Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults

  • Comment
  • Review
  • Diagnostic

Authors


Abstract

Background

Accurate, rapid detection of tuberculosis (TB) and TB drug resistance is critical for improving patient care and decreasing TB transmission. Xpert® MTB/RIF assay is an automated test that can detect both TB and rifampicin resistance, generally within two hours after starting the test, with minimal hands-on technical time. The World Health Organization (WHO) issued initial recommendations on Xpert® MTB/RIF in early 2011. A Cochrane Review on the diagnostic accuracy of Xpert® MTB/RIF for pulmonary TB and rifampicin resistance was published January 2013. We performed this updated Cochrane Review as part of a WHO process to develop updated guidelines on the use of the test.

Objectives

To assess the diagnostic accuracy of Xpert® MTB/RIF for pulmonary TB (TB detection), where Xpert® MTB/RIF was used as both an initial test replacing microscopy and an add-on test following a negative smear microscopy result.

To assess the diagnostic accuracy of Xpert® MTB/RIF for rifampicin resistance detection, where Xpert® MTB/RIF was used as the initial test replacing culture-based drug susceptibility testing (DST).

The populations of interest were adults presumed to have pulmonary, rifampicin-resistant or multidrug-resistant TB (MDR-TB), with or without HIV infection. The settings of interest were intermediate- and peripheral-level laboratories. The latter may be associated with primary health care facilities.

Search methods

We searched for publications in any language up to 7 February 2013 in the following databases: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; ISI Web of Knowledge; MEDION; LILACS; BIOSIS; and SCOPUS. We also searched the metaRegister of Controlled Trials (mRCT) and the search portal of the WHO International Clinical Trials Registry Platform to identify ongoing trials.

Selection criteria

We included randomized controlled trials, cross-sectional studies, and cohort studies using respiratory specimens that allowed for extraction of data evaluating Xpert® MTB/RIF against the reference standard. We excluded gastric fluid specimens. The reference standard for TB was culture and for rifampicin resistance was phenotypic culture-based DST.

Data collection and analysis

For each study, two review authors independently extracted data using a standardized form. When possible, we extracted data for subgroups by smear and HIV status. We assessed the quality of studies using QUADAS-2 and carried out meta-analyses to estimate pooled sensitivity and specificity of Xpert® MTB/RIF separately for TB detection and rifampicin resistance detection. For TB detection, we performed the majority of analyses using a bivariate random-effects model and compared the sensitivity of Xpert® MTB/RIF and smear microscopy against culture as reference standard. For rifampicin resistance detection, we undertook univariate meta-analyses for sensitivity and specificity separately to include studies in which no rifampicin resistance was detected.

Main results

We included 27 unique studies (integrating nine new studies) involving 9557 participants. Sixteen studies (59%) were performed in low- or middle-income countries. For all QUADAS-2 domains, most studies were at low risk of bias and low concern regarding applicability.

As an initial test replacing smear microscopy, Xpert® MTB/RIF pooled sensitivity was 89% [95% Credible Interval (CrI) 85% to 92%] and pooled specificity 99% (95% CrI 98% to 99%), (22 studies, 8998 participants: 2953 confirmed TB, 6045 non-TB).
As an add-on test following a negative smear microscopy result, Xpert®MTB/RIF pooled sensitivity was 67% (95% CrI 60% to 74%) and pooled specificity 99% (95% CrI 98% to 99%; 21 studies, 6950 participants).

For smear-positive, culture-positive TB, Xpert® MTB/RIF pooled sensitivity was 98% (95% CrI 97% to 99%; 21 studies, 1936 participants).

For people with HIV infection, Xpert® MTB/RIF pooled sensitivity was 79% (95% CrI 70% to 86%; seven studies, 1789 participants), and for people without HIV infection, it was 86% (95% CrI 76% to 92%; seven studies, 1470 participants).

Among 180 specimens with nontuberculous mycobacteria (NTM), Xpert® MTB/RIF was positive in only one specimen that grew NTM (14 studies, 2626 participants).

Comparison with smear microscopy

In comparison with smear microscopy, Xpert® MTB/RIF increased TB detection among culture-confirmed cases by 23% (95% CrI 15% to 32%; 21 studies, 8880 participants).

For TB detection, if pooled sensitivity estimates for Xpert® MTB/RIF and smear microscopy are applied to a hypothetical cohort of 1000 patients where 10% of those with symptoms have TB, Xpert® MTB/RIF will diagnose 88 cases and miss 12 cases, whereas sputum microscopy will diagnose 65 cases and miss 35 cases.

