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Host-Directed Therapy for Tuberculosis
( Nakwon Kwak ) 대한결핵 및 호흡기학회 2021 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.129 No.0
Tuberculosis (TB) remains the most severe infectious disease. Although the standard treatment regimen for TB (comprising isoniazid, rifampicin, ethambutol, and pyrazinamide) has been proven to be effective, two major concerns remain to be addressed. First, the standard treatment regimen typically requires a minimum 6 months for completion, with this lengthy treatment leading to increased toxicity and poor adherence. Second, many patients develop permanent respiratory impairment even after successful TB eradication. In light of these problems, host-directed therapy (HDT) has gained attention. HDTs, which are adjunctive treatments, exert their effects by enhancing antibacterial mechanisms and reducing inflammation. By improving autophagy and T-cell responses, HDTs accelerate bacillary clearance. Meanwhile, by modulating proinflammatory mediators and dampening inflammation, inflammation-induced tissue injury is prevented and lung function is spared. Based on these properties, HDTs have the potential to shorten treatment duration and reduce lung injury. In this session, the current concept and progression of HDTs will be presented. After reviewing immune responses to Mycobacterium tuberculosis, laboratory data of HDT candidates will be covered. Moreover, clinical data will be presented. Finally, the future role of HDT in the treatment of TB will be proposed.
( Nakwon Kwak ),( Hongjo Choi ),( Doosoo Jeon ),( Byung Woo Jhun ),( Kyung-wook Jo ),( Young Ae Kang ),( Yong-soo Kwon ),( Myungsun Lee ),( Jeongha Mok ),( Tae-sun Shim ),( Hong-joon Shin ),( Jake Wha 대한결핵 및 호흡기학회 2020 Tuberculosis and Respiratory Diseases Vol.83 No.2
Background: The burden of nontuberculous mycobacterial (NTM) pulmonary disease (PD) is increasing globally. To understand the treatment outcomes and prognosis of NTM-PD, a unified registry is needed. In this project, we aim to construct a multicenter prospective observational cohort with NTM-PD in South Korea (NTM-KOREA). Methods: The primary objective of this study is to analyze treatment outcomes according to the species. In addition, recurrence rate, adverse events, the impact of each drug on treatment outcomes as well as the impact of characteristics of mycobacteriology will be analyzed. The inclusion criteria for the study are as follows: fulfilling the criteria for NTM-PD having one of the following etiologic organisms: Mycobacterium avium complex, M. abscessus subspecies abscessus, M. abscessus subspecies massiliense, or M. kansasii ; receiving the first treatment for NTM-PD after enrollment; age >20 years; and consenting to participate in the study. Seven institutions will participate in patient enrollment and about 500 patients are expected to be enrolled. Participants will be recruited from 1 March 2020 until 19 March 2024 and will be observed through 19 March 2029. During the follow-up period, participants’ clinical course will be tracked and their clinical data as well as NTM isolates will be collected. Conclusion: NTM-KOREA will be the first nationwide observational cohort for NTM-PD in South Korea. It will provide the information to optimize treatment modalities and will contribute to deeper understanding of the treatment outcomes and long-term prognosis of patients with NTM-PD in South Korea.
Kwak Nakwon,Hwang Ha Won,Kim Hyung-Jun,Lee Hyun Woo,Yim Jae-Joon,Lee Chang-Hoon 대한의학회 2022 Journal of Korean medical science Vol.37 No.26
This study aimed to investigate the association between Bacille Calmette-Guérin (BCG) vaccination and nontuberculous mycobacterial pulmonary disease (NTM-PD). Patients in the prospective NTM-PD cohort were matched to healthy controls to measure the association between BCG and NTM-PD development. The clinical course of NTM-PD patients was also evaluated to investigate the association between BCG and NTM-PD progression. BCG scars were not associated with NTM-PD development (adjusted odds ratio [OR], 2.04; 95% confidence interval [CI], 0.96–4.34) or progression (adjusted OR, 1.61; 95% CI, 0.92–2.81). In conclusion, BCG vaccination was not associated with the development or progression of NTM-PD.
