A new point-of-care test to diagnose tuberculosis

In 2017, tuberculosis caused an estimated 1·6 million deaths, including 300 000 deaths among people with HIV, and surpassed HIV/AIDS to become the leading infectious cause of mortality worldwide.1WHOGlobal Tuberculosis Report 2018. World Health Organization, Geneva2018Google Scholar Approximately 36% of tuberculosis cases each year (around 3·5 million cases) are not diagnosed or reported, which might have contributed to the increase in tuberculosis prevalence.2WHOStop TB PartnershipThe missing 3 million: reach, treat, cure everyone. World Health Organization, Geneva2016http://www.stoptb.org/assets/documents/resources/factsheets/Stop%20TB%20infographic%20Missing%203%20Million.pdfDate accessed: January 16, 2019Google Scholar Current diagnostic tools in routine clinical use, including the GeneXpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA), rely on sputum-based testing, which has consistently demonstrated suboptimal diagnostic sensitivity, especially in immunocompromised people with HIV who are unable to produce sputum when admitted to hospital or at increased risk of extrapulmonary disease. Research and development of new tuberculosis diagnostics has been lagging behind knowledge of tuberculosis pathogenesis, which includes incipient and subclinical tuberculosis.3Drain PK Bajema KL Dowdy D et al.Incipient and subclinical tuberculosis: a clinical review of early stages and progression of infection.Clin Microbiol Rev. 2018; 31: e00021-e00028Crossref PubMed Scopus (221) Google Scholar As a result, WHO has prioritised a biomarker-based non-sputum test that could be used at the clinical point of care to rapidly diagnose all forms of tuberculosis (including extrapulmonary tuberculosis) for individuals of all ages, including children.4WHOHigh-priority target product profiles for new tuberculosis diagnostics: report of a consensus meeting. World Health Organization, Geneva2014Google Scholar In The Lancet Infectious Diseases, Tobias Broger and colleagues5Broger T Sossen B du Toit E et al.Novel lipoarabinomannan point-of-care tuberculosis test for people with HIV: a diagnostic accuracy study.Lancet Infect Dis. 2019; (published online May 30.)http://dx.doi.org/10.1016/S1473-3099(19)30001-5Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar evaluated a new urine-based point-of-care test for detecting urine lipoarabinomannan. The first commercial lipoarabinomannan assay, the Alere Determine TB LAM Ag (AlereLAM; Abbott, Chicago, IL, USA), has shown that lipoarabinomannan concentrations correlate with clinical disease severity and risk of mortality,6Drain PK Coleman SM Giddy J et al.Clinic-based urinary lipoarabinomannan as a biomarker of clinical disease severity and mortality among antiretroviral therapy-naive human immunodeficiency virus-infected adults in South Africa.Open Forum Infect Dis. 2017; 4: ofx167Crossref PubMed Scopus (11) Google Scholar and the use of this assay has been shown to improve outcomes for hospital inpatients with HIV in a randomised trial,7Peter JG Zijenah LS Chanda D et al.Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial.Lancet. 2016; 387: 1187-1197Summary Full Text Full Text PDF PubMed Scopus (171) Google Scholar but the assay has only moderate diagnostic sensitivity.8WHOGuidelines for LAM testing. World Health Organization, Geneva2015Google Scholar Broger and colleagues compared the diagnostic accuracy of the new Fujifilm SILVAMP TB LAM assay (FujiLAM; FujiFilm, Tokyo, Japan) with the AlereLAM assay by testing urine samples from three independent cohorts of hospital inpatients with HIV in South Africa. Qualitative results were compared to a microbiological reference standard, and a clinical reference standard that included an empirical diagnosis of tuberculosis. Among 968 participants, the prevalence of pulmonary tuberculosis and CD4 counts were consistent with that of high-risk immunocompromised people with HIV who might be recommended for lipoarabinomannan testing,8WHOGuidelines for LAM testing. World Health Organization, Geneva2015Google Scholar but not widely representative of people with HIV at risk for active tuberculosis. When compared with the microbiological reference standard, FujiLAM had a diagnostic sensitivity of 70·4% (95% CI 53·0 to 83·1) and specificity of 90·8% (86·0 to 94·4), and the AlereLAM had a diagnostic sensitivity of 42·3% (31·7 to 51·8) and specificity of 95·0% (87·7–98·8). The difference between the two assays was statistically