Using TBAg/PHA Ratio for Monitoring TB Treatment: A Prospective Multicenter Study

Wang, Xiaochen; Li, Mingwu; Liu, Guobiao; Wu, Xiaoying; Wan, Rong; Hou, Hongyan; Wu, Shiji; Sun, Ziyong; Kuang, Haobin; Wang, Feng

doi:10.3390/jcm11133780

Cited by 4 publications

(5 citation statements)

References 37 publications

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“…The conclusion about a potential relationship between M. tuberculosis burden and impaired PHA-response was strengthened by the results that treatment normalized PHA-response within 6 weeks, a time frame that led to negative sputum smear/culture tests for approximately half of the patients. The finding of normalization under treatment confirmed recent findings although the time frame was longer [ 11 ]. In addition, although we did not detect significant differences between TB-SR and TB-RR under treatment, this did not exclude a relevance of treatment efficacy since the moderate size of subgroups limited the statistical power of this comparison.…”

Section: Discussionsupporting

confidence: 89%

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Impaired T-cell response to phytohemagglutinin (PHA) in tuberculosis patients is associated with high IL-6 plasma levels and normalizes early during anti-mycobacterial treatment

et al. 2023

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Purpose Human tuberculosis is characterized by immunopathology that affects T-cell phenotype and functions. Previous studies found impaired T-cell response to phytohemagglutinin (PHA) in patients with acute tuberculosis. However, the influence of disease severity, affected T-cell subsets, and underlying mechanisms remain elusive. Methods Here we investigated PHA-induced and antigen-specific T-cell effector cytokines in tuberculosis patients (n = 55) as well as in healthy asymptomatic contacts (n = 32) from Ghana. Effects of Mycobacterium (M.) tuberculosis sputum burden and treatment response were analyzed and compared during follow-up. Finally, cytokine characteristics of the aberrant plasma milieu in tuberculosis were analyzed as a potential cause for impaired PHA response. Results PHA-induced IFN-γ expression was significantly lower in sputum-positive tuberculosis patients as compared to both, contacts and paucibacillary cases, and efficiently discriminated the study groups. T-cell responses to PHA increased significantly early during treatment and this was more pronounced in tuberculosis patients with rapid treatment response. Analysis of alternative cytokines revealed distinct patterns and IL-22, as well as IL-10, showed comparable expression to IFN-γ in response to PHA. Finally, we found that high IL-6 plasma levels were strongly associated with impaired IFN-γ and IL-22 response to PHA. Conclusion We conclude that impaired T-cell response to PHA stimulation in acute tuberculosis patients (i) was potentially caused by the aberrant plasma milieu, (ii) affected differentially polarized T-cell subsets, (iii) normalized early during treatment. This study shed light on the mechanisms of impaired T-cell functions in tuberculosis and yielded promising biomarker candidates for diagnosis and monitoring of treatment response.

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Section: Discussionsupporting

confidence: 89%

“…Especially a combination of antigen-specific and PHA-induced IFN-γ expression from IGRAs (i.e., antigen/PHA ratios) gained promising results [6][7][8][9][10]. In addition, a recent study indicated potential capacity of antigen/PHA ratios to monitor efficacy of treatment [11].…”

Section: Introductionmentioning

confidence: 99%

Impaired T-cell response to phytohemagglutinin (PHA) in tuberculosis patients is associated with high IL-6 plasma levels and normalizes early during anti-mycobacterial treatment

et al. 2023

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“…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].…”

Section: The Role Of Il‐6 On Impaired T‐cell Response and Immunopatho...mentioning

confidence: 67%

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

Ahor,

Vivekanandan,

Harelimana

et al. 2024

Immunology

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Host immune response is key for protection in tuberculosis, but the causative agent, Mycobacterium (M.) tuberculosis, manages to survive despite immune surveillance. Key mechanisms of immune protection have been identified, but the role of immunopathology in the peripheral blood of tuberculosis patients remains unclear. Tuberculosis immunopathology in the blood is characterised by patterns of immunosuppression and hyperinflammation. These seemingly contradictory findings and the pronounced heterogeneity made it difficult to interpret the results from previous studies and to derive implications of immunopathology. However, novel approaches based on comprehensive data analyses and revitalisation of an ancient plasma milieu in vitro assay connected inflammation with immunosuppressive factors in tuberculosis. Moreover, interrelations between the aberrant plasma milieu and immune cell pathology were observed. This review provides an overview of studies on changes in plasma milieu and discusses recent findings linking plasma factors to T‐cell and monocyte/macrophage pathology in pulmonary tuberculosis patients.

