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The Immune Mechanisms of Lung Parenchymal Damage in Tuberculosis and the Role of Host-Directed Therapy.

ABSTRACT: Impaired lung function is common in people with a history of tuberculosis. Host-directed therapy added to tuberculosis treatment may reduce lung damage and result in improved lung function. An understanding of the pathogenesis of pulmonary damage in TB is fundamental to successfully predicting which interventions could be beneficial. In this review, we describe the different features of TB immunopathology that lead to impaired lung function, namely cavities, bronchiectasis, and fibrosis. We discuss the immunological processes that cause lung damage, focusing on studies performed in humans, and using chest radiograph abnormalities as a marker for pulmonary damage. We highlight the roles of matrix metalloproteinases, neutrophils, eicosanoids and cytokines, like tumor necrosis factor-? and interleukin 1?, as well as the role of HIV co-infection. Finally, we focus on various existing drugs that affect one or more of the immunological mediators of lung damage and could therefore play a role as host-directed therapy.

SUBMITTER: Stek C

PROVIDER: S-EPMC6218626 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Immune Mechanisms of Lung Parenchymal Damage in Tuberculosis and the Role of Host-Directed Therapy.

Stek Cari C Allwood Brian B Walker Naomi F NF Wilkinson Robert J RJ Lynen Lutgarde L Meintjes Graeme G

Frontiers in microbiology 20181030

Impaired lung function is common in people with a history of tuberculosis. Host-directed therapy added to tuberculosis treatment may reduce lung damage and result in improved lung function. An understanding of the pathogenesis of pulmonary damage in TB is fundamental to successfully predicting which interventions could be beneficial. In this review, we describe the different features of TB immunopathology that lead to impaired lung function, namely cavities, bronchiectasis, and fibrosis. We disc ...[more]

PMID: 30425706

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Project description:BACKGROUNDMatrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB.METHODSThirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care.RESULTSWhole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1, -8, -9, -12 and -13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe.CONCLUSIONAdjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.TRIAL REGISTRATIONClinicalTrials.gov NCT02774993.FUNDINGSingapore National Medical Research Council (NMRC/CNIG/1120/2014, NMRC/Seedfunding/0010/2014, NMRC/CISSP/2015/009a); the Singapore Infectious Diseases Initiative (SIDI/2013/013); National University Health System (PFFR-28 January 14, NUHSRO/2014/039/BSL3-SeedFunding/Jul/01); the Singapore Immunology Network Immunomonitoring platform (BMRC/IAF/311006, H16/99/b0/011, NRF2017_SISFP09); an ExxonMobil Research Fellowship, NUHS Clinician Scientist Program (NMRC/TA/0042/2015, CSAINV17nov014); the UK Medical Research Council (MR/P023754/1, MR/N006631/1); a NUS Postdoctoral Fellowship (NUHSRO/2017/073/PDF/03); The Royal Society Challenge Grant (CHG\R1\170084); the Sir Henry Dale Fellowship, Wellcome Trust (109377/Z/15/Z); and A*STAR.

Project description:BackgroundCoronavirus disease [severe acute respiratory syndrome coronavirus disease 19 (SARS COVID-19)] has emerged as one of the most challenging diseases of recent decades. After the pandemic outbreak, our knowledge of the virus has expanded and developed, but we face a new wave of atypical complications that require special attention. In addition to the acute complications of COVID-19 infection, late complications of the disease are taking an increasingly important part in the management of affected patients, which are grouped under the collective term "Long COVID". In this work, we present our therapy strategy in three cases of pulmonary cavity as a late complication after COVID-19, as well as perform a literature review of published articles in this matter.Case descriptionThis study includes 3 cases of pulmonary cavities as a late COVID complication. Among them only one patient was vaccinated. The mean duration between the occurrence of Long COVID and SARS COVID-19 disease was 4 weeks in our patients. All patients underwent adequate medical therapy after Long COVID. However, due to the disease progression and significant elevated infections parameters, all patients underwent surgical therapy. One patient underwent uniportal video-assisted thoracoscopic surgery (VATS) lobectomy and decortication of the empyema, whereas we performed thoracotomy for other patients. All patients treated successfully and discharged shortly after the operation. Our literature review provides a total of 12 publications with only 50 patients. No patients received vaccination. The mean interval time between acute infection and the appearance of pulmonary cavities was about 4 weeks. The results showed that most patients were treated with conservative therapies. Only two patients were treated using invasive therapies. Both patients were successfully treated and recovered from the procedures.ConclusionsThis group of late complications COVID patients requires individualized treatment strategy. In the case of an underlying pulmonary cavities, depending on the findings, despite increased perioperative risks, very good results can be achieved by presentation to a specialized and experienced thoracic surgery center.

Dataset Information

The Immune Mechanisms of Lung Parenchymal Damage in Tuberculosis and the Role of Host-Directed Therapy.

Publications

The Immune Mechanisms of Lung Parenchymal Damage in Tuberculosis and the Role of Host-Directed Therapy.

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