Pulmonary Nontuberculous Mycobacteriosis Research Articles

833. Interaction between Aspergillus fumigatus and non-tuberculous mycobacteria

Abstract Background Patients with pulmonary non-tuberculous mycobacteriosis (NTM) have been increasing in Japan in recent years. Furthermore, NTM cases complicated with pulmonary aspergillosis are associated with a poor prognosis. However, little is known about the interaction between Aspergillus spp. and non-tuberculous mycobacterium. Methods To investigate the effect of NTM metabolites on A. fumigatus growth and gene expression, supernatants of M. avium (ATCC 700737) and M. abscessus (ATCC 19977) were added to A. fumigatus (Figure 1 and 2). Results The biofilms and biomass of A. fumigatus exposed to culture supernatant of each NTM were significantly increased compared to the control (Figure 3). The expression of genes involved in the synthesis of secondary metabolites of A. fumigatus, such as gliotoxin, was decreased after the exposure to supernatant by RNA sequencing analysis (Table 1,2). Conclusion Our results suggest that exposure to culture supernatant of NTM may support the growth of A. fumigatus while suppressing the production of some secondary metabolites. We are now trying to reproduce this phenotype in mouse model and to identify the causative agent from NTM culture supernatant and elucidate the mechanism further. Disclosures Masato Tashiro, MD, PhD, Asahi Kasei Pharma Corporation: Advisor/Consultant|Asahi Kasei Pharma Corporation: Honoraria|Sumitomo Pharma Co., Ltd.: Honoraria Koichi Izumikawa, M.D., Ph.D., Asahi Kasei Pharma Corporation: Grant/Research Support|Asahi Kasei Pharma Corporation: Honoraria|Astellas Pharma Inc.: Honoraria|DAIICHI SANKYO COMPANY, LIMITED: Grant/Research Support|DAIICHI SANKYO COMPANY, LIMITED: Honoraria|KYORIN Pharmaceutical Co., Ltd.: Honoraria|Merck & Co., Inc.: Honoraria|Pfizer Japan Inc.: Honoraria|Shionogi & Co., Ltd.: Grant/Research Support|Shionogi & Co., Ltd.: Honoraria|Sumitomo Pharma Co., Ltd.: Grant/Research Support|Sumitomo Pharma Co., Ltd.: Honoraria|TAIHO PHARMACEUTICAL CO., LTD.: Grant/Research Support

СТРАТЕГИЯ ЛЕЧЕНИЯ МИКОБАКТЕРИОЗА ЛЕГКИХ: ПРОБЛЕМА ЛЕКАРСТВЕННОЙ РЕЗИСТЕНТНОСТИ

The pulmonary disease caused by nontuberculous mycobacteria (NTM) is a chronic respiratory infection resulting in declining lung function, worsening life quality, and increasing mortality rates. Most patients with pulmonary nontuberculous mycobacteriosis (PNTM) have concomitant chronic diseases (bronchiectatic disease, COPD, diabetes mellitus, etc.) PNTM is a refractory disease as mycobacteria are located intracellularly in alveolar macrophages. Mycobacteria can develop a biofilm, which impedes antibiotic penetration and protects them. Treatment for PNTM is long-term with low effectiveness due to innate or acquired mycobacterial resistance. The article outlines the modern concepts of drug resistance development in NTM, refractoriness of the disease, and the current mechanisms to overcome it.

Clinical Aspects of Pulmonary Nontuberculous Mycobacteriosis

Nontuberculous mycobacterial (NTM) infections are an emerging problem. Common organisms include Mycobacterium avium, M. intracellulare, and M. kansasii, along with the M. avium intracellulare complex (MAC), which includes both M. avium and M. intracellulare. Typically, NTM infections affect the lungs and subsequently demonstrate a chronic course. Therefore, persistent respiratory symptoms generally indicate of the presence of pulmonary NTM diseases, and chest radiography, along with a sputum examination, are essential for its diagnosis. Because NTM are ubiquitous environmental organisms, a positive culture from a minimum of two separate expectorated sputum samples are required to make a diagnosis. The repertoire of effective drugs for treatment is considerably limited, indicating the need for long-term management with multiple drugs. Establishing a treatment regimen with high therapeutic efficacy and safety is an important issue for the future.

