Browsing by Author "Broger T"

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Diagnostic yield as an important metric for the evaluation of novel tuberculosis tests: rationale and guidance for future research.
(2024-Jul) Broger T; Marx FM; Theron G; Marais BJ; Nicol MP; Kerkhoff AD; Nathavitharana R; Huerga H; Gupta-Wright A; Kohli M; Nichols BE; Muyoyeta M; Meintjes G; Ruhwald M; Peeling RW; Pai NP; Pollock NR; Pai M; Cattamanchi A; Dowdy DW; Dewan P; Denkinger CM; Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia.; Boston Children's Hospital, Boston, MA, USA.; The University of Sydney Infectious Diseases Institute, Sydney, NSW, Australia; Children's Hospital at Westmead, Sydney, NSW, Australia.; Bill & Melinda Gates Foundation, Seattle, WA, USA.; Department of Epidemiology, Epicentre, Paris, France.; McGill International TB Centre, McGill University, Montreal, QC, Canada.; Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA; Department of Medicine, Division of Pulmonary Diseases and Critical Care Medicine, University of California Irvine, Irvine, CA, USA.; Department of Infectious Disease and Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany; DSI-NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Faculty of Science, Stellenbosch University, Stellenbosch, South Africa.; London School of Hygiene & Tropical Medicine, London, UK.; DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.; Department of Infectious Disease and Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany; German Center for Infection Research, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: claudia.denkinger@uni-heidelberg.de.; Department of Infectious Disease and Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany.; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.; Department of Medicine, University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.; Division of HIV, Infectious Diseases, and Global Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, USA; Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA.; Division of Infection and Immunity, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.; Department of Medicine, Centre for Outcomes Research & Evaluation, McGill University, Montreal, QC, Canada.; FIND, Geneva, Switzerland.; Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA, USA.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
Better access to tuberculosis testing is a key priority for fighting tuberculosis, the leading cause of infectious disease deaths in people. Despite the roll-out of molecular WHO-recommended rapid diagnostics to replace sputum smear microscopy over the past decade, a large diagnostic gap remains. Of the estimated 10·6 million people who developed tuberculosis globally in 2022, more than 3·1 million were not diagnosed. An exclusive focus on improving tuberculosis test accuracy alone will not be sufficient to close the diagnostic gap for tuberculosis. Diagnostic yield, which we define as the proportion of people in whom a diagnostic test identifies tuberculosis among all people we attempt to test for tuberculosis, is an important metric not adequately explored. Diagnostic yield is particularly relevant for subpopulations unable to produce sputum such as young children, people living with HIV, and people with subclinical tuberculosis. As more accessible non-sputum specimens (eg, urine, oral swabs, saliva, capillary blood, and breath) are being explored for point-of-care tuberculosis testing, the concept of yield will be of growing importance. Using the example of urine lipoarabinomannan testing, we illustrate how even tests with limited sensitivity can diagnose more people with tuberculosis if they enable increased diagnostic yield. Using tongue swab-based molecular tuberculosis testing as another example, we provide definitions and guidance for the design and conduct of pragmatic studies that assess diagnostic yield. Lastly, we show how diagnostic yield and other important test characteristics, such as cost and implementation feasibility, are essential for increased effective population coverage, which is required for optimal clinical care and transmission impact. We are calling for diagnostic yield to be incorporated into tuberculosis test evaluation processes, including the WHO Grading of Recommendations, Assessment, Development, and Evaluations process, providing a crucial real-life implementation metric that complements traditional accuracy measures.
Diagnostic yield of urine lipoarabinomannan and sputum tuberculosis tests in people living with HIV: a systematic review and meta-analysis of individual participant data.
