title: Metabolomic Profiling of Plasma from Patients with Tuberculosis by Use of Untargeted Mass Spectrometry Reveals Novel Biomarkers for Diagnosis.
abstract: Although tuberculosis (TB) is a reemerging disease that affects people in developing countries and immunocompromised populations in developed countries, the current diagnostic methods are far from optimal. Metabolomics is increasingly being used for studies on infectious diseases. We performed metabolome profiling of plasma samples to identify potential biomarkers for diagnosing TB. We compared the plasma metabolome profiles of TB patients (n = 46) with those of community-acquired pneumonia (CAP) patients (n = 30) and controls without active infection (n = 30) using ultrahigh-performance liquid chromatography-electrospray ionization-quadrupole time of flight mass spectrometry (UHPLC-ESI-QTOFMS). Using multivariate and univariate analyses, four metabolites, 12R-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid [12(R)-HETE], ceramide (d18:1/16:0), cholesterol sulfate, and 4α-formyl-4β-methyl-5α-cholesta-8-en-3β-ol, were identified and found to have significantly higher levels in TB patients than those in CAP patients and controls. In a comparison of TB patients and controls, the four metabolites demonstrated area under the receiver operating characteristic curve (AUC) values of 0.914, 0.912, 0.905, and 0.856, sensitivities of 84.8%, 84.8%, 87.0%, and 89.1%, specificities of 90.0%, 86.7%, 86.7%, and 80.0%, and fold changes of 4.19, 26.15, 6.09, and 1.83, respectively. In a comparison of TB and CAP patients, the four metabolites demonstrated AUC values of 0.793, 0.717, 0.802, and 0.894, sensitivities of 89.1%, 71.7%, 80.4%, and 84.8%, specificities of 63.3%, 66.7%, 70.0%, and 83.3%, and fold changes of 4.69, 3.82, 3.75, and 2.16, respectively. 4α-Formyl-4β-methyl-5α-cholesta-8-en-3β-ol combined with 12(R)-HETE or cholesterol sulfate offered ≥70% sensitivity and ≥90% specificity for differentiating TB patients from controls or CAP patients. These novel plasma biomarkers, especially 12(R)-HETE and 4α-formyl-4β-methyl-5α-cholesta-8-en-3β-ol, alone or in combination, are potentially useful for rapid and noninvasive diagnosis of TB. The present findings may offer insights into the pathogenesis and host response in TB.
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Department of Microbiology, The University of Hong Kong, Hong Kong skplau@hku.hk pcywoo@hku.hk.
authors.forename: Susanna K P
authors.initials: SK
authors.lastname: Lau
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Kim-Chung
authors.initials: KC
authors.lastname: Lee
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Shirly O T
authors.initials: SO
authors.lastname: Curreem
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Wang-Ngai
authors.identifier: http://orcid.org/0000-0003-1275-2464
authors.initials: WN
authors.lastname: Chow
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Kelvin K W
authors.initials: KK
authors.lastname: To
authors.affiliation: Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Department of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Ivan F N
authors.initials: IF
authors.lastname: Hung
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Deborah T Y
authors.initials: DT
authors.lastname: Ho
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Sridhar
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Iris W S
authors.initials: IW
authors.lastname: Li
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Vanessa S Y
authors.initials: VS
authors.lastname: Ding
authors.affiliation: Department of Pathology, Grantham Hospital, Hong Kong.
authors.forename: Eleanor W F
authors.initials: EW
authors.lastname: Koo
authors.affiliation: Tuberculosis & Chest Unit, Grantham Hospital, Hong Kong.
authors.forename: Chi-Fong
authors.initials: CF
authors.lastname: Wong
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Sidney
authors.initials: S
authors.lastname: Tam
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Ching-Wan
authors.initials: CW
authors.lastname: Lam
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Department of Microbiology, The University of Hong Kong, Hong Kong.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Department of Microbiology, The University of Hong Kong, Hong Kong skplau@hku.hk pcywoo@hku.hk.
authors.forename: Patrick C Y
authors.initials: PC
authors.lastname: Woo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood*; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D055442:Metabolome; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D012372:ROC Curve; D012680:Sensitivity and Specificity; D014376:Tuberculosis / Q000175:diagnosis* / Q000473:pathology*; D055815:Young Adult
chemical_list: D015415:Biomarkers