the positivity of Mtb detection in BALF is associated with a younger age, the presence of pulmonary cavities and a positive result of interferon-gamma release assay (IGRA). Sputum-negative patients under 35 years old with positive IGRA and pulmonary cavity had 84.8% positivity of Mtb in BALF.Our study indicated that combination of age, the presence of pulmonary cavity, and the result of IGRA is useful to predict the positivity of Mtb detection in BALF among sputum-negative and non-sputum producing pulmonary TB suspects. Those who are under 35 years old, positive for the presence of pulmonary cavity and IGRA, should undergo bronchoscopy to collect BAFL for Mtb tests, as they have the highest possibility to get bacteriologically confirmation of TB.
Project description:BACKGROUND:Tuberculosis (TB) represents the ninth leading cause of death worldwide. In 2016 are estimated 1.3 million TB deaths among HIV negative people and an additional 374,000 deaths among HIV positive people. In 2016 are estimated 1.4 million new cases of TB in people living with HIV (PLHIV), 74% of whom were living in Africa. In light of these data, the reduction of mortality caused by TB in PLHIV is strongly required specially in low-income countries as Mozambique. According to international guidelines, the initial TB screening in HIV+ patients should be done with the four symptoms screening (4SS: fever, current cough, night sweats and weight loss). The diagnostic test more used in resource-limited countries is smear microscopy (SMEAR). World Health Organization (WHO) recommended Lateral Flow urine LipoArabinoMannan assay (LF-LAM) in immunocompromised patients; in 2010 WHO endorsed the use of Xpert Mycobacterium Tuberculosis/Rifampicin (MTB/RIF) test for rapid TB diagnosis but the assay is not used as screening test in all HIV+ patients irrespectively of symptoms due to cost and logistical barriers. The paper aims to evaluate the cost-effectiveness of three screening protocols: standard (4SS and SMEAR in positive patients to 4SS); MTB/RIF; LF-LAM / MTB/RIF. METHODS:We developed a model to assess the cost-effectiveness of the MTB/RIF protocol versus the common standard and LF-LAM / MTB/RIF protocol. The model considered a sample of 1,000 HIV+ antiretroviral treatment naïve patients in Mozambique. We evaluated disability-adjusted life year (DALY) averted for each protocol, cost per DALY, and incremental cost-effectiveness ratio (ICER), over 1-year, assuming a national healthcare system perspective. The model considered the delayed diagnosis as the time elapsed between a false negative test and the diagnosis and treatment of TB. Additional health system organization delay is defined as the time interval between positive test and treatment initiation caused by a delay in the delivery of results due organization of services. We conducted a sensitivity analysis on more relevant variables. RESULTS:The MTB/RIF protocol was cost-effective as compared to the standard protocol with an ICER of $56.54 per DALY saved. In a cohort of 1,000 patients MTB/RIF and LF-LAM / MTB/RIF protocol generated 1,281 and 1,254 DALY's saved respectively, with a difference of 174 and 147 DALY respect to the standard protocol. The total cost of MTB/RIF protocol was lower ($92,263) than the standard ($147,226) and the LF-LAM / MTB/RIF ($113,196). Therefore, the cost per DALY saved including new infections due to delayed diagnosis with the standard protocol was $79.06, about 5 fold higher than MTB/RIF and LF-LAM / MTB/RIF protocols. The cost of additional TB infections due to delays in diagnosis plus health system delay seemed the more relevant costs. The low sensibility and sensitivity of the standard protocol led to a high number of false negatives, thus delayed TB diagnoses and treatment lead to the development of newly transmitted TB infections. CONCLUSIONS:Our study shows that the MTB/RIF adoption could lead to an increasing of TB case-finding and a reduction in costs compared with standard and LF-LAM / MTB/RIF protocols.
Project description:BACKGROUND:The need for a rapid, molecular test to diagnose tuberculosis (TB) has prompted exploration of TB-LAMP (Eiken; Tokyo, Japan) for use in resource-limited settings. We conducted a systematic review to assess the accuracy of TB-LAMP as a diagnostic test for pulmonary TB. METHODS:We analyzed individual-level data for eligible patients from all studies of TB-LAMP conducted between Jan 2012 and October 2015 to compare the diagnostic accuracy of TB-LAMP with that of smear microscopy and Xpert MTB/RIF® using 3 reference standards of varying stringency. Pooled sensitivity and specificity and pooled differences in sensitivity and specificity were estimated using random effects meta-analysis. Study quality was evaluated using QUADAS-2. RESULTS:Four thousand seven hundred sixty individuals across 13 studies met eligibility criteria. Methodological quality was judged to be low for all studies. TB-LAMP had higher sensitivity than sputum smear microscopy (pooled sensitivity difference + 13·2, 95% CI 4·5-21·9%) and similar sensitivity to Xpert MTB/RIF (pooled sensitivity difference - 2·5, 95% CI -8·0 to + 2·9) using the most stringent reference standard available. Specificity of TB-LAMP was similar to that of sputum smear microscopy (pooled specificity difference - 1·8, 95% CI -3·8 to + 0·2) and Xpert MTB/RIF (pooled specificity difference 0·5, 95% CI -0·9 to + 1·8). CONCLUSIONS:From the perspective of diagnostic accuracy, TB-LAMP may be considered as an alternative test for sputum smear microscopy. Additional factors such as cost, feasibility, and acceptability in settings that continue to rely on sputum smear microscopy should be considered when deciding to adopt this technology. Xpert MTB/RIF should continue to be preferred in settings where resource and infrastructure requirements are adequate and where HIV co-infection or drug-resistance is of concern.