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“…Because of the opposite trends of IFN-γ response with different antigen conditions in NTM-LD and controls, we analyzed the ratio of various combinations of antigen stimulations. Calculation of ratios can eliminate the impact of individual IFN-γ variations on the ELISpot assay, and is also less affected by underlying host immune status [39,40]. In our multiparametric IFN-γ ELISpot assay we found that ratios of RD1/PPD, RD1/anti-CD3, and MTB300/ Candida can significantly differentiate nonprogressive and progressive NTM-LD.…”

Section: Plos Onementioning

confidence: 79%

Multiparameter immunoprofiling for the diagnosis and differentiation of progressive versus nonprogressive nontuberculous mycobacterial lung disease–A pilot study

Marty,

Pathakumari,

Cox

et al. 2024

PLoS ONE

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Clinical prediction of nontuberculous mycobacteria lung disease (NTM-LD) progression remains challenging. We aimed to evaluate antigen-specific immunoprofiling utilizing flow cytometry (FC) of activation-induced markers (AIM) and IFN-γ enzyme-linked immune absorbent spot assay (ELISpot) accurately identifies patients with NTM-LD, and differentiate those with progressive from nonprogressive NTM-LD. A Prospective, single-center, and laboratory technician-blinded pilot study was conducted to evaluate the FC and ELISpot based immunoprofiling in patients with NTM-LD (n = 18) and controls (n = 22). Among 18 NTM-LD patients, 10 NTM-LD patients were classified into nonprogressive, and 8 as progressive NTM-LD based on clinical and radiological features. Peripheral blood mononuclear cells were collected from patients with NTM-LD and control subjects with negative QuantiFERON results. After stimulation with purified protein derivative (PPD), mycobacteria-specific peptide pools (MTB300, RD1-peptides), and control antigens, we performed IFN-γ ELISpot and FC AIM assays to access their diagnostic accuracies by receiver operating curve (ROC) analysis across study groups. Patients with NTM-LD had significantly higher percentage of CD4+/CD8+ T-cells co-expressing CD25+CD134+ in response to PPD stimulation, differentiating between NTM-LD and controls. Among patients with NTM-LD, there was a significant difference in CD25+CD134+ co-expression in MTB300-stimulated CD8+ T-cells (p <0.05; AUC-ROC = 0.831; Sensitivity = 75% [95% CI: 34.9–96.8]; Specificity = 90% [95% CI: 55.5–99.7]) between progressors and nonprogressors. Significant differences in the ratios of antigen-specific IFN-γ ELISpot responses were also seen for RD1-nil/PPD-nil and RD1-nil/anti-CD3-nil between patients with nonprogressive vs. progressive NTM-LD. Our results suggest that multiparameter immunoprofiling can accurately identify patients with NTM-LD and may identify patients at risk of disease progression. A larger longitudinal study is needed to further evaluate this novel immunoprofiling approach.

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Using TBAg/PHA Ratio for Monitoring TB Treatment: A Prospective Multicenter Study

Cited by 4 publications

References 37 publications

Impaired T-cell response to phytohemagglutinin (PHA) in tuberculosis patients is associated with high IL-6 plasma levels and normalizes early during anti-mycobacterial treatment

Impaired T-cell response to phytohemagglutinin (PHA) in tuberculosis patients is associated with high IL-6 plasma levels and normalizes early during anti-mycobacterial treatment

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

Multiparameter immunoprofiling for the diagnosis and differentiation of progressive versus nonprogressive nontuberculous mycobacterial lung disease–A pilot study

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