Diagnosing tuberculosis in hospitalized HIV-infected individuals who cannot produce sputum: is urine lipoarabinomannan testing the answer?

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Abstract

Background

Up to one third of HIV-infected individuals with suspected TB are sputum-scarce. The Alere Determine™ TB LAM Ag lateral flow strip test can be used to diagnose TB in HIV-infected patients with advanced immunosuppression. However, how urine LAM testing should be incorporated into testing algorithms and in the context of specific patient sub-groups remains unclear.

Methods

This study represents a post hoc sub-group analysis of data from a randomized multi-center parent study. The study population consisted of hospitalized HIV-infected patients with suspected TB who were unable to produce sputum and who underwent urine LAM testing. The diagnostic utility of urine LAM for TB in this group was compared to the performance of urine LAM in patients who did produce a sputum sample in the parent study.

Results

There were a total of 187 and 2341 patients in the sputum-scarce and sputum-producing cohorts, respectively. 80 of the sputum-scarce patients underwent testing with urine LAM. In comparison to those who did produce sputum, sputum-scarce patients had a younger age, a lower Karnofsky performance score, and a lower weight and BMI at admission. A greater proportion of sputum-scarce patients were urine LAM positive, compared to those who were able to produce sputum (31% vs. 21%, p = 0.04). A higher proportion of sputum-scarce patients died within 8 weeks of admission (32% vs. 24%, p = 0.013). We inferred that 19% of HIV-infected sputum-scarce patients suspected of TB were diagnosed with tuberculosis by urine LAM testing, with an estimated positive predictive value of 63% (95% CI 43–82%).

Conclusions

Urine LAM testing can effectively identify tuberculosis in HIV-infected patients who are at a higher risk of mortality yet are unable to generate a sputum sample for diagnostic testing. Our findings support the use of urine LAM testing in sputum-scarce hospitalized HIV-infected patients, and its incorporation into diagnostic algorithms for this patient population.

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Most cited references 17

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Tuberculosis case fatality rates in high HIV prevalence populations in sub-Saharan Africa.

A. Harries, Y D Mukadi, Thomas Maher (2001)

Tuberculosis is a leading cause worldwide of morbidity and mortality among HIV-infected people. The HIV era has seen a dramatic increase of the tuberculosis case fatality rate (CFR) in high HIV prevalence populations. Providing care for HIV-infected people must include measures to tackle this high tuberculosis CFR. To analyse the extent of the increased tuberculosis CFR in high HIV prevalence populations in sub-Saharan Africa, the reasons for this increase and the causes of death, in order to identify possible ways of tackling this problem. References were obtained by searching the MEDLINE on 'tuberculosis', 'HIV infection', and 'mortality' (MesH or textword). In addition, available data from National Tuberculosis Programme reports were reviewed. Tuberculosis CFR is closely linked to HIV prevalence. Limited autopsy data suggest that death from HIV-related diseases other than tuberculosis is probably the main reason for the increased CFR in HIV-infected tuberculosis patients. Among HIV-infected tuberculosis patients, the higher tuberculosis CFR in sputum smear-negative and extrapulmonary than in sputum smear-positive tuberculosis cases can also be attributed to misdiagnosis of HIV-related diseases as tuberculosis. The adverse effect of the HIV/AIDS epidemic on general health service performance probably accounts for the higher tuberculosis CFR among HIV-negative tuberculosis patients in high prevalence populations than that in low HIV-prevalence populations. Tackling the problem of the increased tuberculosis CFR in high HIV prevalence populations requires collaboration between tuberculosis control and HIV/AIDS programmes in implementing measures such as improved health services, tuberculosis and HIV control services, preventive treatment for HIV-related diseases and anti-HIV treatment.

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Diagnosing tuberculosis with urine lipoarabinomannan: systematic review and meta-analysis.

