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

  • 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.

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 

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