Rifampicin resistance

For rifampicin resistance detection, Xpert® MTB/RIF pooled sensitivity was 95% (95% CrI 90% to 97%; 17 studies, 555 rifampicin resistance positives) and pooled specificity was 98% (95% CrI 97% to 99%; 24 studies, 2411 rifampicin resistance negatives).

For rifampicin resistance detection, if the pooled accuracy estimates for Xpert® MTB/RIF are applied to a hypothetical cohort of 1000 individuals where 15% of those with symptoms are rifampicin resistant, Xpert® MTB/RIF would correctly identify 143 individuals as rifampicin resistant and miss eight cases, and correctly identify 833 individuals as rifampicin susceptible and misclassify 17 individuals as resistant. Where 5% of those with symptoms are rifampicin resistant, Xpert® MTB/RIF would correctly identify 48 individuals as rifampicin resistant and miss three cases and correctly identify 931 individuals as rifampicin susceptible and misclassify 19 individuals as resistant.

Authors' conclusions

In adults thought to have TB, with or without HIV infection, Xpert® MTB/RIF is sensitive and specific. Compared with smear microscopy, Xpert® MTB/RIF substantially increases TB detection among culture-confirmed cases. Xpert® MTB/RIF has higher sensitivity for TB detection in smear-positive than smear-negative patients. Nonetheless, this test may be valuable as an add-on test following smear microscopy in patients previously found to be smear-negative. For rifampicin resistance detection, Xpert® MTB/RIF provides accurate results and can allow rapid initiation of MDR-TB treatment, pending results from conventional culture and DST. The tests are expensive, so current research evaluating the use of Xpert® MTB/RIF in TB programmes in high TB burden settings will help evaluate how this investment may help start treatment promptly and improve outcomes.

摘要

成人肺结核和利福平耐药性的Xpert® MTB/RIF检测

研究背景

结核病(TB)和TB耐药性快速检测的准确,对于改善患者治疗和减少TB传播至关重要。Xpert® MTB/RIF检测是一种自动测试,通常在开始测试后的两个小时内可以检测到结核病和利福平的耐药性,同时具有最少的人工技术时间。世界卫生组织(WHO)于2011年初发布了关于Xpert® MTB/RIF的初步建议。关于Xpert® MTB/RIF肺结核和利福平耐药性的诊断准确性的Cochrane综述于2013年1月发表。我们更新了这一Cochrane综述,作为世卫组织进程的一部分,以制定关于使用测试的最新指南。

研究目的

评估Xpert® MTB/RIF对肺结核(TB检测)的诊断准确性,其中使用Xpert® MTB/RIF作为替代显微镜的初始试验和阴性涂片显微镜检查结果后的附加试验。

评估Xpert® MTB/RIF对利福平耐药性检测的诊断准确性,其中使用Xpert® MTB/RIF作为替代基于培养的药物敏感性测试(DST)的初始试验。

人群设定为有或没有艾滋病毒感染的,利福平耐药或多重耐药性肺结核病(MDR-TB)的成年人。场所设定为中级和外围级实验室。后者可能与初级保健设施有关。

检索策略

我们不限语言的检索2013年2月7日前的出版物,检索了以下数据库:Cochrane传染病组专业注册库、MEDLINE、EMBASE、ISI知识网、MEDION、LILACS、BIOSIS、和SCOPUS。我们还检索了对照试验的meta注册库(mRCT)和世卫组织国际临床试验注册平台的搜索门户,以确定正在进行的试验。

标准/纳入排除标准

我们纳入了随机对照试验,横断面研究和队列研究,这些研究类型使用的呼吸标本允许根据参考标准提取评估Xpert® MTB/RIF的数据。我们排除了胃液标本。结核病的参考标准是培养,利福平耐药性的参考标准是基于表型培养的DST。

数据收集与分析

对于每项研究,两位综述作者使用标准化表格独立提取数据。在可能的情况下,我们通过涂片和艾滋病毒感染状况提取亚组的数据。我们使用QUADAS-2评估了研究的质量,并进行了meta分析,以分别估计Xpert® MTB/RIF用于TB检测和利福平耐药检测的合并灵敏度和特异性。对于TB检测,我们使用双变量随机效应模型进行了大部分分析,并以细菌培养作为参考标准,比较了Xpert® MTB/RIF和涂片显微镜敏感性。对于利福平耐药性检测,我们分别对敏感性和特异性进行单因素meta分析,以纳入没有检测到利福平耐药性的研究。