Mycobacterium abscessus pulmonary disease : individual patient data meta-analysis
( Nakwon Kwak ),( Margareth Pretti Dalcolmo ),( Charles L. Daley ),( Geoffrey Eather ),( Regina Gayoso ),( Naoki Hasegawa ),( Byung Woo Jhun ),( Won-jung Koh ),( Ho Namkoong ),( Jimyung Park ),( Rache 대한결핵 및 호흡기학회 2018 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.126 No.-
Background: Treatment of Mycobacterium abscessus pulmonary disease (MAB-PD), which is caused by subspecies M. abscessus subspecies abscessus (M. abscessus), M. abscessus subspecies massiliense (M. massiliense), or M. abscessus subspecies bolletii, is challenging. Methods: We conducted an individual patient data meta-analysis based on published studies reporting treatment outcomes for MAB-PD to clarify the treatment outcomes for MAB-PD and the impact of each drug on treatment outcomes. Results: A total of 303 patients with MAB-PD from eight studies were included. The treatment success rate across all patients with MAB-PD was 45.6%. The specific treatment success rates were 33.0% for M. abscessus and 56.7% for M. massiliense pulmonary disease. For MAB-PD, the use of imipenem was associated with treatment success (adjusted odds ratio [aOR], 2.65; 95% confidence interval [CI], 1.36-5.10). For patients with M. abscessus, the use of azithromycin (aOR, 3.29; 95% CI, 1.26-8.62), amikacin (aOR, 1.44; 95% CI, 1.05-1.99), or imipenem (aOR, 7.96; 95% CI, 1.52-41.6) increased the likelihood of treatment success. For patients with M. massiliense, the choice among these drugs did not affect the treatment outcomes. Conclusion: Treatment outcomes for MAB-PD are unsatisfactory. The use of azithromycin, amikacin, or imipenem improves treatment outcomes for patients with M. abscessus pulmonary disease.
Kwak Nakwon,Lee Kyoung-Hee,Woo Jisu,Kim Jiyeon,Lee Chang-Hoon,Yoo Chul-Gyu 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-
Inflammation, oxidative stress, and protease–antiprotease imbalance have been suggested to be a pathogenic triad in chronic obstructive pulmonary disease (COPD). However, it is not clear how proteases interact with components of inflammatory pathways. Therefore, this study aimed to evaluate the effect of neutrophil elastase (NE) on lipopolysaccharide (LPS)-induced interleukin 8 (IL-8) production and determine the molecular mechanism in human bronchial epithelial cells (HBECs). Immortalized bronchial epithelial cells and primary HBECs were used to investigate the impact of NE on LPS-induced IL-8 production. The molecular mechanism by which NE modulated LPS-induced IL-8 production was confirmed in elastase-treated C57BL/6 mice and primary HBECs obtained from COPD patients and healthy controls. The results showed that NE treatment synergistically augmented LPS-induced IL-8 production in both immortalized bronchial epithelial cells and primary HBECs. NE partially degraded peroxisome proliferator-activated receptor gamma (PPARγ), which is known to regulate IL-8 production in the nucleus. Treatment with a PPARγ agonist and overexpression of PPARγ reversed the NE-induced synergistic increase in LPS-induced IL-8 production. Moreover, PPARγ levels were lower in lung homogenates and lung epithelial cells from elastase-treated mice than in those from saline-treated mice. In accordance with the findings in mice, PPARγ levels were lower in primary HBECs from COPD patients than in those from healthy never-smokers or healthy smokers. In conclusion, a vicious cycle of mutual augmentation of protease activity and inflammation resulting from PPARγ degradation plays a role in the pathogenesis of COPD.
