Molecular degree of perturbation of plasma inflammatory markers associated with tuberculosis reveals distinct disease profiles between Indian and Chinese populations

Abstract

Tuberculosis (TB) is a chronic inflammatory disease caused by Mycobacterium tuberculosis infection which causes tremendous morbidity and mortality worldwide. Clinical presentation of TB patients is very diverse and disease heterogeneity is associated with changes in biomarker signatures. Here, we compared at the molecular level the extent of individual inflammatory perturbation of plasma protein and lipid mediators associated with TB in patients in China versus India. We performed a cross-sectional study analyzing the overall degree of inflammatory perturbation in treatment-naïve pulmonary TB patients and uninfected individuals from India (TB: n = 97, healthy: n = 20) and China (TB: n = 100, healthy: n = 11). We employed the molecular degree of perturbation (MDP) adapted to plasma biomarkers to examine the overall changes in inflammation between these countries. M. tuberculosis infection caused a significant degree of molecular perturbation in patients from both countries, with higher perturbation detected in India. Interestingly, there were differences in biomarker perturbation patterns and the overall degree of inflammation. Patients with severe TB exhibited increased MDP values and Indian patients with this condition exhibited even higher degree of perturbation compared to Chinese patients. Network analyses identified IFN-α, IFN-β, IL-1RI and TNF-α as combined biomarkers that account for the overall molecular perturbation in the entire study population. Our results delineate the magnitude of the systemic inflammatory perturbation in pulmonary TB and reveal qualitative changes in inflammatory profiles between two countries with high disease prevalence.

Integration of metabolomics and transcriptomics reveals novel biomarkers in the blood for tuberculosis diagnosis in children

“…We have previously defined the molecular degree of perturbation (MDP) as a metric that compares mRNA transcript expression or metabolite abundance to the mean of expression or abundance in the reference group 35,36 . The accumulated standard deviation of all metabolites > 2 absolute standard deviations from the reference were calculated using the MDP package 37 .…”

Changes in inflammatory protein and lipid mediator profiles persist after antitubercular treatment of pulmonary and extrapulmonary tuberculosis: A prospective cohort study

“…The molecular degree of perturbation (MDP) was calculated to infer the overall inflammatory profile of TB over the course of antitubercular treatment. The MDP method used for the present study has been described previously [19] and is an adaptation of the molecular distance to health described by Pankla et al [24] and employed to non-genomic measurements [25]. Healthy uninfected controls were defined as the "reference" group, and the average level and standard deviation of this reference group were calculated for the plasma concentrations of each inflammatory marker.…”

“…Baseline and post treatment plasma samples originated from persons with signs and symptoms indicative of active TB and who were HIV-uninfected and who were not undertaking antitubercular therapy or healthy controls that were enrolled into a prospective clinical protocol to assess response to chemotherapy (NCT01071603) conducted at the Henan Chest Hospital (HCH) in Zhengzhou, China from 2010 to 2012, as described previously [6,15,16]. Individuals with pulmonary tuberculosis (PTB) were similar to those presenting with extra pulmonary tuberculosis (EPTB) with regard to age (median [IQR] in years: 27 [23-44.7] vs. 27 [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36], respectively; P = 0.1933; Supplemental Table 1) and gender (P = 0.4916, Table S1), with higher frequency of male individuals (61.7% vs. 52% vs. respectively).…”

“…When applied to the blood transcriptome, MDP largely reflects immunological activation status [12,19]. Here, we employed this statistical approach in plasma concentrations of biomarkers [25] to assess global effects of PTB or EPTB on the blood inflammatory status that significantly differs from that detected in healthy controls (raw data is found in Supplemental File 1). To answer this question, we performed an exploratory analysis comparing the PTB and EPTB groups with healthy controls (n = 11) who were matched by age and sex (median age: 35 years, IQR: 23-40; 45.4% of male individuals).…”

Impact of Persistent Anemia on Systemic Inflammation and Tuberculosis Outcomes in Persons Living With HIV

“…Given that the majority of anemic patients persisted with anemia during the time of ATT regardless of the gradual increase in hemoglobin levels, we tested whether such condition was related to a chronic and unresolved inflammatory disturbance. To do so, we employed a mathematical maneuver named Molecular Degree of Perturbation (MDP), which has been used by our group and others to estimate the overall degree of inflammation and/or immune activation (18)(19)(20). In the present study, we included cells (from CBC), viral load, CD4 counts and biochemical parameters (creatinine, urea, total and direct bilirubin, albumin, alkaline phosphatase, uric acid, AST, GGT, ALT and total proteins) to create a score henceforth named Degree of Inflammatory Perturbation (DIP) ( Figure 4A).…”