主要结果

我们纳入27项独特研究(整合为9项新研究),涉及9557名受试者。16项研究(59%)在低收入或中等收入国家进行。采用QUADAS-2条目评价,大多数研究的偏倚风险偏低,且对适用性的关注较低。

作为替代涂片镜检的初步测试,Xpert® MTB/RIF合并灵敏度为89%[95%可信区间(CrI)85%为至92%],合并特异性99%(95%CrI为98%至99%),(22项研究,8998名受试者:2953确诊肺结咳,6045非肺结核)。
作为阴性涂片镜检结果后的附加测试,Xpert® MTB/RIF合并灵敏度为67%(95%CrI为60%至74%),合并特异性为99%(95%CrI为98%至99%;21项研究,6950名受试者)。

对于涂片阳性,培养阳性的结核病,Xpert® MTB/RIF合并灵敏度为98%(95%CrI为97%至99%;21项研究,1936名受试者)。

对于HIV感染者,Xpert® MTB/RIF合并灵敏度为79%(95%CrI为70%至86%;7项研究,1789名受试者),而对于没有感染艾滋病毒的人群,其为86%(95%CrI为76%至92%;7项研究,1470名受试者)。

在含非结核分枝杆菌(NTM)的180个标本中,只有一个生长NTM的标本中,Xpert® MTB/RIF为阳性(14项研究,2626名受试者)。

与涂片镜检比较

与涂片镜检相比,Xpert® MTB/RIF在细菌培养确诊病例中增加了23%的TB检出(95%CrI为15%至32%;21项研究,8880名受试者)。

对于TB检测,如果结合Xpert® MTB/RIF和涂片镜检进行敏感性估计,将两种方法应用于1000名患者的假设组,其中10%的有症状者患有TB,则Xpert® MTB/RIF将诊断88例,漏诊12例,而痰液显微镜可诊断65例,漏诊35例。

利福平耐药

对于利福平耐药检测,Xpert® MTB/RIF合并敏感度为95%(95%CrI为90%至97%;17项研究,555例利福平耐药阳性),合并特异性为98%(95%CrI为97%至99%;24项研究,2411利福平耐药性阴性)。

对于利福平抗性检测,如果将Xpert® MTB/RIF的合并准确度估计值应用于1000名患者的假设队列,其中15%的症状患者具有利福平耐药性,则Xpert® MTB/RIF将正确识别143名患者为利福平耐药,漏诊8例,正确识别833人作为利福平敏感,并误将17人列为耐药。如果5%的症状为利福平耐药,Xpert® MTB/RIF将正确鉴定48人为利福平耐药,漏诊3例,正确鉴定931人为利福平敏感,并误认为19人为耐药。

作者结论

在有结核病的成年人中,无论有或没有艾滋病毒感染,Xpert® MTB/RIF检测都是敏感和准确的。与涂片显微镜相比,Xpert® MTB/RIF在培养确诊 病例中大大增加了TB检出率。Xpert® MTB/RIF对涂片阳性的结核病检测敏感性比涂片阴性患者高。尽管如此,这项测试作为涂片阴性的患者的附加试验也可能是有价值的。 对于利福平耐药性检测,Xpert® MTB/RIF可提供准确的结果,并可以快速启动MDR-TB治疗,同时等待等待传统培养和DST的结果。 这项测试是昂贵的,因此目前在高TB负担环境中评估在结核病进程中使用Xpert® MTB/RIF的研究,将有助于评估这一投资如何有助于及时开始治疗并改善结果。

翻译注解

译者:李文元,审校:孙瑾。北京中医药大学循证医学中心

Plain language summary

Xpert MTB/RIF test for diagnosing pulmonary tuberculosis and rifampicin resistance in adults

Tuberculosis (TB) causes tremendous suffering worldwide, especially in low-income and middle-income countries. In 2012, 8.6 million people developed TB disease (active TB) for the first time and around 1.3 million people died. Most people with TB can be cured if the disease is diagnosed and properly treated. One of the problems in treating TB is that the bacteria become resistant to antibiotics. Detecting TB and TB drug resistance quickly is important for improving health, reducing deaths, and decreasing the spread of TB in communities.

Xpert® MTB/RIF is a new test that quickly detects TB and rifampicin resistance at the same time. Rifampicin is an important drug for treating people with TB. Since the test is automated, it does not require expert staff or an advanced laboratory.