( Jinyoung Moon ),( Nakwon Kwak ),( Jin Lim ),( Dong Jin Go ),( Jae Hyun Lee ),( Jin Kyun Park ),( Eun Bong Lee ),( Yeong Wook Song ),( Jai Il Youn ),( Eun Young Lee ) 대한류마티스학회 2015 대한류마티스학회지 Vol.22 No.4
Nowadays, tumor necrosis factor-α (TNF-α) blockers are used for treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis, and psoriasis. Paradoxically, there are some reports on the appearance of psoriasis after administration of TNF-α blockers. Here, we report on a patient with monoarthritis in a knee joint who experienced psoriasis after TNF-α blocker therapy (adalimumab and etanercept). Oral medication was not a treatment option due to patient intolerance; thus, we tried ustekinumab, an anti-interleukin (IL)-12/23 monoclonal antibody used for treatment of psoriasis. Following ustekinumab injection, psoriatic skin lesions and joint symptoms were much improved. However, in the following period, joint pain and swelling became aggravated and synovial fluid cytokine levels including IL-6 and IL-17 were elevated. The treatment was changed to tocilizumab, a humanized monoclonal antibody against IL-6 receptor. After injection, knee joint swelling rapidly subsided without worsening of psoriatic skin lesions. (J Rheum Dis 2015;22:263-268)
( Joong-yub Kim ),( Nakwon Kwak ),( Jae-joon Yim ) 대한결핵 및 호흡기학회 2021 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.129 No.0
Background While treatment compliance and effectiveness in patients with nontuberculous mycobacterial pulmonary disease (NTMPD) are suspected to vary by age, they are largely undocumented and current guideline recommendations are congruent regardless of age. We compared clinical characteristics and outcomes of patients with pulmonary disease caused by Mycobacterium avium complex (MAC), most common NTM species globally, across different age groups. Methods MAC-PD patients treated at Seoul National University Hospital between 2009 and 2019 were divided into five age groups; <50, 50-59, 60-69, 70-79, and ≥80 years. Baseline characteristics and treatment success rate across age groups were elucidated retrospectively. Treatment success connoted at least 12 months of sustained culture negativity while on therapy. To assess the difference in the trend of the proportion and the distribution of variables in the age groups, Mantel-Haenszel chi-squared test was applied for categorical variables, Analysis of Variance for normal distributed continuous variables and Kruskal-Wallis test for non-parametric continuous variables, respectively. Results Among 665 patients included for analysis, 62 patients (9.3%) aged under 50 years, 162 patients (24.4%) aged 50-59 years, 202 patients (30.4%) aged 60-69 years, 193 patients (29.0%) aged 70-79 years, and 46 patients (6.9%) aged 80 years or more. Proportion of patients with interstitial lung disease (3.2% vs. 1.9% vs. 1.0% vs. 4.1% vs. 8.7%, P=0.041), cerebrovascular disease (0.0% vs. 2.5% vs. 4.5% vs. 9.8% vs. 8.7%, P=0.005), dementia (0.0% vs. 0.0% vs. 1.0% vs. 3.6% vs. 6.5%, P=0.006) and male proportion (22.6% vs. 19.1% vs. 34.7% vs. 48.2% vs 54.3%, P<0.001) increased in older groups. Treatment success rate decreased gradually from younger groups to older groups (45.2% vs. 43.2% vs. 39.1% vs. 37.8% vs. 17.4%, P=0.023). Conclusions MAC-PD patients aged 80 years or more have drastically lower treatment success rate than younger patients. Age-related factors should be considered when initiating or maintaining treatment.
( Eunhye Bae ),( Sangwon Yoon ),( Nakwon Kwak ),( Sun Mi Choi ),( Jinwoo Lee ),( Young Sik Park ),( Chang-hoon Lee ),( Sang-min Lee ),( Chul-gyu Yoo ),( Young Whan Kim ),( Jaeyoung Cho ) 대한결핵 및 호흡기학회 2020 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.128 No.-
Background The overlap syndrome of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) is associated with increased mortality. The objective of this study was to assess all-cause mortality in patients with COPD, OSA, and the overlap syndrome, and to evaluate which polysomnographic indices―apnea-hypopnea index (AHI) or measurements of the hypoxemic load―better predict mortality within 10 years. Methods Adults who underwent polysomnography, spirometry and bronchodilator response tests from 2000 to 2018 were included, and were divided into four groups according to the presence of COPD and moderate to severe (AHI >15/h) OSA. We estimated mortality by Cox models adjusting for demographic/anthropometric covariates and comorbidities, which was called the clinical model. To evaluate prognostic performance, we compared the concordance index (C-index) of clinical and extended models incorporating one of polysomnographic indices―AHI, sleep time spent with SpO2 < 90% (TS90), mean and lowest SpO2. Results Patients with overlap syndrome of COPD and moderate to severe OSA had the highest risk of death (adjusted hazard ratio, 3.19; 95% confidence interval, 1.02 to 9.96). The C-indices of the extended models with TS90 (%) and mean SpO2 were significantly higher than that of the clinical model (0.765 vs. 0.737; 0.756 vs. 0.737; all P <0.05). However, the C-index of the extended model with AHI was not (0.739 vs. 0.737; P=0.15). Conclusions All-cause mortality was highest in patients with the overlap syndrome. The measurements of the hypoxemic load, not AHI, better predicted mortality in patients with COPD, OSA, and the overlap syndrome.