Browsing by Author "Ruhwald M"

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A Prospective Evaluation of the Diagnostic Accuracy of the Point-of-Care VISITECT CD4 Advanced Disease Test in 7 Countries.
(2025-Feb-04) Gils T; Hella J; Jacobs BKM; Sossen B; Mukoka M; Muyoyeta M; Nakabugo E; Van Nguyen H; Ubolyam S; Macé A; Vermeulen M; Nyangu S; Sanjase N; Sasamalo M; Dinh HT; Ngo TA; Manosuthi W; Jirajariyavej S; Denkinger CM; Nguyen NV; Avihingsanon A; Nakiyingi L; Székely R; Kerkhoff AD; MacPherson P; Meintjes G; Reither K; Ruhwald M; School of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom.; German Centre for Infection Research, Heidelberg University Hospital, Heidelberg, Germany.; Viet Tiep Hospital, Hai Phong, Viet Nam.; Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand.; National Lung Hospital, Ha Noi, Viet Nam.; Taksin Hospital, Bangkok, Thailand.; Global Health Institute, University of Antwerp, Wilrijk, Belgium.; Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.; Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.; University of Basel, Basel, Switzerland.; Public Health Group, Malawi-Liverpool-Wellcome Programme, Blantyre, Malawi.; Ifakara Health Institute, Dar es Salaam, Tanzania.; Wellcome Centre for Infectious Diseases Research in 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, University of California, San Francisco, San Francisco, California, USA.; Clinical Research Unit, Swiss Tropical and Public Health Institute, Allschwil, Switzerland.; Department of Pathology, Kamuzu University of Health Sciences, Blantyre, Malawi.; HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross AIDS Research Centre and Center of Excellence in Tuberculosis, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.; Foundation for Innovative New Diagnostics, the Global Alliance for Diagnostics, Geneva, Switzerland.; Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom.; Division of Infectious Disease and Tropical Medicine, Heidelberg University Hospital and Faculty of Medicine, Heidelberg University, Heidelberg, Germany.; Infectious Diseases Institute, Makerere University, Kampala, Uganda.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: CD4 measurement is pivotal in the management of advanced human immunodeficiency virus (HIV) disease. VISITECT CD4 Advanced Disease (VISITECT; AccuBio, Ltd) is an instrument-free, point-of-care, semiquantitative test allowing visual identification of CD4 ≤ 200 cells/µL or >200 cells/ µL from finger-prick or venous blood. METHODS: As part of a diagnostic accuracy study of FUJIFILM SILVAMP TB LAM, people with HIV ≥18 years old were prospectively recruited in 7 countries from outpatient departments if a tuberculosis symptom was present, and from inpatient departments. Participants provided venous blood for CD4 measurement using flow cytometry (reference standard) and finger-prick blood for VISITECT (index text), performed at point-of-care. Sensitivity, specificity, and positive and negative predictive values of VISITECT to determine CD4 ≤ 200 cells/ µL were evaluated. RESULTS: Among 1604 participants, the median flow cytometry CD4 was 367 cells/µL (interquartile range, 128-626 cells/µL) and 521 (32.5%) had CD4 ≤ 200 cells/µL. VISITECT sensitivity was 92.7% (483/521; 95% confidence interval [CI], 90.1%-94.7%) and specificity was 61.4% (665/1083; 95% CI, 58.4%-64.3%). For participants with CD4 0-100, 101-200, 201-300, 301-500, and >500 cells/µL, VISITECT misclassified 4.5% (95% CI, 2.5%-7.2%), 12.5 (95% CI, 8.0%-18.2%), 74.1% (95% CI, 67.0%-80.5%), 48.0% (95% CI, 42.5%-53.6%), and 22.6% (95% CI, 19.3%-26.3%), respectively. CONCLUSIONS: VISITECT's sensitivity, but not specificity, met the World Health Organization's minimal sensitivity and specificity threshold of 80% for point-of-care CD4 tests. VISITECT's quality needs to be assessed and its accuracy optimized. VISITECT's utility as CD4 triage test should be investigated. Clinical Trials Registration. NCT04089423.
Diagnostic accuracy of a novel point-of-care urine lipoarabinomannan assay for the detection of tuberculosis among adult outpatients in Zambia: a prospective cross-sectional study.
