A rapid triage test for active pulmonary tuberculosis in adult patients with persistent cough

Rushdy Ahmad; Liangxia Xie; Margaret Pyle; Marta F Suarez; Tobias Broger; Dan Steinberg; Shaali M Ame; Marilla G Lucero; Matthew J Szucs; Melanie MacMullan; Frode S Berven; Arup Dutta; Diozele M Sanvictores; Veronica L Tallo; Robert Bencher; Dominic P Eisinger; Usha Dhingra; Saikat Deb; Said M Ali; Saurabh Mehta; Wafaie W Fawzi; Ian D Riley; Sunil Sazawal; Zul Premji; Robert Black; Christopher J L Murray; Bill Rodriguez; Steven A Carr; David R Walt; Michael A Gillette

doi:10.1126/scitranslmed.aaw8287

A rapid triage test for active pulmonary tuberculosis in adult patients with persistent cough

Sci Transl Med. 2019 Oct 23;11(515):eaaw8287. doi: 10.1126/scitranslmed.aaw8287.

Authors

Rushdy Ahmad¹, Liangxia Xie^{2

3

4}, Margaret Pyle⁵, Marta F Suarez⁶, Tobias Broger⁷, Dan Steinberg⁸, Shaali M Ame⁹, Marilla G Lucero¹⁰, Matthew J Szucs¹¹, Melanie MacMullan¹¹, Frode S Berven¹², Arup Dutta¹³, Diozele M Sanvictores¹⁰, Veronica L Tallo¹⁰, Robert Bencher¹⁴, Dominic P Eisinger¹⁴, Usha Dhingra¹³, Saikat Deb¹³, Said M Ali⁹, Saurabh Mehta¹⁵, Wafaie W Fawzi¹⁶, Ian D Riley¹⁷, Sunil Sazawal¹³, Zul Premji¹⁸, Robert Black¹⁹, Christopher J L Murray²⁰, Bill Rodriguez²¹, Steven A Carr¹¹, David R Walt^{22

3

4}, Michael A Gillette^{1

23}

Affiliations

¹ Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA. dwalt@bwh.harvard.edu qrushdy@gmail.com gillette@broadinstitute.org.
² Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA 02115, USA.
³ Wyss Institute for Biologically Inspired Engineering at Harvard University, 3 Blackfan Circle, Boston, MA 02115, USA.
⁴ Department of Chemistry, Tufts University, Medford, MA 02155, USA.
⁵ University of Maryland Medical Center, 22 South Greene Street, Baltimore, MD 21201, USA.
⁶ Daktari Diagnostics, 85 Bolton Street, Cambridge, MA 02140, USA.
⁷ Foundation for Innovative New Diagnostics, 9 Chemin des Mines, 1202 Geneva, Switzerland.
⁸ Salford Systems, 9685 Via Excelencia, Suite 208, San Diego, CA 92126, USA.
⁹ Public Health Laboratory-Ivo de Carneri, Wawi, Chake Chake, Pemba 5501021, Tanzania.
¹⁰ Research Institute for Tropical Medicine, 9002 Research Drive, Filinvest Corporate City, Alabang, Muntinlupa City, 1781, Metro Manila, Philippines.
¹¹ Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA.
¹² Proteomics Unit, Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
¹³ Center for Public Health Kinetics, 214A Vinobapuri, Lajpat Nagar-II, New Delhi 110024, India.
¹⁴ Myriad RBM Inc., 3300 Duval Rd., Austin, TX 78759, USA.
¹⁵ Institute for Nutritional Sciences, Global Health, and Technology, Cornell University, 314 Savage Hall, Ithaca, NY 14850, USA.
¹⁶ Department of Global Health and Population, Harvard School of Public Health, 665 Huntington Avenue, Building 1, Room 1102, Boston, MA 02115, USA.
¹⁷ The University of Queensland, Brisbane, QLD 4072, Australia.
¹⁸ Department of Parasitology and Entomology, Muhimbili University of Health and Allied Sciences, United Nations Road, Dar es Salaam 0702172, Tanzania.
¹⁹ Institute for International Programs, Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
²⁰ Institute for Health Metrics and Evaluation, University of Washington, 2301 5th Avenue, Suite 600, Seattle, WA 98121, USA.
²¹ Draper Richards Kaplan Foundation, 535 Boylston Street, Boston, MA 02116, USA.
²² Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA 02115, USA. dwalt@bwh.harvard.edu qrushdy@gmail.com gillette@broadinstitute.org.
²³ Massachusetts General Hospital Division of Pulmonary and Critical Care Medicine, 55 Fruit Street, Boston, MA 02114, USA.

PMID: 31645455
DOI: 10.1126/scitranslmed.aaw8287

Abstract

Improved tuberculosis (TB) prevention and control depend critically on the development of a simple, readily accessible rapid triage test to stratify TB risk. We hypothesized that a blood protein-based host response signature for active TB (ATB) could distinguish it from other TB-like disease (OTD) in adult patients with persistent cough, thereby providing a foundation for a point-of-care (POC) triage test for ATB. Three adult cohorts consisting of ATB suspects were recruited. A bead-based immunoassay and machine learning algorithms identified a panel of four host blood proteins, interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF), that distinguished ATB from OTD. An ultrasensitive POC-amenable single-molecule array (Simoa) panel was configured, and the ATB diagnostic algorithm underwent blind validation in an independent, multinational cohort in which ATB was distinguished from OTD with receiver operator characteristic-area under the curve (ROC-AUC) of 0.80 [95% confidence interval (CI), 0.75 to 0.85], 80% sensitivity (95% CI, 73 to 85%), and 65% specificity (95% CI, 57 to 71%). When host antibodies against TB antigen Ag85B were added to the panel, performance improved to 86% sensitivity and 69% specificity. A blood-based host response panel consisting of four proteins and antibodies to one TB antigen can help to differentiate ATB from other causes of persistent cough in patients with and without HIV infection from Africa, Asia, and South America. Performance characteristics approach World Health Organization (WHO) target product profile accuracy requirements and may provide the foundation for an urgently needed blood-based POC TB triage test.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Bacterial / analysis
Cough / diagnosis*
Cough / microbiology
Cough / pathology
Humans
Machine Learning
Point-of-Care Systems
Triage / methods*
Tuberculosis, Pulmonary / diagnosis*
Tuberculosis, Pulmonary / microbiology
Tuberculosis, Pulmonary / pathology

Substances

Antibodies, Bacterial