(2023-Jun) Broger T; Koeppel L; Huerga H; Miller P; Gupta-Wright A; Blanc FX; Esmail A; Reeve BWP; Floridia M; Kerkhoff AD; Ciccacci F; Kasaro MP; Thit SS; Bastard M; Ferlazzo G; Yoon C; Van Hoving DJ; Sossen B; García JI; Cummings MJ; Wake RM; Hanson J; Cattamanchi A; Meintjes G; Maartens G; Wood R; Theron G; Dheda K; Olaru ID; Denkinger CM; Population Health Program, Tuberculosis Group, Texas Biomedical Research Institute, San Antonio, TX, USA.; National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy.; Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA; Trauma Center, University of California San Francisco, San Francisco, CA, USA; Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA.; Division of Emergency Medicine, University of Cape Town, Cape Town, South Africa; Division of Emergency Medicine, Stellenbosch University, Cape Town, South Africa.; The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.; Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.; Faculty of Infectious and Tropical Diseases, Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, UK; Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute, University of Cape Town, Cape Town, South Africa; South African MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa.; Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Irving Medical Center, New York, NY, USA; Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA.; Division of Infectious Disease and Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany.; New Zealand Institute for Plant and Food Research, Auckland, New Zealand.; Department of Medicine, University of Cape Town, Cape Town, South Africa; Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.; Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA; Department of Medicine, Division of Pulmonary Diseases and Critical Care Medicine, University of California Irvine, Irvine, CA, USA.; Department of Medicine, University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.; UniCamillus, International University of Health and Medical Science, Rome, Italy; Community of Sant'Egidio, DREAM programme, Rome, Italy.; Field Epidemiology Department, Epicentre, Paris, France.; Department of Medicine, Médecins Sans Frontières, Paris, France.; Division of Infectious Disease and Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany; Clinical Research Department, London School of Hygiene & Tropical Medicine, London, UK.; Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute, University of Cape Town, Cape Town, South Africa; South African MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia; UNC Global Projects, LLC Zambia, Lusaka, Zambia.; Institute for Global Health, University College London, London, UK; Clinical Research Department, London School of Hygiene & Tropical Medicine, London, UK.; Centre for Healthcare-Associated Infections, Antimicrobial Resistance and Mycoses, National Institute for Communicable Diseases, Johannesburg, South Africa; Institute for Infection and Immunity, St George's University of London, London, UK.; Department of Medicine, Division of Pulmonary and Critical Care Medicine, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA; Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA.; Department of Medicine, University of Medicine 2, Yangon, Myanmar.; Service de Pneumologie, l'institut du thorax, Nantes Université, CHU Nantes, Nantes, France.; Division of Infectious Disease and Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany; German Center for Infection Research, partner site, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: claudia.denkinger@uni-heidelberg.de.; DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; South African Medical Research Council Centre for Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: Sputum is the most widely used sample to diagnose active tuberculosis, but many people living with HIV are unable to produce sputum. Urine, in contrast, is readily available. We hypothesised that sample availability influences the diagnostic yield of various tuberculosis tests. METHODS: In this systematic review and meta-analysis of individual participant data, we compared the diagnostic yield of point-of-care urine-based lipoarabinomannan tests with that of sputum-based nucleic acid amplification tests (NAATs) and sputum smear microscopy (SSM). We used microbiologically confirmed tuberculosis based on positive culture or NAAT from any body site as the denominator and accounted for sample provision. We searched PubMed, Web of Science, Embase, African Journals Online, and clinicaltrials.gov from database inception to Feb 24, 2022 for randomised controlled trials, cross-sectional studies, and cohort studies that assessed urine lipoarabinomannan point-of-care tests and sputum NAATs for active tuberculosis detection in participants irrespective of tuberculosis symptoms, HIV status, CD4 cell count, or study setting. We excluded studies in which recruitment was not consecutive, systematic, or random; provision of sputum or urine was an inclusion criterion; less than 30 participants were diagnosed with tuberculosis; early research assays without clearly defined cutoffs were tested; and humans were not studied. We extracted study-level data, and authors of eligible studies were invited to contribute deidentified individual participant data. The main outcomes were the tuberculosis diagnostic yields of urine lipoarabinomannan tests, sputum NAATs, and SSM. Diagnostic yields were predicted using Bayesian random-effects and mixed-effects meta-analyses. This study is registered with PROSPERO, CRD42021230337. FINDINGS: We identified 844 records, from which 20 datasets and 10 202 participants (4561 [45%] male participants and 5641 [55%] female participants) were included in the meta-analysis. All studies assessed sputum Xpert (MTB/RIF or Ultra, Cepheid, Sunnyvale, CA, USA) and urine Alere Determine TB LAM (AlereLAM, Abbott, Chicago, IL, USA) in people living with HIV aged 15 years or older. Nearly all (9957 [98%] of 10 202) participants provided urine, and 82% (8360 of 10 202) provided sputum within 2 days. In studies that enrolled unselected inpatients irrespective of tuberculosis symptoms, only 54% (1084 of 1993) of participants provided sputum, whereas 99% (1966 of 1993) provided urine. Diagnostic yield was 41% (95% credible interval [CrI] 15-66) for AlereLAM, 61% (95% Crl 25-88) for Xpert, and 32% (95% Crl 10-55) for SSM. Heterogeneity existed across studies in the diagnostic yield, influenced by CD4 cell count, tuberculosis symptoms, and clinical setting. In predefined subgroup analyses, all tests had higher yields in symptomatic participants, and AlereLAM yield was higher in those with low CD4 counts and inpatients. AlereLAM and Xpert yields were similar among inpatients in studies enrolling unselected participants who were not assessed for tuberculosis symptoms (51% vs 47%). AlereLAM and Xpert together had a yield of 71% in unselected inpatients, supporting the implementation of combined testing strategies. INTERPRETATION: AlereLAM, with its rapid turnaround time and simplicity, should be prioritised to inform tuberculosis therapy among inpatients who are HIV-positive, regardless of symptoms or CD4 cell count. The yield of sputum-based tuberculosis tests is undermined by people living with HIV who cannot produce sputum, whereas nearly all participants are able to provide urine. The strengths of this meta-analysis are its large size, the carefully harmonised denominator, and the use of Bayesian random-effects and mixed-effects models to predict yields; however, data were geographically restricted, clinically diagnosed tuberculosis was not considered in the denominator, and little information exists on strategies for obtaining sputum samples. FUNDING: FIND, the Global Alliance for Diagnostics.
