Aging increases the systemic molecular degree of inflammatory perturbation in patients with tuberculosis

Abstract

Tuberculosis (TB) is a chronic infection that can affect individuals of all ages. The description of determinants of immunopathogenesis in TB is of tremendous interest due to the perspective of finding a reliable host-directed therapy to reduce disease burden. The association between specific biomarker profiles related to inflammation and the diverse clinical disease presentations in TB has been extensively studied in adults. However, relatively scarce data on profiling the inflammatory responses in pediatric TB are available. Here, we employed the molecular degree of perturbation (MDP) score adapted to plasma biomarkers in two distinct databanks from studies that examined either adults or children presenting with pulmonary or extrapulmonary disease. We used multidimensional statistical analyses to characterize the impact of age on the overall changes in the systemic inflammation profiles in subpopulation of TB patients. Our findings indicate that TB results in significant increases in molecular perturbation, with the highest values being detected in adult patients. Furthermore, there were unique differences in the biomarker perturbation patterns and the overall degree of inflammation according to disease site and age. Importantly, the molecular degree of perturbation was not influenced by sex. Our results revealed that aging is an important determinant of the differences in quality and magnitude of systemic inflammatory perturbation in distinct clinical forms of TB.

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 – 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 ).…”

Chronic Hepatitis B Infection Is Associated with Increased Molecular Degree of Inflammatory Perturbation in Peripheral Blood

“…Then, we calculated the MDP score (as described in Methods) to directly test whether the differences in plasma concentrations found above would result in augmented overall inflammatory disturbance in HBV infection ( Figure 2 and Supplementary Table S3 ). A similar approach has been recently employed by us to characterize systemic inflammation and activation, providing important insights into the pathophysiology of a variety of infectious diseases [ 17 , 18 , 19 , 20 ].…”

“…To further explore the nuances of the inflammatory perturbation of individual markers, as well as their direct effect on overall MDP values, we employed network analysis based on Spearman’s correlation matrices, as previously described [ 17 , 18 , 19 , 20 ] ( Figure 3 ).…”

“…The molecular inflammatory perturbation is based on the MDP method, used and recently published by our group [ 18 , 19 , 20 ]. In the present study, we inputted the plasma concentrations of a defined set of pre-selected biomarkers based on previously published studies from our group [ 23 , 24 , 25 ].…”

“…In the present study, using the molecular degree of perturbation (MDP) approach previously published by our group in a number of disease settings [ 17 , 18 , 19 , 20 , 21 , 22 ], a vast number of cytokines, chemokines, and acute phase proteins were analyzed from samples of chronic carriers of hepatitis B and of those with a history of natural HBV exposure, in order to identify differentially expressed markers associated with the immune pathogenesis of persistent HBV viral replication that may contribute to the high global burden disease.…”