Pulmonary Chromomycosis Caused by Exophiala dermatitidis in a Patient with Pulmonary Non-tuberculous Mycobacteriosis

Pulmonary Chromomycosis Caused by <i>Exophiala dermatitidis</i> in a Patient with Pulmonary Non-tuberculous Mycobacteriosis

Treatment Outcomes of Non-tuberculous mycobacteriosis (NTM) in children with Cystic Fibrosis

Aim and objectives: To describe presentation and treatment course of children with cystic fibrosis and pulmonary NTM disease at Aga khan University in last 5 years Methods: A retrospective chart review of children diagnosed with cystic fibrosis at the Aga Khan University, Karachi and NTM Pulmonary disease between January 2015 to Dec 2019 will be conducted. We will evaluate clinical and laboratory profile of these children and present descriptive demographic and treatment-related statistics. Results will be presented as median age at diagnosis (IQR), median weight for age z scores at presentation and after treatment, sputum/PFTs/radiological findings as proportions (percentages) and treatment outcomes (sputum clearance, improvement in weight and PFTs, death). Conclusions: We will present clinical profiles of children with CF and NTM managed at Aga Khan University in the last 5 years and highlight challenges encountered in diagnosis and management of NTM in this population

Prevalence of depressive symptoms and related risk factors in Japanese patients with pulmonary nontuberculous mycobacteriosis

ABSTRACT The objective of this study was to administer commonly used tools, the Center for Epidemiological Studies Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale – Depression subscale (HADS-D), to screen for depressive symptoms in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD). In addition, we sought to identify whether differences existed in the prevalence of depressive symptoms as assessed by CES-D and HADS-D, and by various predictors of depression. The presence of depressive symptoms in 95 patients with NTM-PD was assessed using the CES-D and HADS-D. Data regarding age, body mass index, pulmonary function, dyspnea, cough, and exercise capacity were obtained to examine their independent contribution as predictors of depressive symptoms. The prevalence of depressive symptoms was 37.9% based on CES-D and 26.3% based on HADS-D. The prevalence of depressive symptoms based on CES-D and HADS-D revealed significant differences between the two instruments. Analysis suggested that the presence of cough is a significant predictor of depressive symptoms as assessed by both CES-D and HADS-D. Countermeasures are necessary because some patients with NTM-PD disease have depressive symptoms. It is possible that assessment of the prevalence of depressive symptoms differs in accordance with the screening tool used.

Coinfection With Multiple Nontuberculous Mycobacteria as a Possible Exacerbating Factor in Pulmonary Nontuberculous Mycobacteriosis: Clone Library Analysis Using the 16S Ribosomal RNA Gene

Mycobacterial culture is the gold standard for the diagnosis of nontuberculous Mycobacterium (NTM) infections. However, this method is not suitable for detection of coinfection with different NTMs. The goal of this study was to determine if clone library analysis of BAL fluid (BALF) was useful for detection of NTM phylotypes, including multiple NTM phylotypes, in pulmonary NTM infections. BALF samples obtained from 120 patients with suspected pulmonary NTM infections were retrospectively evaluated by using the mycobacterial culture and clone library methods between July 2010 and August2016. In total, 55 (45.8%) patients were diagnosed as NTM positive according to results of mycobacterial culture, and 52 patients were NTM positive as determined by using the clone library method. Furthermore, 45 (86.5%) and seven (13.5%) patients exhibited a single phylotype (mono-phylotype group) and multiple phylotypes of NTM (multi-phylotype group), respectively. Compared with the mono-phylotype group, the multi-phylotype group had a significantly higher incidence of adverse chest CT findings (P= .048). In addition, 11 patients who were NTM negative according to results of BALF mycobacterial culture were determined to be NTM positive according to the clone library method. Six of these 11 patients were eventually diagnosed as NTM positive by using mycobacterial culture results within 6.2 ± 2.1months following the initial sample collection. Coinfection multiple phylotypes could be associated with adverse clinical findings. In addition, patients who test positive for NTM genes but negative for mycobacterial culture may be diagnosed with NTM lung infection within 1 year of the initial sample collection. Further follow-up of these patients may facilitate early detection of NTM species.

