Diagnostic accuracy, incremental yield and prognostic value of Determine TB-LAM for routine diagnostic testing for tuberculosis in HIV-infected patients requiring acute hospital admission in South Africa: a prospective cohort

Abstract

Background: We previously reported that one-third of HIV-positive adults requiring medical admission to a South African district hospital had laboratory-confirmed tuberculosis (TB) and that almost two-thirds of cases could be rapidly diagnosed using Xpert MTB/RIF-testing of concentrated urine samples obtained on the first day of admission. Implementation of urine-based, routine, point-of-care TB screening is an attractive intervention that might be facilitated by use of a simple, low-cost diagnostic tool, such as the Determine TB-LAM lateral-flow rapid test for HIV-associated TB.

Methods: Sputum, urine and blood samples were systematically obtained from unselected HIV-positive adults within 24 hours of admission to a South African township hospital. Additional clinical samples were obtained during hospitalization as clinically indicated. TB was defined by the detection of Mycobacterium tuberculosis in any sample using Xpert MTB/RIF or liquid culture. The diagnostic yield, accuracy and prognostic value of urine-lipoarabinomannan (LAM) testing were determined, but urine-LAM results did not inform treatment decisions.

Results: Consecutive HIV-positive adult acute medical admissions not already receiving TB treatment (n = 427) were enrolled regardless of clinical presentation or symptoms. TB was diagnosed in 139 patients (TB prevalence 32.6%; median CD4 count 80 cells/μL). In the first 24 hours of admission, sputum (spot and/or induced) samples were obtained from 37.0% of patients and urine samples from 99.5% of patients (P < 0.001). The diagnostic yields from these specimens were 19.4% (n = 27/139) for sputum-microscopy, 26.6% (n = 37/139) for sputum-Xpert, 38.1% (n = 53/139) for urine-LAM and 52.5% (n = 73/139) for sputum-Xpert/urine-LAM combined (P < 0.01). Corresponding yields among patients with CD4 counts <100 cells/μL were 18.9%, 24.3%, 55.4% and 63.5%, respectively (P < 0.01). The diagnostic yield of urine-LAM was unrelated to respiratory symptoms, and LAM assay specificity (using a grade-2 cut-off) was 98.9% (274/277; 95% confidence interval [CI] 96.9-99.8). Among TB cases, positive urine-LAM status was strongly associated with mortality at 90 days (adjusted hazard ratio 4.20; 95% CI 1.50-11.75).

Conclusions: Routine testing for TB in newly admitted HIV-positive adults using Determine TB-LAM to test urine provides major incremental diagnostic yield with very high specificity when used in combination with sputum testing and has important utility among those without respiratory TB symptoms and/or unable to produce sputum. The assay also rapidly identifies individuals with a poor prognosis.

Keywords: Africa; Determine TB-LAM; Diagnosis; HIV; Hospital; LAM; Lipoarabinomannan; Screening; Tuberculosis; Urine; Xpert.

Fig. 1

Flow diagram showing the study population and the numbers of patients included. HIV human immunodeficiency virus, TB tuberculosis

Fig. 2

Venn diagrams showing the proportions of (a) total tuberculosis (TB) diagnoses (n = 139) or (b) TB diagnoses in patients with CD4 cell counts <100 cells/μL (n = 74) and the proportions (diagnostic yields) which could be made using smear microscopy, sputum Xpert or urine-lipoarabinomannan (LAM) (these tests were all conducted on samples obtained within 24 hours of admission). AFB Acid-fast bacilli

Fig. 3

Bar charts displaying the diagnostic yields of urine-lipoarabinomannan (LAM) testing stratified according to (a) patient CD4 cell count, (b) World Health Organization anaemia severity categorization, (c) self-reported cough and (d) self-reported sputum production. The numbers of patients in each stratum that were urine-LAM-positive are shown beneath each chart

Fig. 4

Cumulative probability of death within 90 days of study enrolment of patients with confirmed HIV-associated tuberculosis (n = 136 with urine samples available), stratified according to urine-lipoarabinomannan (LAM) status. For ease of viewing, a magnified view is shown in the upper right