Our objectives were to determine the diagnostic accuracy (sensitivity and specificity) for TB detection and rifampicin resistance detection. Sensitivity shows how often the test gives a positive result in people who really have TB. Specificity shows how often the test gives a negative result in people who do not have TB.

We included studies of adults with or without HIV infection thought to have pulmonary TB (TB in the lungs) or rifampicin resistance, and were most interested in the use of Xpert® MTB/RIF outside of the most advanced laboratories.

We also compared the sensitivity of Xpert® MTB/RIF to that of smear microscopy, the test commonly used for TB diagnosis in low- and middle-income countries. Smear microscopy is low-cost and fairly easy to do, but requires trained staff and is a hassle for patients, who must provide at least two sputum samples. Also, microscopy gives no information about drug resistance.

We searched for publications in any language up to 7 February 2013 and considered the study's risk of giving biased results.

What the results say

We included 27 studies involving around 9500 people. Most studies were performed in low- or middle-income countries. We thought most studies had a low risk of bias.

The key findings were:

For TB detection, Xpert® MTB/RIF was accurate (it was highly sensitive (89%), detecting almost all cases; and specific (99%), that is, not registering positive in people who were actually negative).

For rifampicin resistance detection, Xpert® MTB/RIF was accurate that is sensitive (95%) and specific (98%).

Xpert® MTB/RIF appeared to have similar accuracy in people with and without HIV infection.

Applying the findings of the review to an imaginary group of 1000 people who go to their doctor with symptoms, but where only 100 of them (10%) actually have TB, Xpert® MTB/RIF would diagnose 88 cases and miss 12 cases, whereas smear microscopy would diagnose 65 cases and miss 35 cases.

To summarize, our review shows that Xpert® MTB/RIF is more accurate than smear microscopy for diagnosing TB and also accurate for detecting rifampicin resistance. Xpert® MTB/RIF may be useful in many countries, as it does not require advanced laboratory facilities or expert staff.

Laički sažetak

Xpert® MTB/RIF test za plućnu tuberkulozu i rezistenciju na rifampicin u odraslih

Tuberkuloza (TB) je uzrok velikog pobola širom svijeta, osobito u zemljama niskih i srednjih prihoda. Tijekom 2012. godine je 8,6 milijuna osoba razvilo aktivnu TB po prvi put, a širom svijeta je oko 1,3 milijuna osoba umrlo od TB. Većina oboljelih od TB mogu se izliječiti ako se bolest dijagnosticira i prikladno liječi. Jedan od problema liječenja TB jest što bakterije postaju otporne na antibiotike. Otkrivanje TB i otpornosti na TB lijekove je važno kako bi se poboljšalo zdravlje, smanjila smrtnost i smanjilo širenje TB u zajednicama.

Xpert® MTB/RIF je novi dijagnostički test koji brzo otkriva TB i otpornost (rezistenciju) na lijek rifampicin u isto vrijeme. Rifampicin je važan lijek za liječenje oboljelih od TB. Budući je test automatiziran, ne zahtijeva stručno osoblje ili napredni laboratorij.

U ovom Cochrane sustavnom pregledu ispitana je dijagnostička točnost (osjetljivost i specifičnost) testa Xpert® MTB/RIF za otkrivanje TB i otpornosti na rifampicin. Osjetljivost je pokazatelj koji nam govori koliko često test daje pozitivne rezultate u osoba koje stvarno imaju TB. Specifičnost pokazuje koliko često test daje negativne rezultate u osoba koje nemaju TB.

Uključene su studije u kojima su sudjelovale osobe s ili bez HIV infekcije za koje se smatralo da imaju plućnu TB (TB u plućima) ili otpornost na rifampicin te u kojima je uglavnom ispitana uporaba testa Xpert® MTB/RIF izvan naprednih laboratorija.

Također je uspoređena ostjetljivost testa Xpert® MTB/RIF s razmazom na mikroskopu, testom koji se često koristi za dijagnosticiranje TB u zemljama niskih i srednjih prihoda. Mikroskopija uzroka je pretraga niske cijene i lako je provediva, ali zahtijeva obrazovano osoblje i može biti gnjavaža za pacijente koji trebaju dati na analizu uzorak od najmanje dva ispljuvka. Također valja napomenuti da mikroskopija ne daje informaciju o otpornosti na lijek.

Pretražena je medicinska literatura kako bi se našle studije objavljene na bilo kojem jeziku do 7. veljače 2013. i analiziran je mogući rizik od pristranosti u tim studijama.

