Consensus Statement of Nontuberculous Mycobacterial Lung Disease in Taiwan

Edited by Jann-Yuan Wang, Meng-Chih Lin, Jin-Yuan Shih
Journal of the Formosan Medical Association, Volume 119, Supplement 1,
Pages E1-E12, S1-S84 (June 2020)
Highlights
Time to be familiar with nontuberculous mycobacterial lung disease - An emerging disease with diverse clinical outcomes
Jann-Yuan Wang, Jin-Yuan Shih, Meng-Chih Lin
 
Review Article
Nontuberculous mycobacterial lung disease epidemiology in Taiwan: A systematic review
Meng-Rui Lee, Lih-Yu Chang, Jen-Chung Ko, Hao-Chien Wang, Yi-Wen Huang
Abstract
Nontuberculous mycobacteria (NTM) are critical emerging global infectious pathogens. Though NTM can be mere colonizers when isolated from human specimens, NTM are also responsible for diverse human infections. NTM–lung disease (NTM-LD) is the most common human disease entity. The present review aims to provide general insight into NTM-LD epidemiology in Taiwan.In reviewing NTM epidemiology in Taiwan, we discovered three distinguishing features. First, NTM disease incidence has increased in Taiwan over the past decade. Second, the distribution of NTM varies geographically in Taiwan. Mycobacterium avium-intracellulare complex (MAC) is the dominant species in northern Taiwan, whereas Mycobacterium abscessus complex and MAC may be equally dominant in southern Taiwan. Third, researchers in Taiwan have published valuable research investigating NTM among special patient populations, including patients in intensive care units, with ventilator dependency, with pulmonary tuberculosis, and who are infected with specific NTM species. The largest obstacle to clarifying NTM epidemiology in Taiwan may be the lack of routine NTM species identification in laboratories. Increased awareness of NTM diseases and acknowledgment that NTM species identification is crucial and guides clinical management are essential steps for facilitating the identification of NTM species in laboratories.
 
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Host immune response against environmental nontuberculous mycobacteria and the risk populations of nontuberculous mycobacterial lung disease
Chin-Chung Shu, Ming-Fang Wu, Sheng-Wei Pan, Ting-Shu Wu, Hsin-Chih Lai, Meng-Chih Lin 
Abstract
Nontuberculous mycobacterial lung disease (NTM-LD) prevalence has been increasing over the recent decades. Numerous host factors are associated with NTM-LD development, including susceptible phenotypes such as ciliary defect and lung structural change, pulmonary clearance defect with poor clearance of secretions, and immune suppression. Specifically, regarding the susceptible host phenotypes without clear pathogenesis, a slender body, pectus excavatum, and postmenopausal female status are common. Also, decreased host immunity to NTM, especially T helper 1 cell responses is frequently observed. Even so, the underlying mechanisms remain unclear and relevant large-scale studies are lacking. Infections due to host genetics associated defects are mostly untreatable but rare in Asia, particularly Taiwan. Nevertheless, some risks for NTM-LD are controllable over disease progression. We suggest that clinicians first manage host factors and deal with the controllable characteristics of NTM-LD, followed by optimizing anti-NTM treatment. Further researches focusing on NTM-LD pathogenesis, especially the host–NTM interaction may advance understanding the nature of the disease and develop efficient therapeutic regimens.
 
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Clinical relevance and diagnosis of nontuberculous mycobacterial pulmonary disease in populations at risk
Jia-Yih Feng, Wei-Chih Chen, Ying-Ying Chen, Wei-Juin Su 
Abstract
The lungs are the most common disease site of nontuberculous mycobacteria (NTM). However, the isolation of NTM in a respiratory specimen does not indicate lung disease (LD). Differentiation between NTM colonization and NTM-LD remains challenging. In this brief review, we summarize the clinical impact of NTM-LD on morbidity and mortality in high-risk populations. The diagnosis criteria for NTM-LD—including clinical features, radiological presentations, and microbiological evidence—are also reviewed, according to the latest American Thoracic Society (ATS)/Infectious Disease Society of America (IDSA) guideline and the British Thoracic Society (BTS) guideline. However, the diagnosis of NTM-LD does not necessitate the initiation of anti-NTM treatment. Both environmental, host, and bacterial factors should be considered to identify patients that require NTM-LD treatment.
 
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Identification and drug susceptibility testing for nontuberculous mycobacteria
Wei-Chang Huang, Ming-Chih Yu, Yi-Wen Huang 
Abstract
Great progress has recently been made in methodologies for identifying nontuberculous mycobacteria (NTM). Recommendations for drug susceptibility testing (DST) of NTM have been expanded and updated by the Clinical and Laboratory Standards Institute and are crucial in the management of NTM infections. This article summarizes the clinically relevant molecular methods used to discriminate NTM species and updates the information on DST. Furthermore, recent progress on new antimicrobials against NTM infections is reviewed.
 
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Nonpharmacological treatment for patients with nontuberculous mycobacterial lung disease
Chou-Chin Lan, Sheng-Ru Lai, Jung-Yien Chien 
Abstract
Patients with nontuberculous mycobacterial lung disease (NTM-LD) often have significant exercise intolerance and poorer health-related quality of life (HRQL). The goals of treatment for NTM-LD should include reducing the severity of symptoms, improving HRQL, and reducing acute exacerbations. Nonpharmacological treatment, including pulmonary rehabilitation program and optimal nutritional strategy, should be one part of treatment for NTM-LD. A pulmonary rehabilitation (PR) program can comprise education, airway clearance techniques instruction, exercise training program, and inspiratory muscle training (IMT). Airway clearance techniques can improve the volume of sputum expectorated, cough symptom, breathlessness, and HRQL. Exercise training can improve exercise capacity and HRQL, and reduce acute exacerbations and dyspnea. Clinical benefits of IMT remain controversial but high-intensity IMT has been shown to be effective in increasing respiratory muscle strength with concurrent improvement of HRQL and exercise capacity. Body weight and muscle mass loss are common in patients with NTM-LD. An adequate protein and caloric diet combined with antioxidant nutrients might be the most appropriate dietary strategy. Comprehensive treatment for NTM-LD should include the combination of both pharmacological and nonpharmacological treatments. The management programs should be tailored to the individual's condition.
 