Actual practice of standard treatment for pulmonary nontuberculous mycobacteriosis in Japan.

The details of the practice of treating nontuberculous mycobacterial pulmonary disease (NTMPD) have not been studied in Japan. We studied a random sample of 2% (184) of the 9,200 patients with incident NTM-PD in 2010 who received standard three-drug therapy for at least some of their treatment between 2010 and 2014. The median duration of the standard treatment period was 248 days (IQR 56-540 days). Although 59% of the patients were treated with standard therapy for more than 6 months, only 41% were treated for 12 months. Fifty-three patients (29%) initiated treatment with substandard regimen, and 18 (34%) of those patients received treatment regimens that can lead to the development of macrolide resistance (MR)(CLR monotherapy or CLR+RIF). Furthermore, initially, 184 receiving the standard treatment, 49 patients (27%) eventually deviated from it, and 31 patients (63%) received regimens increasing the risk of developing MR. The sporadic administration of macrolide monotherapy was observed before and after the administration of the standard treatment for 50 patients (27.7%) and 41 patients (27.2%), respectively. Approximately 60% of the treated patients did not continue the standard regimen for more than 12 months and 42% were at risk for developing MR before and after receiving the standard treatment. It is important to educate physicians and patients about the correct and safe management of NTMPD.

Various Clinical and Pathological Findings of Pulmonary Non-tuberculous Mycobacteriosis―

近年，呼吸器疾患の臨床現場において非結核性抗酸菌症（特にMycobacterium avium complex症，以下MAC症）の重要性が高まりつつある．肺MAC症の主要な病型として，ⅰ）fibrocavitary disease，およびⅱ）nodular／bronchiectatic disease，の2つの型がある．ⅰ）の病型においては，空洞形成が，ⅱ）の病型においては，小結節と気管支拡張が特徴的である．病理学的には，ⅰ）fibrocavitary diseaseにおいては滲出性肉芽腫病変を呈し，病変部にMAC菌体量が多かった（感染型）．一方，ⅱ）nodular／bronchiectatic diseaseにおいては増殖性肉芽腫病変を呈し，MAC菌体量は少なかった（宿主応答型）．さらにAIDS患者に認められる播種性MAC症の病態も加え，多彩な臨床・病理像を肉芽腫形成の視点から解説した．

A Case of Metachronous Multiple Lung Cancers Coexistent with Pulmonary Non-tuberculous Mycobacteriosis

A Case of Metachronous Multiple Lung Cancers Coexistent with Pulmonary Non-tuberculous Mycobacteriosis

同側他肺葉に肺非結核性抗酸菌症による肉芽腫を合併した原発性肺癌根治切除の1例

同側他肺葉に肺非結核性抗酸菌症による肉芽腫を合併した原発性肺癌根治切除の1例

Pulmonary Nontuberculous Mycobacteriosis and Chronic Lower Respiratory Tract Infections in Patients with Allergic Bronchopulmonary Mycosis without Cystic Fibrosis.

Objective The frequency of pulmonary nontuberculous mycobacteriosis (pNTM), chronic lower respiratory tract infections (cLRTIs), and pneumonia in patients with allergic bronchopulmonary mycosis (ABPM) without cystic fibrosis has not yet been fully investigated. Methods We retrospectively analyzed 42 patients with ABPM focusing on the frequency of pNTM and cLRTIs, acute exacerbation of cLRTIs, and pneumonia. Results During a median follow-up period of 2,299 days (range, 118-6,138 days), 7 patients developed pNTM (mainly Mycobacterium avium complex), and 21 patients developed cLRTI (mostly from Staphylococcus aureus followed by Pseudomonas aeruginosa). Twelve patients developed 21 episodes of acute exacerbation of cLRTIs, and 4 patients developed pneumonia. Conclusion Patients with ABPM can have concomitant NTM infection and, not uncommonly, cLRTI, and they can also sometimes develop pneumonia or an acute exacerbation of cLRTI.