J Minion, E. Leung, E Talbot … (2011)

Lipoarabinomannan (LAM) is a potential marker of active tuberculosis (TB). We performed a systematic review and meta-analysis regarding use of urinary LAM assays for diagnosing active TB. We systematically searched for published and unpublished studies that evaluated urinary LAM for active TB diagnosis. Extracted data were pooled using bivariate random effects models and hierarchical summary receiver operating characteristic curves. Heterogeneity was explored through subgroup analysis and meta-regression. Quality was assessed according to standardised QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. In seven studies that assessed test accuracy in microbiologically confirmed cases only, estimates of sensitivity ranged from 13% to 93%, while specificity ranged from 87% to 99%. In five studies that assessed accuracy in clinical and confirmed TB cases, sensitivity ranged from 8% to 80%, while specificity ranged from 88% to 99%. In five studies with results stratified by HIV status, sensitivity was 3-53% higher in HIV-positive than HIV-negative subgroups; sensitivity was highest with advanced immunosuppression. The LAM urinary assay has several characteristics that make it attractive for diagnosing active TB, but has suboptimal sensitivity for routine clinical use. Further studies are needed to evaluate the potential value of the LAM assay in individuals with advanced HIV or for diagnosis of paediatric TB.

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Diagnostic accuracy of a urine lipoarabinomannan strip-test for TB detection in HIV-infected hospitalised patients.

Jonathan Peter, Grant Theron, Richard Nellis van Zyl-Smit … (2012)

Lack of point-of-care tests for tuberculosis (TB) result in diagnostic delay, and increased mortality and healthcare-related costs. The urine Determine(TM) TB-LAM point-of-care strip-test was evaluated in 335 prospectively-recruited hospitalised patients with suspected TB-HIV co-infection (group 1) and from 88 HIV-infected hospitalised patients with non-TB diagnoses (group 2). Cut-off point-specific analyses were performed using: 1) a microbiological reference standard (culture positive versus negative); and 2) a composite reference standard (exclusion of patients with clinical-TB from the culture-negative group). Using the microbiological reference and the manufacturer-recommended grade-1 cut-off point, LAM sensitivity and specificity was 66% (95% CI 57-74%). By contrast, using the composite reference sensitivity was 60% (95% CI 53-67%) and specificity improved to 96% (95% CI 89-100%) (p=0.001). The same pattern was seen when the grade-2 cut-off point was used (specificity 75% versus 96%; p=0.01). In group two patients specificity was poor using the grade-1 cut-off point, but improved significantly when the grade-2 cut-off point was used (90% versus 99%; p=0.009). The grade-2 cut-off point also offered superior inter-reader reliability (p=0.002). Sensitivity was highest in those with a CD4 <200 cells per mL. LAM combined with smear-microscopy was able to rule-in TB in 71% of Mycobacterium tuberculosis culture-positive patients. This preliminary study indicates that the LAM strip-test may be a potentially useful rapid rule-in test for TB in hospitalised patients with advanced immunosuppression. The grade 2, but not the manufacturer-recommended grade 1 cut-off point, offered superior rule-in utility and inter-reader reliability. Larger studies to evaluate cut-off points and diagnostic accuracy are urgently required.

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Author and article information

Contributors

Keertan Dheda:

ORCID: http://orcid.org/0000-0001-7709-5341

keertan.dheda@uct.ac.za

Journal

Journal ID (nlm-ta): BMC Infect Dis

Journal ID (iso-abbrev): BMC Infect. Dis

Title: BMC Infectious Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2334

Publication date (Electronic): 28 December 2017

Publication date PMC-release: 28 December 2017

Publication date Collection: 2017

Volume: 17

Electronic Location Identifier: 803

Affiliations

[1 ]ISNI 0000 0004 1937 1151, GRID grid.7836.a, Lung Infection and Immunity Unit, Division of Pulmonology and University of Cape Town Lung Institute, Department of Medicine, , University of Cape Town, ; H47 Old Main Building, Groote Schuur Hospital, Observatory, Cape Town, 7925 South Africa

[2 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Division of Respirology, Department of Medicine, , St. Michael’s Hospital and West Park Healthcare Centre, University of Toronto, ; Toronto, Canada

[3 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Surgery, , Mount Sinai Hospital, University of Toronto, ; Toronto, Canada

[4 ]ISNI 0000 0004 1937 1151, GRID grid.7836.a, Institute of Infectious Diseases and Molecular Medicine, , University of Cape Town, ; Cape Town, South Africa

Author information

Keertan Dheda http://orcid.org/0000-0001-7709-5341

Article

Publisher ID: 2914

DOI: 10.1186/s12879-017-2914-7

PMC ID: 5745979

PubMed ID: 29282005

SO-VID: c908bcae-513b-4e4f-9871-21f91614d112

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.