Project description:Detection of active tuberculosis (TB) before antiretroviral therapy (ART) initiation is important, but optimal diagnostic methods for use in resource-limited settings are lacking. We assessed the prevalence of TB, evaluated the diagnostic yield of Xpert MTB/RIF in comparison with smear microscopy and culture, and the impact of Xpert results on clinical management in HIV-positive adults eligible for ART at health centers in a region of Ethiopia.Participants were prospectively recruited and followed up at 5 health centers. Trained nurses collected data on socio-demographic characteristics, medical history and symptoms, and performed physical examination. Two paired morning sputum samples were obtained, and lymph node aspirates in case of lymphadenopathy. Diagnostic yield of Xpert MTB/RIF in sputum was compared with smear microscopy and liquid culture.TB was diagnosed in 145/812 participants (17.9%), with bacteriological confirmation in 137 (16.9%). Among bacteriologically confirmed cases, 31 were smear-positive (22.6%), 96 were Xpert-positive (70.1%), and 123 were culture-positive (89.8%). Xpert MTB/RIF increased the TB detection rate by 64 cases (47.4%) compared with smear microscopy. The overall sensitivity of Xpert MTB/RIF was 66.4%, and was not significantly lower when testing one compared with two samples. While Xpert MTB/RIF was 46.7% sensitive among patients with CD4 cell counts >200 cells/mm(3), this increased to 82.9% in those with CD4 cell counts ?100 cells/mm(3). Compared with Xpert-positive TB patients, Xpert-negative cases had less advanced HIV and TB disease characteristics.Previously undiagnosed TB is common among HIV-positive individuals managed in Ethiopian health centers. Xpert MTB/RIF increased TB case detection, especially in patients with advanced immunosuppression. An algorithm based on the use of a single morning sputum sample for individuals with negative sputum smear microscopy could be considered for intensified case finding in patients eligible for ART. However, technical and cost-effectiveness issues relevant for low-income countries warrant further study.
Project description:Xpert MTB/RIF assay is a highly sensitive test for TB diagnosis, but still costly to most low-income countries. Several implementation strategies instead of frontline have been suggested; however with scarce data. We assessed accuracy of different Xpert MTB/RIF implementation strategies to inform national roll-out.This was a cross-sectional study of 1,924 adult presumptive TB patients in five regional referral hospitals of Uganda. Two sputum samples were collected, one for fluorescent microscopy (FM) and Xpert MTB/RIF examined at the study site laboratories. The second sample was sent to the Uganda Supra National TB reference laboratory for culture using both Lowenstein Jensen (LJ) and liquid culture (MGIT). We compared the sensitivities of FM, Xpert MTB/RIF and the incremental sensitivity of Xpert MTB/RIF among patients negative on FM using LJ and/or MGIT as a reference standard.A total 1924 patients were enrolled of which 1596 (83%) patients had at least one laboratory result and 1083 respondents had a complete set of all the laboratory results. A total of 328 (30%) were TB positive on LJ and /or MGIT culture. The sensitivity of FM was n (%; 95% confidence interval) 246 (63.5%; 57.9-68.7) overall compared to 52 (55.4%; 44.1-66.3) among HIV positive individuals, while the sensitivity of Xpert MTB/RIF was 300 (76.2%; 71.7-80.7) and 69 (71.6%; 60.5-81.1) overall and among HIV positive individuals respectively. Overall incremental sensitivity of Xpert MTB/RIF was 60 (36.5%; 27.7-46.0) and 20 (41.7%; 25.5-59.2) among HIV positive individuals.Xpert MTB/RIF has a higher sensitivity than FM both in general population and HIV positive population. Xpert MTB/RIF offers a significant increase in terms of diagnostic sensitivity even when it is deployed selectively i.e. among smear negative presumptive TB patients. Our results support frontline use of Xpert MTB/RIF assay in high HIV/TB prevalent countries. In settings with limited access, mechanisms to refer smear negative sputum samples to Xpert MTB/RIF hubs are recommended.
Project description:<h4>Background</h4>Diagnosis of pulmonary (PTB) and extra-pulmonary tuberculosis (EPTB) in smear-negative patients can be difficult. We assessed retrospectively the performance of Xpert MTB/RIF system (Xpert, Cepheid) in diagnosing smear-negative tuberculosis (TB), which represents the most common form of TB in a low incidence setting.<h4>Methods</h4>Performance of Xpert was compared to acid-fast microscopic examination using Ziehl-Neelsen (ZN) stain in patients with culture-confirmed TB.<h4>Results</h4>386 Mycobacterium tuberculosis (MTB) culture-positive samples were detected out of 5170 specimens tested with smear microscopy, Xpert and culture: 323 were both culture- and Xpert-positive, and 63 culture-positive only. Of these, 234 (60.6%) were smear-negative. In addition Xpert detected 40 probable TB cases, based on clinical findings, which were culture-negative. Compared to culture, Xpert showed an overall sensitivity of 83.7% and a specificity of 99.1%; sensitivity was higher for respiratory samples (86.5%) than for non-respiratory samples (76.8%). Xpert sensitivity for smear-negative culture-confirmed TB was 73.1% and was not influenced by TB localization. As sensitivity of microscopy alone was poor (39.4%), Xpert improved both diagnosis of pulmonary TB (? = 36.5%) and extra-pulmonary TB (? = 63.4%).<h4>Conclusions</h4>Xpert MTB/RIF is a sensitive method for rapid diagnosis of TB compared to the conventional ZN staining. Xpert can serve as a sensitive and time-saving diagnostic method for microbiological diagnosis of smear-negative TB in countries with a low TB prevalence.