The Long-term Clinical Course of Chronic Eosinophilic Pneumonia.

Objective The long-term clinical course and prognosis of patients with chronic eosinophilic pneumonia (CEP) including factors predictive of the relapse of CEP have not been fully investigated. The aim of the present study was to investigate these issues. Methods We retrospectively investigated the rate of relapse and prognosis in 73 patients diagnosed as having CEP. Results Systemic corticosteroid therapy was administered at a prednisolone dose of 29.4±7.6 mg/day. During a median follow-up period of 1,939 days, 27 patients suffered from relapse of CEP. Two patients developed steroid-induced diabetes mellitus, and 1 patient developed pulmonary nontuberculous mycobacteriosis. Five patients died; however, none died of CEP. A history of smoking was the only independent negative risk factor for relapse of CEP [hazard ratio, 0.37 (0.14-0.98)]. Conclusion Patients with CEP frequently relapse. During the follow-up, metabolic and infectious complications under prolonged corticosteroid therapy are problematic. A history of smoking was a negative factor for predicting the risk of CEP relapse.

肺非結核性抗酸菌症に対する手術術式の検討

肺非結核性抗酸菌症に対する手術術式の検討

Epidemiology and clinical features of pulmonary nontuberculous mycobacteriosis in Nagasaki, Japan.

Background and ObjectivesRecent reports indicate that the incidence of nontuberculous mycobacterial-lung disease (NTM-LD) is increasing. This study aimed to investigate the epidemiology and clinical features of NTM-LD patients in Nagasaki prefecture, Japan to identify the negative prognostic factors for NTM-LD in Japan.MethodsThe medical records of patients newly diagnosed with NTM-LD in eleven hospitals in Nagasaki prefecture between January 2001 and February 2010 were reviewed. Data regarding the annual population of each region and the incidence of all forms of tuberculosis were collected to assess geographic variations in NTM-LD incidence, isolates, and radiological features.ResultsA total 975 patients were diagnosed with NTM-LD. The incidence increased over the study period and reached 11.0 and 10.1 per 100,000 population in 2008 and 2009, respectively. M. intracellulare was the most common pathogen in the southern region, and M. avium most common in other regions. The most common radiographic pattern was the nodular-bronchiectatic pattern. Age >60 years, body mass index <18.5 kg/m2, underlying lung disease, and cavitary pattern were the negative prognostic factors at the 1-year follow-up.ConclusionsThe incidence of NTM-LD has been increasing in Nagasaki prefecture. The isolates and radiographic features of patients vary markedly by region.

胸腔鏡下肺葉切除術による空洞病変切除後に，対側肺空洞病変の縮小をみた肺非結核性抗酸菌症の1例

胸腔鏡下肺葉切除術による空洞病変切除後に，対側肺空洞病変の縮小をみた肺非結核性抗酸菌症の1例

Epithelioid Cell Granuloma Detection in the Sputum of Patients with Pulmonary Tuberculosis