(2021-Nov) Muyoyeta M; Kerkhoff AD; Chilukutu L; Moreau E; Schumacher SG; Ruhwald M; These authors contributed equally to this work.; Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia.; Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California San Francisco, San Francisco, CA, USA.; Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia Mondemuy@gmail.com.; Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: A novel, rapid, point-of-care urine-based lipoarabinomannan assay (Fujifilm SILVAMP TB LAM ("FujiLAM")) has previously demonstrated substantially higher sensitivity for tuberculosis (TB) compared with the commercially available Determine TB LAM assay using biobanked specimens. However, FujiLAM has not been prospectively evaluated using fresh urine specimens. Therefore, we determined the diagnostic accuracy of FujiLAM among HIV-positive and HIV-negative outpatients with presumptive TB in Zambia. METHODS: Adult (≥18 years old) presumptive TB patients presenting to two outpatient public health facilities in Lusaka were included. All patients submitted sputa samples for smear microscopy, Xpert MTB/RIF and mycobacterial culture, and urine samples for the FujiLAM assay. Microbiologically confirmed TB was defined by the detection of RESULTS: 151 adults with paired sputum microbiological tests and urine FujiLAM results were included; 45% were HIV-positive. Overall, 34 out of 151 (23%) patients had culture-confirmed pulmonary TB. The overall sensitivity and specificity of FujiLAM was 77% (95% CI 59-89%) and 92% (95% CI 86-96%), respectively. FujiLAM's sensitivity among HIV-positive patients was 75% (95% CI 43-95%) compared with 75% (95% CI 51-91%) among HIV-negative patients. The sensitivity of FujiLAM in patients with smear-positive, confirmed pulmonary TB was 87% (95% CI 60-98%) compared with 68% (95% CI 43-87%) among patients with smear-negative, confirmed pulmonary TB. CONCLUSIONS: FujiLAM demonstrated high sensitivity for the detection of TB among both HIV-positive and HIV-negative adults, and also demonstrated good specificity despite the lack of systematic extrapulmonary sampling to inform a comprehensive microbiological reference standard.
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.
Prospective multicentre accuracy evaluation of the FUJIFILM SILVAMP TB LAM test for the diagnosis of tuberculosis in people living with HIV demonstrates lot-to-lot variability.
(2024) Székely R; Sossen B; Mukoka M; Muyoyeta M; Nakabugo E; Hella J; Nguyen HV; Ubolyam S; Chikamatsu K; Macé A; Vermeulen M; Centner CM; Nyangu S; Sanjase N; Sasamalo M; Dinh HT; Ngo TA; Manosuthi W; Jirajariyavej S; Mitarai S; Nguyen NV; Avihingsanon A; Reither K; Nakiyingi L; Kerkhoff AD; MacPherson P; Meintjes G; Denkinger CM; Ruhwald M; Clinical Research Department, London School of Hygiene & Tropical Medicine, London, United Kingdom.; HIV-NAT, Thai Red Cross AIDS Research Centre and Centre of Excellence in Tuberculosis, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.; Viet Tiep Hospital, Hai Phong, Viet Nam.; Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand.; National Lung Hospital, Ha Noi, Viet Nam.; Taksin Hospital, Bangkok, Thailand.; Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.; University of Basel, Basel, Switzerland.; Department of Mycobacterium Reference and Research, Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, Japan.; Public Health Group, Malawi-Liverpool-Wellcome Programme, Blantyre, Malawi.; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.; Ifakara Health Institute, Dar es Salaam, Tanzania.; FIND, The Global Alliance for Diagnostics, Geneva, Switzerland.; Department of Pathology, Kamuzu University of Health Sciences, Blantyre, Malawi.; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.; Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California San Francisco, San Francisco, CA, United States of America.; Division of Infectious Disease and Tropical Medicine, Heidelberg University Hospital and Faculty of Medicine, Heidelberg University, Heidelberg, Germany.; Infectious Diseases Institute, Makerere University, Kampala, Uganda.; Swiss Tropical and Public Health Institute, Allschwil, Switzerland.; German Centre for Infection Research (DZIF), Partner site Heidelberg University Hospital, Heidelberg, Germany.; Division of Medical Microbiology, University of Cape Town and National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis. This prospective trial in seven high tuberculosis burden countries evaluated the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatients and outpatients living with HIV. Diagnostic performance of FujiLAM was assessed against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard (eMRS), and a composite reference standard including clinical evaluation. Of 1637 participants considered for the analysis, 296 (18%) were tuberculosis positive by eMRS. Median age was 40 years, median CD4 cell count was 369 cells/ul, and 52% were female. Overall FujiLAM sensitivity was 54·4% (95% CI: 48·7-60·0), overall specificity was 85·2% (83·2-87·0) against eMRS. Sensitivity and specificity estimates varied between sites, ranging from 26·5% (95% CI: 17·4%-38·0%) to 73·2% (60·4%-83·0%), and 75·0 (65·0%-82·9%) to 96·5 (92·1%-98·5%), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study. Lot variability limited interpretation of FujiLAM test performance. Although results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics. The trial is registered at clinicaltrials.gov (NCT04089423).
Urine-Xpert Ultra for the diagnosis of tuberculosis in people living with HIV: a prospective, multicentre, diagnostic accuracy study.
