Please use this identifier to cite or link to this item: https://doi.org/10.1172/JCI141895
Title: Doxycycline host-directed therapy in human pulmonary tuberculosis.
Authors: MIOW QING HAO 
Vallejo, Andres F
Wang, Yu
HONG JIA MEI 
BAI CHEN 
Teo, Felicia Sw
Wang, Alvin Dingyuan
Loh, Hong Rong
Tan Tuan Zea 
Ding, Ying
She, Hoi Wah
Gan, Suay Hong
Paton, Nicholas I
Lum, Josephine
Tay, Alicia
Chee, Cynthia Be
PAUL ANANTHARAJAH TAMBYAH 
Polak, Marta E
Wang, Yee Tang
Singhal, Amit
Elkington, Paul
Friedland, Jon S
CATHERINE ONG WEI MIN 
Keywords: Clinical Trials
Infectious disease
Tuberculosis
Issue Date: 15-Jun-2021
Publisher: American Society for Clinical Investigation
Citation: MIOW QING HAO, Vallejo, Andres F, Wang, Yu, HONG JIA MEI, BAI CHEN, Teo, Felicia Sw, Wang, Alvin Dingyuan, Loh, Hong Rong, Tan Tuan Zea, Ding, Ying, She, Hoi Wah, Gan, Suay Hong, Paton, Nicholas I, Lum, Josephine, Tay, Alicia, Chee, Cynthia Be, PAUL ANANTHARAJAH TAMBYAH, Polak, Marta E, Wang, Yee Tang, Singhal, Amit, Elkington, Paul, Friedland, Jon S, CATHERINE ONG WEI MIN (2021-06-15). Doxycycline host-directed therapy in human pulmonary tuberculosis.. Journal of Clinical Investigation. ScholarBank@NUS Repository. https://doi.org/10.1172/JCI141895
Abstract: BACKGROUND: Matrix metalloproteinases (MMPs) are implicated as key regulators of tissue destruction in tuberculosis (TB) and may be a target for host-directed therapy. Here, we conducted a Phase 2 randomized, double-blind, placebo-controlled trial investigating doxycycline, a licensed broad spectrum MMP inhibitor, in pulmonary TB patients. METHODS: Thirty pulmonary TB patients were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either doxycycline 100 mg or placebo twice a day for 14 days in addition to standard care. RESULTS: There were significant changes in the host transcriptome, and suppression of systemic and respiratory markers of tissue destruction with the doxycycline intervention. Whole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression patterns in TB towards normality, with more rapid down-regulation of type I and II interferon and innate immune response genes and concurrent up-regulation of B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline was discontinued, concurrent with suppression of plasma MMP-1. In respiratory samples, doxycycline reduced MMP-1, -8, -9, -12 and -13 concentrations, suppressed type I collagen and elastin destruction, and reduced pulmonary cavity volume despite unchanged sputum Mycobacterium tuberculosis loads between the study arms. Two weeks of adjunctive doxycycline with standard anti-TB treatment was well-tolerated, with no serious adverse events related to doxycycline. CONCLUSION: These data demonstrate that adjunctive doxycycline with standard anti-TB treatment suppresses pathological MMPs in pulmonary tuberculosis patients, and suggest that larger studies on adjunctive doxycycline to limit immunopathology in TB are merited.
Source Title: Journal of Clinical Investigation
URI: https://scholarbank.nus.edu.sg/handle/10635/194051
ISSN: 0021-9738
1558-8238
DOI: 10.1172/JCI141895
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