Plasma Metabolomics in the Diagnosis of Pulmonary Tuberculosis and Early Identification of Multidrug Resistance Pubblico

Abstract

Introduction: The lack of peripheral blood biomarkers for active tuberculosis (TB) disease is a major obstacle to development of point of care tests for diagnosis and treatment monitoring. Plasma high resolution metabolomics (HRM) is an innovative method to discover and evaluate peripheral blood biomarkers such as those derived from the cell envelope of Mycobacterium tuberculosis (Mtb).

Methods: We compared plasma HRM from 17 patients with active TB disease to 16 household contacts without active TB. We used a suspect screening approach to identify metabolites matching known lipids from the Mtb cell envelope based on retention time and accurate mass matches. Mtb lipid suspects were tested for association with disease status using the linear model for microarray data. To identify biomarkers of treatment response, we performed plasma HRM on 61 patients at the time of diagnosis and after 4 weeks and 8 weeks of anti-TB therapy. We included 17 patients later found to have multidrug resistant (MDR) TB and 44 patients with drug susceptible TB. A mixed effects model was used to evaluate the effect of MDR status on metabolite intensity and the change in intensity over time.

Results: Plasma HRM identified four Mtb lipid suspects significantly increased in active TB patients and undetectable in most household contacts: phosphatidylglycerol (PG), monoacylglycerophosphoinositol (Lyso-PI), monoacylated diacylglycerophosphoinositolmonomannoside (Ac1PIM1), and monoacylglycerophosphoinositolmonomannoside (Lyso-PIM1) (p<0.001 for all). These metabolites provided excellent classification accuracy for active TB disease (AUC 0.95). During treatment, the intensity of Lyso-PIM1 was significantly lower in patients with MDR TB compared to those with drug susceptible TB disease (p=0.01). Of the other 29 Mtb lipid suspects significantly different between MDR TB and drug susceptible TB patients receiving treatment (raw p≤0.05), 27 were also lower in MDR TB patients.

Conclusions: Lyso-PIM1, Lyso-PI, PG and Ac1PIM1 provided excellent classification accuracy for the diagnosis of active TB disease. Additionally, the intensity of Lyso-PIM1 was significantly lower in MDR TB patients during treatment. If confirmed in large studies, further development of these biomarkers could lead to a rapid point of care test for diagnosis and treatment response in active TB disease.

Table of Contents

Table of Contents

Introduction……………………………………………………………………………1-2

Background…………………………………………………………………………….3-7

Methods………………………………………………………………………………...8-13

Results……………………………………………………………………….…….....14-17

Discussion…………………………………………………………………………….18-25

References…………………………………………………………………………...26-28

Tables.…………….…………………………………………………………….......29-32

Figures……………………...……………………………………………………..….33-38

List of Tables

Table 1…..………………….…………………………………….………………………29

Table 2……………………………………..……………………………………………..30

Table 3…………………………………………..……………………………………..…31

Table 4…………………………………….…….…………….…………………........32

List of Figures

Figure 1…..……………………………………………………….………………………33

Figure 2…………………………………………………………………………………...34

Figure 3………………………………………………………………………………...…35

Figure 4……….………………………………………………………………….........36

Figure 5…………………………………………………………………………………...37

Figure 6………………………………………………………………………………...…38

About this Master's Thesis

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Master's Thesis
Language	English
Research Field	Chemistry, Biochemistry Health Sciences, Medicine and Surgery Health Sciences, Epidemiology
Parola chiave	Tuberculosis Drug Resistance Metabolomics Diagnosis Biomarkers
Committee Chair / Thesis Advisor	Blumberg, Henry Michael, Emory University Ziegler, Thomas R, Emory University
Committee Members	Jones, Dean P, Emory University Qayed, Muna, Emory University Kempker, Russell Ryan, Emory University Klein, Mitchel, Emory University

Ultima modifica

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	Plasma Metabolomics in the Diagnosis of Pulmonary Tuberculosis and Early Identification of Multidrug Resistance ()	2018-08-28 15:40:27 -0400	Press to Select an action Download

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions