title: Test characteristics and potential impact of the urine LAM lateral flow assay in HIV-infected outpatients under investigation for TB and able to self-expectorate sputum for diagnostic testing.
abstract: BACKGROUND
  The commercially available urine LAM strip test, a point-of-care tuberculosis (TB) assay, requires evaluation in a primary care setting where it is most needed. There is currently inadequate data to guide implementation in TB and HIV-endemic settings.
  
  
  METHODS
  Adult HIV-infected outpatients with suspected pulmonary TB able to self-expectorate sputum from four primary clinics in South Africa, Zambia and Tanzania underwent diagnostic evaluation [sputum smear microscopy, Xpert-MTB/RIF, and culture (reference standard)] as part of a prospective parent study. Urine LAM testing (grade-2 cut-point) was performed on archived samples. Performance characteristics of LAM alone or in combination with sputum-based diagnostics were evaluated. Potential impact on 2 and 6-month morbidity (TBscore), patient dropout rates, and prognosis (death/ loss to follow-up) were evaluated.
  
  
  RESULTS
  Among 583 participants with suspected TB that were HIV-infected or refused testing, the overall LAM sensitivity (95 % CI; n/N) and in the CD4 ≤ 100 cells/mm(3) sub-group was 22.7 % (16.6-28.7; 41/181) and 30.4 % (17.1-43.7; 14/46), respectively. Overall specificity was 93.0 % (90.5-95.6; 361/388). Amongst culture-positive TB cases, adjunctive LAM testing did not improve the sensitivity of either sputum Xpert-MTB/RIF [78.2 % (69.8-86.7; 72/92) versus 76.1 % (67.4-84.8; 70/92), p = 0.7] or smear-microscopy [56.2 % (45.9-66.5; 50/89) versus 43.8 % (33.5-54.1; 39/89), p = 0.1). Clinic-based LAM, as an adjunct to either smear microscopy or Xpert MTB/RIF same-day testing, would neither have decreased patient dropout, nor increased same-day treatment initiation in this clinical setting where same-day chest radiography was available. LAM positivity was associated with 6-month lost-to-follow-up/death (AOR 4.4; p = 0.002) but not TBscore (at baseline or change in TBscore 2-months post-treatment) (p = 0.17).
  
  
  CONCLUSIONS
  In African HIV-TB co-infected outpatients able to self-expectorate sputum LAM had limited sensitivity even at low CD4 counts, and offered no significant incremental diagnostic yield over Xpert-MTB/RIF or smear microscopy. In primary care clinics with chest radiography and where empiric TB treatment is common, LAM seems unlikely to improve rates of same-day treatment initiation and patient dropout, however, the ability of LAM to identify patients at high risk of death or lost-to-follow-up may offer important prognostic value.
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology & UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. Jonny.Peter@uct.ac.za.|TB Vaccine group, Jenner Institute, University of Oxford, Oxford, UK. Jonny.Peter@uct.ac.za.|Department of Medicine, University of Cape Town, Cape Town, South Africa. Jonny.Peter@uct.ac.za.
authors.forename: Jonny
authors.initials: J
authors.lastname: Peter
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology & UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. Grant.Theron@uct.ac.za.
authors.forename: Grant
authors.initials: G
authors.lastname: Theron
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology & UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. duncanchanda@gmail.com.|Institute for Medical Research & Training (IMReT), University Teaching Hospital, Lusaka, Zambia. duncanchanda@gmail.com.
authors.forename: Duncan
authors.initials: D
authors.lastname: Chanda
authors.affiliation: National Institute of Medical Research, Mbeya Medical Research Centre, Mbeya, Tanzania. pclowes@nimr-mmrc.org.|Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich (LMU), Munich, Germany. pclowes@nimr-mmrc.org.
authors.forename: Petra
authors.initials: P
authors.lastname: Clowes
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich (LMU), Munich, Germany. arachow@mmrp.org.|German Centre for Infection Research (DZIF), Munich, Germany. arachow@mmrp.org.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rachow
authors.affiliation: Department of Medicine, University of Cape Town, Cape Town, South Africa. lesosky@gmail.com.
authors.forename: Maia
authors.initials: M
authors.lastname: Lesosky
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich (LMU), Munich, Germany. hoelscher@lrz.uni-muenchen.de.|German Centre for Infection Research (DZIF), Munich, Germany. hoelscher@lrz.uni-muenchen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
authors.affiliation: Institute for Medical Research & Training (IMReT), University Teaching Hospital, Lusaka, Zambia. pbmwaba2000@yahoo.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Mwaba
authors.affiliation: South African Medical Research Council, Durban, South Africa, KwaZulu Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa. alexanderpym@hotmail.com.
authors.forename: Alex
authors.initials: A
authors.lastname: Pym
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology & UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. keertan.dheda@uct.ac.za.|Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. keertan.dheda@uct.ac.za.
authors.forename: Keertan
authors.initials: K
authors.lastname: Dheda
mesh_terms: D000328:Adult; D000368:Aged; D000554:Ambulatory Care Facilities; D001681:Biological Assay; D018791:CD4 Lymphocyte Count; D060085:Coinfection; D003430:Cross-Sectional Studies; D003955:Diagnostic Tests, Routine; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D006801:Humans; D008070:Lipopolysaccharides / Q000652:urine*; D008297:Male; D008875:Middle Aged; D010045:Outpatients; D019095:Point-of-Care Systems; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D013019:South Africa; D013183:Sputum / Q000382:microbiology*; D013636:Tanzania; D014376:Tuberculosis / Q000175:diagnosis; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000175:diagnosis* / Q000276:immunology; D016482:Urinalysis; D055815:Young Adult; D015024:Zambia
chemical_list: D008070:Lipopolysaccharides; C050016:lipoarabinomannan