Diagnosis

The development of the Xpert MTB/RIF assay (Cepheid, Sunnyvale, United States of America [USA]) was a significant step forward for improving the diagnosis of TB and the detection of rifampicin resistance globally. However, Xpert MTB/RIF sensitivity is suboptimal, particularly in smear-negative and HIV-associated TB patients. The Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, USA), hereafter referred to as Xpert Ultra, was developed by Cepheid as the next-generation assay to overcome these limitations. It uses the same GeneXpert^® platform as the Xpert MTB/RIF.

The political declaration at the first United Nations (UN) high-level meeting on tuberculosis (TB) held on 26 September 2018 included commitments by Member States to four new global targets (1), which were subsequently renewed at the second UN high-level meeting on TB on 22 September 2023 (2). One of these targets is that at least 90 per cent of the estimated number of people who develop TB are reached with quality-assured diagnosis and treatment in the 5-year period 2023–2027 (2).

Among 105 countries possessing representative data on resistance to fluoroquinolones from the past 15 years, the proportion of MDR/RR-TB cases with resistance to any fluoroquinolone for which testing was done was 20.1% (95% CI: 15.5–25.0%). Thus, rapid and early testing for the detection of fluoroquinolone resistance is essential for determining eligibility for treatment with the all-oral 9–12 month standardized shorter regimen for MDR/RR-TB.

Rapid detection of TB and rifampicin resistance is increasingly available as new technologies are developed and adopted by countries. However, what has also emerged is the relatively high burden of isoniazid-resistant, rifampicin-susceptible TB that is often undiagnosed. Globally, isoniazid-resistant, rifampicin-susceptible TB is estimated to occur in 13.1% (95% CI: 9.9–16.9%) of new cases and 17.4% (95% CI: 0.5–54.0%) of previously treated cases (14).

Genotypic (molecular) methods have considerable advantages for scaling up programmatic management and surveillance of DR-TB, offering rapid diagnosis, standardized testing, potential for high throughput and fewer requirements for laboratory biosafety. Molecular tests for detecting drug resistance – for example, the GenoType MTBDRsl assay (Hain Lifescience, Nehren, Germany), hereafter referred to as MTBDRsl (17) – have shown promise for the diagnosis of DR-TB.

In 2008, WHO approved the use of commercial LPAs for detecting MTBC in combination with resistance to rifampicin and isoniazid in sputum smear-positive specimens (direct testing) and in cultured isolates of MTBC (indirect testing). A systematic review at that time evaluated the diagnostic accuracy of two commercially available LPAs – the INNO-LiPA Rif.TB assay (Innogenetics, Ghent, Belgium), and the GenoType^® MTBDRplus (version 1), hereafter referred to as Hain version 1 – and provided evidence for WHO’s endorsement (37, 38).

A commercial molecular assay, the Loopamp^ᵀᴹ Mycobacterium tuberculosis complex (MTBC) detection kit (Eiken Chemical Company, Tokyo, Japan), is based on loop-mediated isothermal amplification (LAMP) reaction. Referred to as TB-LAMP, this is a manual assay that requires less than 1 hour to perform and can be read with the naked eye under UV light. Because it requires little infrastructure and is relatively easy to use, TB-LAMP is being explored for use as a rapid diagnostic test that would be an alternative to smear microscopy in resource-limited settings.

Methods used to develop World Health Organization guidelines

To develop new or update existing guidelines for methods and tools to diagnose tuberculosis (TB), the World Health Organization (WHO) Global TB Programme commissions systematic reviews on the performance or use of the tool or method in question. A systematic review provides a summary of the current literature on diagnostic accuracy or user aspects, for the diagnosis of TB or the detection of anti-TB drug resistance in adults or children (or both) with signs and symptoms of TB.

Advanced HIV disease: for adults, adolescents, and children aged 5 years or more, “advanced HIV disease” is defined as a CD4 cell count of less than 200 cells/mm³ or a WHO clinical stage 3 or 4 event at presentation for care. All children with HIV aged under 5 years should be considered as having advanced disease at presentation.

Age groups: the following definitions for adults and children are used in these guidelines for the purpose of implementing recommendations (countries may have other definitions under their national regulations)² :

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