Urine lipoarabinomannan glycan in HIV-negative patients with pulmonary tuberculosis correlates with disease severity

We read with great interest the recent publication by Paris et al in Science Translational Medicine, which explored the coupling of nanocage technology with high-affinity chemical dye baits to improve accuracy of urine-based diagnostics in active Mycobacterium tuberculosis (Mtb) disease (1). This approach, where bacterial components are detected in the readily-collectable urine to diagnose disease remote to the urinary tract, forms the basis of currently available lateral flow tests using lipoarabinomannan (LAM), an outer surface glycan almost unique to Mtb (2,3). However, this test only reaches a sensitivity of around 70% in HIV-Mtb coinfection, and is greatest in the profoundly immunosuppressed with blood CD4 counts below 50 cells/mm3. It is particularly insensitive (<20%) in tuberculosis (TB) patients who are HIV uninfected (4). Thus, WHO recommends that the currently available lateral flow-LAM is not regarded as a screening test for TB, and is only used as an adjunctive test to assist in the diagnosis of TB in HIV co-infected adult patients with low CD4 counts, or who are seriously ill (5).

The paper by Paris et al elegantly demonstrated that the limitation of the utility of current methods to detect urinary LAM is largely down to LAM load in the sample. Recognising the challenge of raising monoclonal antibodies against complex carbohydrates such as LAM, the authors use the novel high affinity chemical bait RB221 immobilised within an open-mesh hydrogel nanoparticle cage (6), or nanocage, to sequester LAM from urine, prior to elution and detection. The process increased the sensitivity of LAM detection in the urine of HIV-uninfected patients with TB disease by 100 to 1000-fold. Commendably, they then further propose means by which to develop this diagnostic test into a lateral flow immunoassay, describing technology that is deployable in low-income settings (5). The modestly-sized proof of principle cohort of HIV-negative patients achieved a sensitivity >90% for diagnosis of TB, and the authors correctly acknowledge the need to validate these findings in larger cohorts whilst also making the case that nanocage-based LAM diagnostic tests have potential to become applicable for HIV-negative TB patients. Whilst we agree with this view, we also felt that this new technology with more sensitive LAM detection could also have a valuable role and more immediate clinical benefit within the HIV-TB co-infected population (1,7).

As the existing urinary LAM test can yield significant mortality reduction in HIV co-infected TB patients (8), the greater sensitivity of the nanocage-based LAM detection, without apparent reduction in specificity, is likely to contribute even more by offering a rapid diagnostic in situations where prompt and correct treatment initiation is often difficult to achieve yet may be life-saving (9). Furthermore, in a proportion of patients with advanced HIV infection (up to 20% in sub-Saharan Africa), TB disease manifests as part of an immune reconstitution inflammatory syndrome (IRIS) only after commencement of antiretroviral therapy (10). Given that this also carries significant morbidity and mortality, we believe that the more sensitive nanocage-based urinary LAM test has the potential to detect subclinical systemic TB infection in this subgroup of patients, identifying those that may benefit from pre-emptive anti-tuberculosis therapy that could prevent severe “unmasking” TB IRIS.

References
1. Paris L, Magni R, Zaidi F, Araujo R, Saini N, Harpole M, et al. Urine lipoarabinomannan glycan in HIV-negative patients with pulmonary tuberculosis correlates with disease severity. Sci Transl Med. 2017 Dec 13;9(420).
2. Shah M, Hanrahan C, Wang ZY, Dendukuri N, Lawn SD, Denkinger CM, et al. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults. Cochrane Database Syst Rev. 2016 May 10;(5):CD011420.
3. Qvist T, Johansen IS, Pressler T, Høiby N, Andersen AB, Katzenstein TL, et al. Urine lipoarabinomannan point-of-care testing in patients affected by pulmonary nontuberculous mycobacteria--experiences from the Danish Cystic Fibrosis cohort study. BMC Infect Dis. 2014 Dec 4;14:655.
4. Minion J, Leung E, Talbot E, Dheda K, Pai M, Menzies D. Diagnosing tuberculosis with urine lipoarabinomannan: systematic review and meta-analysis. Eur Respir J. 2011 Dec;38(6):1398–1405.
5. WHO | The use of lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis and screening of active tuberculosis in people living with HIV [Internet]. [cited 2018 Jan 15]. Available from: http://www.who.int/tb/publications/use-of-lf-lam-tb-hiv/en/
6. Tamburro D, Fredolini C, Espina V, Douglas TA, Ranganathan A, Ilag L, et al. Multifunctional core-shell nanoparticles: discovery of previously invisible biomarkers. J Am Chem Soc. 2011 Nov 30;133(47):19178–19188.
7. Hamasur B, Bruchfeld J, van Helden P, Källenius G, Svenson S. A sensitive urinary lipoarabinomannan test for tuberculosis. PLoS ONE. 2015 Apr 23;10(4):e0123457.
8. Peter JG, Zijenah LS, Chanda D, Clowes P, Lesosky M, Gina P, 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. The Lancet. 2016 Mar 19;387(10024):1187–1197.
9. Dheda K, Barry CE, Maartens G. Tuberculosis. The Lancet. 2016 Mar 19;387(10024):1211–1226.
10. Bell LCK, Breen R, Miller RF, Noursadeghi M, Lipman M. Paradoxical reactions and immune reconstitution inflammatory syndrome in tuberculosis. Int J Infect Dis. 2015 Mar;32:39–45.