Association of Antigen-Stimulated Release of Tumor Necrosis Factor-Alpha in Whole Blood with Response to Chemotherapy in Patients with Pulmonary Multidrug-Resistant Tuberculosis

Abstract

Background: We have previously reported that TNF-α levels correlate to total mycobacterial burden in tuberculosis (TB) patients. Objective: To characterize the dynamics of cytokine responses in TB patients during chemotherapy to identify potential surrogate markers for effective treatment. Methods: Following induction by culture filtrate proteins in whole blood, production patterns of TNF-α, IL-10, IFN-γ and IL-12 were measured in 23 non-multidrug-resistant (MDR)-TB and 16 MDR-TB patients and in 31 healthy controls. Rates of mycobacterial clearance from the sputum were then measured and compared. Results: Prior to the initiation of chemotherapy, TNF-α and IL-10 levels were significantly higher in TB patients than in healthy controls while IFN-γ and IL-12 levels were similar. During chemotherapy, the levels of all 4 cytokines increased. We evaluated these responses separately in patients that did and did not clear their sputum culture at 2 and 6 months. At 2 months, decreases in both IFN-γ and IL-12 correlated strongly with a successful early response, while after 6 months of therapy, when half (7/14) of MDR-TB patients were still sputum culture positive, downregulation of TNF-α was uniquely correlated with sputum conversion between the groups. Conclusion: Our findings suggest the possibility that the regulation of TNF-α production in whole blood may be a more specific indicator of sputum conversion at 6 months than IFN-γ, IL-12 or IL-10 in MDR-TB patients.

Effect of Chemotherapy on Whole-Blood Cytokine Responses to Mycobacterium tuberculosis Antigens in a Small Cohort of Patients with Pulmonary Tuberculosis

“…In addition, Eum et al recently demonstrated that whole-blood TNF levels in response to culture filtrate proteins were uniquely correlated with sputum conversion in patients treated for multidrug-resistant TB (15). However, they reported a decrease in TNF in sputum-negative patients at 6 months, while we observed an increase.…”

“…It has been suggested that the IFN-␥/IL-10 ratio might be used to successfully predict the development of active disease after exposure to TB (24). In addition, Eum et al recently showed that the regulation of TNF during therapy might be better than IFN-␥ in predicting sputum conversion at 6 months (15).…”

Correlation of Serum IL-4 Levels in New and MDR Tuberculosis Patients

“…IL-10 activates B and Th2 cells while inhibiting Th1 cytokine production. Activated Th2 cells secrete IL-4, which also inhibits Th1 cell activity and inactivates macrophages [10].…”

Cytokines for monitoring anti-tuberculous therapy: A systematic review

“…The largest studies that followed patients longitudinally over the course of treatment were by Eum et al [30] (38 participants with active TB, with blood samples collected after 0, 2, 6 months of treatment) and Sai et al [39] (123 participants with active TB, with blood samples collected after 0, 2, 4, 6 months of treatment). Other relatively large longitudinal studies were those by Millington et al (23 participants with active TB) [36] and Singh et al [41] (21 participants with active TB).…”

“…The largest study, by Eum et al, using ELISA, reported an increase in TNF-a responses with treatment [30]. Five studies using flow cytometry [31,33,35,38,44], three of which were cross-sectional [31,38,44], reported a reduction in TNF-a responses.…”