Plasma cytokine levels characterize disease pathogenesis and treatment response in tuberculosis patients

Abstract

Background Mycobacterium (M.) tuberculosis-caused immunopathology is characterized by aberrant expression of plasma cytokines in human tuberculosis. Disease severity and long-term anti-mycobacterial treatment are potentially influenced by immunopathology and normalization of plasma cytokine levels during therapy may indicate treatment efficacy and recovery. Study design and methods In this study, we analyzed the concentrations of selected plasma cytokines (i.e., IL-6, IP-10, IL-10, IL-22, IFNγ, GM-CSF, IL-8) and M. tuberculosis sputum burden in patients with tuberculosis (n = 76). Cytokine levels were compared to healthy contacts (n = 40) and changes under treatment were monitored (i.e., 6 and 16 weeks after treatment start). According to differences in M. tuberculosis sputum burden and conversion, tuberculosis patients were classified as paucibacillary as well as ‘rapid’ or ‘slow’ treatment responders. A subgroup of tuberculosis patients had fatal disease courses. Results Six of seven cytokines were significantly higher in tuberculosis patients as compared to contacts and four of these (i.e., IL-6, IP-10, IL-10, and IL-22) were detectable in the majority of tuberculosis patients. IL-6 showed the strongest discriminating capacity for tuberculosis disease and in combination with IL-10 concentrations efficiently classified paucibacillary tuberculosis cases as well as those with fatal disease outcome. In addition, IL-6 and IP-10 levels decreased significantly after 6 weeks of treatment and analyses of subgroups with differential treatment response showed delayed decline of IL-6 levels in slow treatment responders. Conclusions Combinations of different plasma cytokine (namely, IL-6, IL-10, and IP-10) efficiently classified tuberculosis patients with differential mycobacterial burden and especially IL-6 qualified as a biomarker candidate for early treatment response.

Immunopathology in human pulmonary tuberculosis: Inflammatory changes in the plasma milieu and impaired host immune cell functions

“…High IL‐6 plasma levels decrease rapidly under treatment [20, 59], and normalisation was also seen for PHA‐induced response [92, 127]. In accordance, a recent study by Vivekanandan et al found that impaired PHA response in tuberculosis patients before treatment was associated with high IL‐6 plasma levels [92].…”

“…Differences in the severity and stages of tuberculosis disease may also contribute to inconsistent results of previous studies. Inflammatory cytokines (e.g., IL‐6, TNF‐α and IFN‐γ) were shown to be associated with disease severity and/or higher mycobacterial burden [20, 37, 43, 59, 73, 74]. In accordance, several studies detected decreasing plasma levels of inflammatory cytokines during treatment [20, 21, 37, 44, 59, 68, 73, 75–77].…”

“…Inflammatory cytokines (e.g., IL‐6, TNF‐α and IFN‐γ) were shown to be associated with disease severity and/or higher mycobacterial burden [20, 37, 43, 59, 73, 74]. In accordance, several studies detected decreasing plasma levels of inflammatory cytokines during treatment [20, 21, 37, 44, 59, 68, 73, 75–77]. Such markers may also provide clinically relevant information as some were described to predict treatment outcomes [78–83] and others may indicate the risk of recurrent tuberculosis [70, 84, 85].…”

“…However, to provide an overview of candidates, we screened studies based on a case/control design comparing ‘plasma’ or ‘serum’ samples from patients with pulmonary tuberculosis (before treatment) and matched controls. Sixty studies were identified that meet these criteria [7–66]. The selection criteria used for the definition of ‘controls’ varied between the studies, and this is at least partially due to a missing gold standard for the classification of ‘controls’ in human tuberculosis.…”

Monocyte pathology in human tuberculosis is due to plasma milieu changes and aberrant STAT signalling

“…In addition, we could show recently that aberrant high IL‐6 plasma levels were associated with impaired mitogen‐induced IFN‐γ expression by T cells in patients with tuberculosis [18]. Changes in the plasma milieu and aberrant cytokine concentrations in tuberculosis patients have been described [19–21]. These results rendered a role of the plasma milieu in tuberculosis immunopathology likely and suggested similarity to inflammatory syndromes in different diseases (reviewed in Ref.…”