(2024-Dec) Sossen B; Székely R; Mukoka M; Muyoyeta M; Nakabugo E; Hella J; Van Nguyen H; Ubolyam S; Erkosar B; Vermeulen M; Centner CM; Nyangu S; Sanjase N; Sasamalo M; Dinh HT; Ngo TA; Manosuthi W; Jirajariyavej S; Nguyen NV; Avihingsanon A; Kerkhoff AD; Denkinger CM; Reither K; Nakiyingi L; MacPherson P; Meintjes G; Ruhwald M; Division of Medical Microbiology, University of Cape Town, Cape Town, South Africa; National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa.; Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia.; Viet Tiep Hospital, Hai Phong, Viet Nam.; Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand.; National Lung Hospital, Ha Noi, Viet Nam.; Taksin Hospital, Bangkok, Thailand.; Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Wellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.; Public Health Group, Malawi-Liverpool-Wellcome Programme, Blantyre, Malawi; Department of Pathology, Kamuzu University of Health Sciences, Blantyre, Malawi.; Wellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.; Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.; Ifakara Health Institute, Dar es Salaam, Tanzania.; Public Health Group, Malawi-Liverpool-Wellcome Programme, Blantyre, Malawi; School of Health and Wellbeing, University of Glasgow, Glasgow, UK; Clinical Research Department, London School of Hygiene & Tropical Medicine, London, UK.; Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland.; HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand; Center of Excellence in Tuberculosis, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.; FIND, Geneva, Switzerland; Division of Infectious Disease and Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany; Faculty of Medicine, Heidelberg University, Heidelberg, Germany; German Centre for infection Research (DZIF), partner site Heidelberg University Hospital, Heidelberg, Germany.; Division of HIV, Infectious Diseases, and Global Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California San Francisco, San Francisco, CA, USA.; FIND, Geneva, Switzerland.; FIND, Geneva, Switzerland. Electronic address: morten.ruhwald@finddx.org.; Infectious Diseases Institute, Makerere University, Kampala, Uganda.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: Diagnostic delays for tuberculosis are common, with high resultant mortality. Urine-Xpert Ultra (Cepheid) could improve time to diagnosis of tuberculosis disease and rifampicin resistance. We previously reported on lot-to-lot variation of the Fujifilm SILVAMP TB LAM. In this prespecified secondary analysis of the same cohort, we aimed to determine the diagnostic yield and accuracy of Urine-Xpert Ultra for tuberculosis in people with HIV, compared with an extended microbiological reference standard (eMRS) and composite reference standard (CRS) and also compared with Determine TB LAM Ag (AlereLAM, Abbott). METHODS: In this prospective, multicentre, diagnostic accuracy study, we recruited consecutive inpatients and outpatients (aged ≥18 years) with HIV from 13 hospitals and clinics in seven countries (Malawi, South Africa, Tanzania, Thailand, Uganda, Viet Nam, and Zambia). Patients with no isoniazid preventive therapy in the past 6 months and fewer than three doses of tuberculosis treatment in the past 60 days were included. Reference and index testing was performed in real time. The primary outcome of this secondary analysis was the diagnostic yield and accuracy of Urine-Xpert Ultra compared with the eMRS and CRS. Diagnostic accuracy was compared with AlereLAM and diagnostic yield was compared with both AlereLAM and Sputum-Xpert Ultra. This study was registered with ClinicalTrials.gov, NCT04089423, and is complete. FINDINGS: Between Dec 13, 2019, and Aug 5, 2021, 3528 potentially eligible individuals were screened and 1731 were enrolled, of whom 1602 (92·5%) were classifiable by the eMRS (median age 40 years [IQR 33-48], 838 [52·3%] of 1602 were female, 764 [47·7%] were male, 937 [58·5%] were outpatients, 665 [41·5%] were inpatients, median CD4 count was 374 cells per μL [IQR 138-630], and 254 [15·9%] had microbiologically confirmed tuberculosis). Against eMRS as reference, sensitivities of Urine-Xpert Ultra and AlereLAM were 32·7% (95% CI 27·2-38·7) and 30·7% (25·4-36·6) and specificities were 98·0% (97·1-98·6) and 90·4% (88·7-91·8), respectively. Against CRS as reference, sensitivities of Urine-Xpert Ultra and AlereLAM were 21·1% (95% CI 17·6-25·1), and 30·5% (26·4-34·9), and specificities were 99·1% (98·3-99·6) and 95·1% (93·5-96·3), respectively. The combination of Sputum-Xpert Ultra with AlereLAM or Urine-Xpert Ultra diagnosed 202 (77·1%) and 204 (77·9%) of 262 eMRS-positive participants, respectively, in incompletely overlapping groups; combining all three tests diagnosed 214 (81·7%) of 262 eMRS-positive participants INTERPRETATION: Urine-Xpert Ultra could offer promising clinical utility in addition to AlereLAM and Sputum-Xpert Ultra. In inpatient settings where both AlereLAM and Urine-Xpert Ultra are possible, both should be offered to support rapid diagnosis and treatment. FUNDING: Global Health Innovative Technology Fund, KfW Development Bank, Commonwealth of Australia represented by the Department of Foreign Affairs and Trade, and the Netherlands Enterprise Agency.