Background: Epithelioid cell granulomas (ECG) are evident in the histology of various pulmonary diseases, including pulmonary tuberculosis (PTB); however, the diagnostic value of ECG in sputum cytology for patients with granulomatous lung diseases is unclear. Methods: To evaluate the value of identifying ECG in the sputum of patients with PTB and other respiratory diseases, we retrospectively reviewed the cytology database and clinical profiles of patients admitted to our department between 2003 and 2011. Results: Of the 11,782 patients examined by sputum cytology, ECG was detected in the cytology specimens of 32 (0.3%) patients. Thirty-one of these patients had PTB, and the remaining patient had pulmonary nontuberculous mycobacteriosis (PNTM). There were no ECG-positive cases among patients with other respiratory diseases, with the exception of one patient with comorbid lung cancer and PTB. The incidence of ECG was significantly higher in PTB (0.8%, 31/3716 cases) than in PNTM (0.09%, 1/1117 cases, P>0.05). Langhans giant cells with (2 cases) and without (5 cases) necrosis was detected only in PTB specimens. Clinical findings in the PTB cases included cavities (68%) on radiography and positive sputum smear for acid-fast bacilli (90%); the PNTM case also showed cavity and smear-positive sputum. Conclusion: In our population of patients with various respiratory diseases, the existence of ECG in sputum cytology was rare and limited to pulmonary mycobacteriosis, particularly PTB. We suggest ECG detection is a useful aid for diagnosing unsuspected and infective PTB, and is associated with disease severity.

A Steady Increase in Nontuberculous Mycobacteriosis Mortality and Estimated Prevalence in Japan

Pulmonary disease caused by nontuberculous mycobacteria is generally reported to have a good prognosis. However, the actual mortality rate over time has not been reported in a large-scale survey. To determine the annual trend in mortality from nontuberculous mycobacteriosis, based on nearly four decades of patient data, and to estimate the prevalence of these cases in 2005. The annual mortality rate and regional distribution of nontuberculous mycobacteriosis-related deaths in Japan were obtained from Vital Statistics of Japan, which is published annually. The crude and age-adjusted mortality rates and associated regional differences were calculated from the Japanese census data. A 5-year follow-up study including 309 patients with pulmonary nontuberculous mycobacteriosis who visited and registered at our institute from 2004 to 2006 was conducted to determine the 5-year prognosis and the annual mortality rate. The crude mortality rates for both sexes have increased since 1970, and the mortality rate from pulmonary disease was greater in women after 2005. The age-adjusted rates of disease also showed a gradual increase until 2010 in women. Geographically, higher standardized mortality ratios were observed in middle and western Japan, particularly in the southern coastal regions along the Pacific Ocean. In a clinical follow-up study, the mortality rate was approximately 1-2% annually. The prevalence of pulmonary nontuberculous mycobacteriosis was estimated to be 6- to 10-fold higher than the annual incidence. There was a constant and steady increase of nontuberculous mycobacteriosis-related mortality in Japan, and this mortality rate showed significant geographical variation. The prevalence of environmental mycobacterial disease in Japan is higher than reported in most other countries.

当院での肺非結核性抗酸菌症の外科治療

当院での肺非結核性抗酸菌症の外科治療

A study of relapse/recurrence cases after surgical treatment for patients with pulmonary nontuberculous mycobacteriosis

This is a retrospective study on relapse/recurrence of surgical cases of pulmonary nontuberculous mycobacteriosis (NTM). Surgical treatment was performed at one hospital and by one surgeon. Fifty patients had undergone surgical treatment from August 2004 to July 2011 in hospital. From this group, 37 patients were selected after one year, and of these, 9 patients had a relapse/recurrence (group A) and the others (28 patients without relapse/recurrence, group B). Data was recorded about their age, gender, pre-operative image score, cavernous lesions, residual lesions after operation, drugs of pre-operative chemotherapy, the duration of pre-operative chemotherapy, the duration of any follow-up after operation, type of mycobacteria, the results of bacterial cultivation of surgical specimens, type of mycobacterium and operative procedure. Three factors, the result of bacterial cultivation of surgical specimens, duration of chemotherapy before operation and existence of residual lesions, showed a significant difference statistically. No case with major surgical complication and hospital death was recognized. The visible foci should be removed as thoroughly as possible. Pre-operative chemotherapy should not be continued unnecessarily, and surgical treatment should be chosen at an early stage. The results of bacterial cultures of surgical specimens could be very useful for predicting the possibility of relapse/recurrence after operation. Surgical treatments of our patients were carried out safely. However, as the patients have a risk of relapse/recurrence, they require careful monitoring and post-operative chemotherapy over along period.