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Underestimation of the incremental diagnostic yield of HIV-associated tuberculosis in studies of the Determine TB-LAM Ag urine assay

Lawn, Stephen D.a,b; Kerkhoff, Andrew D.b,d; Burton, Rosiee,f; Meintjes, Graemec,e

doi: 10.1097/QAD.0000000000000305

aDepartment of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

bThe Desmond Tutu HIV Centre

cClinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

dGeorge Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA

eDepartment of Medicine, Faculty of Health Sciences, University of Cape Town

fKhayelitsha District Hospital, Cape Town, South Africa.

Correspondence to Stephen D. Lawn, Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Tel: +44 20 7927 2546; e-mail:

Received 7 April, 2014

Revised 9 April, 2014

Accepted 10 April, 2014

We read with interest the study from Uganda reported by Shah et al. [1] regarding the diagnosis of tuberculosis (TB) among HIV-infected patients, most of whom were hospital in-patients. Using a culture-based reference standard, the diagnostic yields from testing sputum samples with fluorescence microscopy and the Xpert MTB/RIF assay were compared with the yield from testing urine using a simple lateral-flow assay (Determine TB-LAM Ag; Alere Inc., Waltham, Massachusetts, USA). The latter is a low-cost, point-of-care test that provides a rapid diagnosis of TB by detection of lipoarabinomannan (LAM) in urine. This is emerging as a useful diagnostic tool among defined subgroups of HIV-infected patients with low CD4+ cells counts, poor prognostic characteristics (e.g. advanced anaemia), and those with highest risk of death [2–5].

Shah et al. [1] found that the urine LAM lateral-flow assay provided an useful incremental yield when used as an add-on test in combination with sputum assays. Compared with the yield from sputum smear fluorescence microscopy alone, additional use of the urine LAM assay increased the sensitivity from 42% to 67%. Similarly, compared with testing of sputum with the Xpert MTB/RIF assay alone, additional use of the urine LAM assay increased the yield from 76% to 85% [1]. These valuable data add to the growing evidence base supporting implementation of the urine LAM assay as an add-on test that allows rapid TB diagnosis in patients with low CD4+ cell counts.

In a previous study of HIV-infected out-patients, we similarly found that the urine LAM lateral-flow assay provided an incremental diagnostic yield when used in combination with sputum-based testing [6]. However, more recently generated data [7] suggest that published studies to date (including our own out-patient study) [6] may potentially have underestimated the true incremental yield of the urine LAM assay. Previous studies have selectively included only patients able to produce sputum samples since analysis of these has formed the mainstay of the reference standard for assessment of diagnostic accuracy. Thus, the findings and conclusions of these studies are restricted to ‘sputum producers’.

In a recently completed study of HIV-associated TB diagnosis in South Africa, we intensively investigated unselected HIV-positive patients requiring medical admission to a district hospital in Cape Town [7]. Regardless of clinical presentation and respiratory symptoms, a large number of respiratory and nonrespiratory samples were collected when possible. However, only 37% of patients could produce sputum samples during the first 24 h of admission despite careful instruction, assistance from a dedicated study nurse and the use of nebulized sputum induction when feasible. In contrast, 98% of the patients readily provided a urine sample.

The overall prevalence of microbiologically defined TB was 32.6%, but many cases could only be diagnosed during admission using nonrespiratory samples. Using clinical samples obtained during the first 24 h of admission, the diagnostic yield using the urine LAM test far exceeded that from testing sputum samples. The LAM lateral-flow tests were read using grade 2 cut-off in accordance with consensus among investigators [8] and specificity was extremely high (98.9%). Compared with the yield from fluorescence microscopy of sputum smears, additional use of the urine LAM assay increased the diagnostic yield enormously (2.5-fold). Similarly, compared with the yield from testing sputum with the Xpert MTB/RIF assay, additional use of urine LAM assay increased the yield by 2.0-fold. Of note, two-thirds of true-positive urine LAM results were among TB patients who could not produce sputum samples and these would not have been included in studies selectively investigating patients able to produce sputum.

We suspect that underestimation of the diagnostic yield of urine LAM assays is likely to be much greater among studies of in-patients rather than out-patients. In our previous study of ambulatory out-patients, satisfactory sputum samples could be obtained from 90% of the patients with the assistance of sputum induction [6,9]. In contrast, in-patients in hospitals in sub-Saharan Africa are typically very ill indeed and physical incapacitation means that obtaining sputum samples is often very challenging. Such in-patients are often excluded from studies of TB diagnostics on this basis and so potential selection bias is great.

In conclusion, studies of the incremental diagnostic yield and clinical impact of urine LAM assays should not be restricted to investigation of patients who are able to produce sputum samples. Moreover, we suggest the urine LAM assay would best be used as a routine screening test among HIV-infected medical in-patients rather than as a test for selective investigation of a subset of patients traditionally identified as ‘TB suspects’ on the basis of respiratory symptoms.

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S.D.L. and G.M. are funded by the Wellcome Trust, London.

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Conflicts of interest

There are no conflicts of interest.

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