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Treatment of pulmonary disease caused by Mycobacterium kansasii
Hung-Ling Huang, Po-Liang Lu, Chen-Hsiang Lee, Inn-Wen Chong 
Abstract

As a cause of lung disease (LD), Mycobacterium kansasii is regarded as a highly virulent species among nontuberculous mycobacteria (NTM). Both the frequency of M. kansasii isolates and global prevalence of M. kansasii–LD have increased gradually over recent decades. Treatment of M. kansasii–LD is recommended because of the disease's poor prognosis and fatal outcome. The decision on the optimal time point for treatment initiation should be based on both the benefits and risks posed by multiple antimicrobial agents.

For treatment-naïve patients with M. kansasii–LD, rifampin-containing multiple antimicrobial regimens for ≥12 months after culture negative conversion are effective. However, some challenges remain, such as determining the precise length of treatment duration as well as addressing intolerable adverse effects, the uncertain effectiveness of isoniazid and ethambutol in treatment, the uncertain correlation between in vitro drug susceptibility testing and clinical outcomes, and the increasing prevalence of clarithromycin-resistant M. kansasii isolates. Short-course and effective therapies must be developed. New candidate drugs, such as tedizoid and clofazimine, exhibit excellent antimycobacterial activity against M. kansasii in vitro, but in vivo studies of their clinical applications are lacking.

This paper reviews the treatment, outcomes and future directions in patients with M. kansasii–LD.

 
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Treatment for Mycobacterium abscessus complex–lung disease
Ya-Wei Weng, Chun-Kai Huang, Cheng-Len Sy, Kuan-Sheng Wu, Hung-Chin Tsai, Susan Shin-Jung Lee 
Abstract
Nontuberculous mycobacterial infections and colonization are becoming more prevalent worldwide. Mycobacterium abscessus complex (MABC) is one of the predominant pathogens capable of a wide spectrum of infections, with 50% of infections involving the lungs. The decision to commence treatment is determined according to the severity of the disease, risk of progressive disease, presence of comorbidities, and goals of treatment. MABC is resistant to standard antituberculous agents and has variable drug susceptibility across different geographical locations, therefore, antibiotic susceptibility testing of all clinically significant isolates is crucial for selecting a treatment strategy. Pulmonary infections due to MABC is difficult to cure using the currently recommended regimens from the American Thoracic Society and British Thoracic Society. Macrolides are the cornerstone of treatment, but the efficacy of macrolide-based chemotherapy may be compromised by resistance. Despite the introduction of new drugs for treatment, treatment outcomes remain unsatisfactory. The combination of surgical resection of limited lung disease regions with a multidrug, macrolide-based therapy offers the optimal chance of achieving clinical cure of the disease. This review focuses on medical treatment of MABC–lung disease and the efficacy of new agents, such as clofazimine, amikacin inhalation therapy, tigecycline and linezolid, for treating MABC–lung disease.
 
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Treatment for Mycobacterium avium complex lung disease
Sheng-Wei Pan, Chin-Chung Shu, Jia-Yih Feng, Wei-Juin Su 
Abstract
Mycobacterium avium complex (MAC) is the major pathologic nontuberculous mycobacteria causing lung disease (LD) in humans worldwide. Although the burden of MAC-LD has increased over the past two decades, treatment remains difficult because of intolerance of long-term antibiotics, lack of adherence to guidelines, and disease recurrence. The current guidelines recommend antibiotic initiation for patients with MAC-LD and severe disease and in those with disease progression. Thus, physicians should consider antibiotic treatment for patients with MAC-LD and cavitary pulmonary lesions or symptomatic non-cavitary nodular bronchiectasis pattern at initial visits and also for those with clinical deterioration during follow-up. The standard three-drug regimen should be macrolide, rifamycin, and ethambutol. Physicians should monitor side effects in patients and maintain the regimen for 12 months, beginning from when sputum conversion has been obtained. With adherence to guideline-based therapy, treatment is successful in two thirds of treatment-naïve patients without macrolide resistance. Without adherence, macrolide resistance can occur, which leads to poor outcomes in patients with MAC-LD. Although the discovery of new treatment options is warranted, adherence to guidelines remains most crucial in treating patients with MAC-LD. It is worth mentioning that the majority of current recommendations are based on observational studies or small-scale clinical trials.
 
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Recent advances and controversies in surgical intervention of nontuberculous mycobacterial lung disease: A literature review
Yu-Ting Tseng, Chien-Te Pan, Shun-Mao Yang, Sheng-Pin Yu, Pei-Ming Huang
Abstract
The prevalence of nontuberculous mycobacterial lung disease (NTM-LD) has increased in Western and Asian nations in recent decades. While surgery may improve the outcome of more complex cases, many inconsistencies exist in the current literature regarding the management, growing emergence, and challenges of drug-resistant forms of NTM-LD, the indications and timing of surgical treatment, and perioperative multimodal therapy of NTM-LD. Moreover, data regarding the comparative treatments, risk factors of pulmonary resection for NTM-LD, and the long-term outcomes of microbiological recurrence are limited. This review will focus on outlining the outcomes of recently optimized surgical approaches, as well as providing an overview of the roles of perioperative multimodalities therapies in the treatment of NTM-LD.