significant for diagnostic sensitivity (difference 28·1%), but not for specificity (difference −4·2%). Based on these results, the authors concluded that the FujiLAM assay had improved diagnostic sensitivity, without compromising specificity, compared with the AlereLAM assay. Appropriate validation of point-of-care tests intended for use in resource-limited settings can be complicated, and considering diagnostic sensitivity and specificity in isolation might not accurately represent the real clinical value of a test.9Drain PK Hyle EP Noubary F et al.Diagnostic point-of-care tests in resource-limited settings.Lancet Infect Dis. 2014; 14: 239-249Summary Full Text Full Text PDF PubMed Scopus (420) Google Scholar Ideally, a point-of-care test would have higher diagnostic sensitivity and similar specificity, and could be used both to detect and exclude tuberculosis in this clinical setting. The two currently available urine lipoarabinomannan assays, with lower sensitivity, would primarily be used as so-called diagnostic rule-in tests, whereby a positive test result would be used to identify patients with tuberculosis, but a negative result would not necessarily exclude tuberculosis. Comparison of positive likelihood ratios might be more appropriate, since this ratio accounts for both sensitivity and specificity. The positive likelihood ratio is used in clinical medicine to determine whether a diagnostic test result changes the pretest probability that a disease exists (ie, active tuberculosis). When comparing diagnostic accuracy results against either the microbiological reference standard or the clinical reference standard, both of which the authors pointed out might be imperfect reference standards, the calculated positive likelihood ratio values were similar. The new FujiLAM assay will require further characterisation and validation in prospective studies using appropriate clinical, laboratory, and biomarker reference standards, with collection of participant outcomes and latent class modelling to adjudicate discordant results. The global health community now has two non-sputum biomarker assays that might be useful in clinical point-of-care settings to diagnose tuberculosis in people with HIV in endemic countries. Compared with the AlereLAM assay, the new FujiLAM assay includes novel monoclonal antibodies and enhanced detection technology to enable higher diagnostic sensitivity.10Sigal GB Pinter A Lowary TL et al.A novel sensitive immunoassay targeting the MTX-lipoarabinomannan epitope meets the WHO's performance target for tuberculosis diagnosis.J Clin Microbiol. 2018; 56: e01338-e01418Crossref PubMed Scopus (73) Google Scholar However, the use of FujiLAM might be less desirable since it has more operator steps and a longer time to result than AlereLAM. Similar to AlereLAM, the FujiLAM assay might require further optimisation for use as a diagnostic test among the larger population of people without HIV. Furthermore, validation and implementation studies in both adults and children are needed to broaden recommendations for urine lipoarabinomannan testing, to reliably diagnose tuberculosis, rapidly initiate appropriate therapy, and reduce tuberculosis mortality worldwide. The development of a second simple, rapid, point-of-care test is a major step forward for advancing tuberculosis diagnostics and could save lives as a result of early detection and treatment. However, as has been observed with the AlereLAM assay, WHO endorsement8WHOGuidelines for LAM testing. World Health Organization, Geneva2015Google Scholar and inclusion on the Essential Diagnostics List might not necessarily lead to rapid uptake.11Médecins Sans FrontièresStop TB PartnershipOut of step 2017. TB policies in 29 countries. A survey of prevention, testing and treatment policies and practices. Médecins Sans Frontières, Geneva2017Google Scholar For lives to be saved by the use of these point-of-care tests, implementation and modelling studies are needed to provide more guidance for national tuberculosis programmes. We declare no competing interests. Novel lipoarabinomannan point-of-care tuberculosis test for people with HIV: a diagnostic accuracy studyIn comparison to AlereLAM, FujiLAM offers superior diagnostic sensitivity, while maintaining specificity, and could transform rapid point-of-care tuberculosis diagnosis for hospital inpatients with HIV. The applicability of FujiLAM for settings of intended use requires prospective assessment. Full-Text PDF Open Access