Tuberculosis test results using fresh versus biobanked urine samples with FujiLAM.
(2020-Jan) Broger T; Muyoyeta M; Kerkhoff AD; Denkinger CM; Moreau E; FIND, 1202 Geneva, Switzerland. Electronic address: emmanuel.moreau@finddx.org.; FIND, 1202 Geneva, Switzerland.; FIND, 1202 Geneva, Switzerland; Division of Tropical Medicine, Center of Infectious Diseases, University of Heidelberg, Heidelberg, Germany.; Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, Department of Medicine, University of California, San Francisco, CA, USA.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
User perspectives and preferences on a novel TB LAM diagnostic (Fujifilm SILVAMP TB LAM)-a qualitative study in Malawi and Zambia.
(2022) Herrmann Y; Lainati F; Castro MDM; Mwamba CP; Kumwenda M; Muyoyeta M; Broger T; Heinrich N; Olbrich L; Corbett EL; McMahon SA; Engel N; Denkinger CM; Malawi-Liverpool-Wellcome Clinical Research Programme (MLW), Public Health Group, Blantyre, Malawi.; London School of Hygiene and Tropical Medicine, Infectious and Tropical Diseases, London, United Kingdom.; Division for Infectious Diseases, LMU Hospital, Munich, Germany.; Maastricht University, Department of Health, Ethics & Society, Research School for Public Health and Primary Care, Maastricht, The Netherlands.; Centre for Infectious Disease Research in Zambia, Social & Behavioural Science Group, Lusaka, Zambia.; International Health Department, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.; Centre for Infectious Disease Research in Zambia, Tuberculosis Department, Lusaka, Zambia.; Division of Clinical Infectious Disease and Tropical Medicine, Centre for Infectious Diseases, Heidelberg University Hospital, Heidelberg, Germany.; German Centre for Infection Research (DZIF), Partner Site Heidelberg University Hospital, Heidelberg, Germany.; Heidelberg University Hospital, Heidelberg Institute of Global Health, Heidelberg, Germany.; German Centre for Infection Research (DZIF), Partner Site Munich, Munich, Germany.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
Widely available tuberculosis (TB) diagnostics use sputum samples. However, many patients, particularly children and patients living with HIV (PLHIV), struggle to provide sputum. Urine diagnostics are a promising approach to circumvent this challenge while delivering reliable and timely diagnosis. This qualitative study in two high TB/HIV burden countries assesses values and preferences of end-users, along with potential barriers for the implementation of the novel Fujifilm SILVAMP TB-LAM (FujiLAM, Fujifilm, Japan) urine test. Between September 2020 and March 2021, we conducted 42 semi-structured interviews with patients, health care providers (HCPs) and decision makers (DMs) (e.g., in national TB programs) in Malawi and Zambia. Interviews were transcribed verbatim and analyzed using a framework approach supported by NVIVO. Findings aligned with the pre-existing Health Equity Implementation Framework, which guided the presentation of results. The ease and convenience of urine-based testing was described as empowering among patients and HCPs who lamented the difficulty of sputum collection, however HCPs expressed concerns that a shift in agency to the patient may affect clinic workflows (e.g., due to less control over collection). Implementation facilitators, such as shorter turnaround times, were welcomed by operators and patients alike. The decentralization of diagnostics was considered possible with FujiLAM by HCPs and DMs due to low infrastructure requirements. Finally, our findings support efforts for eliminating the CD4 count as an eligibility criterion for LAM testing, to facilitate implementation and benefit a wider range of patients. Our study identified barriers and facilitators relevant to scale-up of urine LAM tests in Malawi and Zambia. FujiLAM could positively impact health equity, as it would particularly benefit patient groups currently underserved by existing TB diagnostics. Participants view the approach as a viable, acceptable, and likely sustainable option in low- and middle-income countries, though adaptations may be required to current health care processes for deployment. Trial registration: German Clinical Trials Register, DRKS00021003. URL: https://www.drks.de/drks_web/setLocale_EN.do.