Što kažu rezultati

Uključeno je 27 studija s više od 9500 ispitanika. Većina studija provedene su u zemljama s niskim i srednjim prihodima. Većina studija imala je nizik rizik od pristranosti (bile su visoke metodološke kvalitete).

Ključni rezultati su:

Za dijagnozu TB Xpert® MTB/RIF test pokazao je dijagnostičku točnost (visoko je osjetljiv: 89%), otkrio je gotovo sve slučajeve i bio je visoko specifičan (99%) što znači da nije obilježio kao pozitivne osobe koje zapravo nemaju TB).

Za otkrivanje otpornosti na rifampicin Xpert® MTB/RIF test je bio dijagnostički točan, odnosno osjetljiv (95%) i specifičan (98%).

Čini se da Xpert® MTB/RIF ima sličnu dijagnostičku točnost u osoba sa i bez HIV infekcije.

Ako se rezultati ovog sutavnog pregleda primijene na zamišljenu skupinu od 1000 osoba koje dođu kod svojega liječnika zbog simptoma, ali samo 100 njih (10%) zaista ima TB, test Xpert® MTB/RIF bi dijagnosticirao 88 slučajeva i promašio dijagnosticirati 12 slučajeva TB, dok bi mikroskopija dijagnosticirala 65 slučajeva, a promašila 35 slučajeva.

Zaključno, ovaj sustavni pregled literature pokazuje da je test Xpert® MTB/RIF točniji nego mikroskopija za dijagnosticiranje TB i otkrivanje otpornosti na lijek rifampicin. Xpert® MTB/RIF može se koristiti u brojnim zemljama jer ne zahtijeva napredne laboratorijske uvjete niti stručno osoblje.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Livia Puljak
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr 

概要

Xpert MTB/RIF测试用于诊断成人肺结核和利福平耐药性

结核病在世界范围,特别是在低收入和中等收入国家,给人们带来了巨大的痛苦。2012年,共有860万人首次出现结核病(活动性结核病),约有130万人死亡。如果得到诊断和合适的治疗,大多数结核病患者可以被治愈。治疗结核病的一个问题是细菌对抗生素的耐药性。快速检测结核病和结核病耐药性对于改善健康状况,减少死亡和减少社区结核病的传播至关重要。

Xpert® MTB/RIF是一种能够快速同时检测TB和利福平耐药性的新试验。利福平是治疗结核病的重要药物。由于测试是自动化的,因此不需要专业人员或先进的实验室。

我们的目标是确定结核病检测和利福平耐药性检测的诊断准确性(敏感性和特异性)。敏感度显示对于真正患有结核病的人,该测试给出阳性结果的频率。特异性显示对于没有患结核病的人,该测试给出阴性结果的频率。

我们纳入了有或没有艾滋病毒感染,被认为有肺结核(肺部的结核病)或利福平耐药的成年人的研究,并且最感兴趣的是在最先进的实验室之外使用Xpert® MTB/RIF。

我们还比较了Xpert® MTB/RIF与涂片镜检的敏感度,涂片镜检通常用于低收入和中等收入国家的结核病诊断。涂片镜检成本低且相当容易做到,但需要经过培训的工作人员,并且由于必须至少提供两种痰样品,对患者来说很麻烦。此外,显微镜不提供关于耐药性的信息。

我们不限制语言,检索了2013年2月7日之前的出版物,并考虑到了研究报告偏倚结果的风险。

结果如下

我们纳入27项研究,涉及约9500人。大多数研究在低收入或中等收入国家进行。我们认为大多数研究的偏倚风险较低。

关键发现是:

对于结核病检测,Xpert® MTB/RIF是准确的(高灵敏度(89%),检测几乎所有病例;高特异性(99%),即在实际上阴性的人中没有检测阳性。

对于利福平耐药性检测,就灵敏度(95%)和特异性(98%)而言,Xpert® MTB/RIF是准确的。

Xpert® MTB/RIF在有和没有艾滋病毒感染的人中似乎具有相似的准确性。

将综述结果应用于1000人的假想人群,这个人群都出现症状,但其中只有100人(10%)实际上有结核病,Xpert® MTB/RIF可诊断出88例,漏诊12例,而涂片显微镜可诊断65例,漏诊35例。

总之,我们的综述显示,Xpert® MTB/RIF比用于诊断结核病的涂片镜检更准确,并且也能准确地检测利福平耐药性。Xpert® MTB/RIF可能在许多国家有用,因为它不需要先进的实验室设施或专业人员。

翻译注解

译者:李文元,审校:孙瑾。北京中医药大学循证医学中心

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