DNA Methylation Profiling for the Diagnosis and Prognosis of Patients with Nontuberculous Mycobacterium Lung Disease

The incidence of nontuberculous Mycobacterium (NTM) lung disease is rapidly increasing; however, its diagnosis and prognosis remain unclear while selecting patients who will respond to appropriate treatment. Differences in DNA methylation patterns between NTM patients with good or poor prognosis could provide important therapeutic targets. We used the Illumina MethylationEPIC (850k) DNA methylation microarray to determine the pattern between differentially methylated regions (DMRs) in NTM patients with good or poor prognosis (n = 4/group). Moreover, we merged and compared 20 healthy controls from previous Illumina Methylation450k DNA methylation microarray data. We selected and visualized the DMRs in the form of heatmaps, and enriched terms associated with these DMRs were identified by functional annotation with the “pathfinder” package. In total, 461 and 293 DMRs (|Log2 fold change| > 0.1 and p < 0.03) were more methylated in patients with four poor and four good prognoses, respectively. Furthermore, 337 and 771 DMRs (|Log2 fold change| > 0.08 and p < 0.001) were more methylated in eight NTM patients and 20 healthy controls, respectively. TGFBr1 was significantly less methylated, whereas HLA-DR1 and HLA-DR5 were more methylated in patients with poor prognosis (compared to those with good prognosis). LRP5, E2F1, and ADCY3 were the top three less-methylated genes in NTM patients (compared with the controls). The mTOR and Wnt signaling pathway-related genes were less methylated in patients with NTM. Collectively, genes related to Th1-cell differentiation, such as TGFBr1 and HLA-DR, may be used as biomarkers for predicting the treatment response in patients with NTM lung disease.

Bronchial Brushing and Diagnosis of Pulmonary Nontuberculous Mycobacteria Infection

<b><i>Background:</i></b> The optimal bronchoscopy procedure for diagnosis of pulmonary nontuberculous mycobacteria (NTM) infection is unclear. <b><i>Objective:</i></b> This study investigated the usefulness of bronchial brushing in bronchoscopy for diagnosis of pulmonary NTM infection in patients with suspected NTM lung disease and nodular bronchiectasis on chest computed tomography (CT) images. <b><i>Methods:</i></b> Bronchoscopy was prospectively performed for 69 patients with clinically suspected pulmonary NTM infection on chest CT from December 2017 through December 2019. Before and after bronchial brushing, bronchial washing was performed with 20 or 40 mL of normal sterile saline at the same segmental or subsegmental bronchi. Before and after bronchial brushing, samples of the washing fluid (pre- and postbrushing samples) and brush deposits (brush samples) were obtained and cultured separately. <b><i>Results:</i></b> NTM was detected in 37 of the 69 (53.6%) patients (<i>Mycobacterium avium</i> in 27, <i>Mycobacterium intracellulare</i> in 7, <i>M. abscessus</i> in 2, and <i>M. kansasii</i> in 2). NTM was detected in 34 (49.3%) prebrushing samples, in 27 (39.1%) postbrushing samples, and in 20 (29.0%) brush samples from the 69 patients. In 2 (2.9%) patients, NTM was detected only in postbrushing samples; in 1 (1.4%) patient, NTM was detected only in a brush sample. As compared with bronchial washing only, additional bronchial brushing increased the NTM culture-positive rate by 4.3% (3/69). Bronchial brushing caused bleeding, requiring hemostasis in 5 (7.2%) patients. <b><i>Conclusion:</i></b> Additional bronchial brushing increased the NTM culture-positive rate by only 4.3% (3/69), as compared with bronchial washing alone. Thus, the usefulness of brushing appears to be limited.

Adding Another Piece to the Puzzle of Why NTM Infections Are Relatively Uncommon despite Their Ubiquitous Nature

ABSTRACT Since nontuberculous mycobacteria (NTM) are pervasive in the environment and NTM infections are relatively uncommon, underlying hereditary or acquired host susceptibility factors should be sought for in most NTM-infected patients. To facilitate identification of underlying risk factors, it is useful to classify NTM disease into skin-soft tissue infections, isolated NTM lung disease, and extrapulmonary visceral/disseminated disease because the latter two categories have unique sets of underlying host risk factors. Nakajima and coworkers (M. Nakajima, M. Matsuyama, M. Kawaguchi, T. Kiwamoto, et al., mBio 12:e01947-20, 2021, https://doi.org/10.1128/mBio.01947-20) in a recent issue of mBio found that Nrf2 (nuclear factor erythroid 2-related factor 2), a transcription factor that is induced by oxidative stress but induces antioxidant molecules, provides protection against an NTM infection in a murine model. While they showed that Nrf2 induction of Nramp-1 enhanced phagosome-lysosome fusion, we discuss other potential mechanisms by which oxidative stress predisposes to and Nrf2 protects against NTM infections.

Trace Elements in Urban Particulate Matters: Variations in Serum Levels, Inhalation Bioaccessibility, Health and Disease Effects

Trace elements-bound to particulate matters are often become entrained in human respiratory airway, deposited in human nasal cavity and made available for absorption by human tracheobronchial. It has been assumed that variability and bioaccessibility of elements in the serum correlate with some health and diseases. This chapter is a summary of previous works on bioaccessibility of trace elements bound to inhale particulates using different kinds of simulated body fluids. Presented also are evidences of serum variation in some respiratory diseases, such as chronic obstructive pulmonary disease (with or without hypertension), emphysema, bronchiectasis and bronchial asthma, non-tuberculose mycobacterial (NTM) lung disease, idiopathic pulmonary fibrosis (IPF).

Chronic Pulmonary Aspergillosis Following Nontuberculous Mycobacterial Infections: An Emerging Disease

Chronic pulmonary aspergillosis (CPA) following nontuberculous mycobacterial (NTM) lung disease is being increasingly recognized, especially in countries where tuberculosis is not endemic, with an incidence rate of 3.9–16.7%. NTM lung disease has been identified as a predictor of mortality in CPA patients. The major risk factors for NTM-associated CPA include fibrocavitary NTM lung disease, the presence of pulmonary emphysema, and high-dose corticosteroid use. The onset of CPA is 1.5–7 years following the diagnosis of NTM lung disease. The diagnosis can be made using standard criteria; however, serological diagnosis using Aspergillus precipitin has demonstrated a higher sensitivity and specificity when compared with fungal culture from respiratory specimens. Treatment is challenging since rifampicin and oral triazoles should not be used concomitantly. The prognosis is poor, and the factors associated with worse prognosis are corticosteroid use and high C-reactive protein level.

Comorbidities associated with nontuberculous mycobacterial disease in Japanese adults: a claims-data analysis

Background Nontuberculous mycobacterial (NTM) lung disease is one of a growing number of chronic health problems that is difficult to cure in aging societies. While it is important to be vigilant about associated comorbidities in order to provide better patient care, data on the prevalence of comorbidities stratified by country or region are scarce. We aimed to elucidate the comorbidities associated with NTM disease based on Japanese health insurance claims data. Methods Cross-sectional analyses were performed using the claims data for 2014 provided by the Japan Medical Data Center Co., Ltd. Patients aged 20–75 years with ≥3 claims associated with NTM disease were identified and matched to 10 sex-and-age-matched controls that had never made a claim for NTM disease. Thirty-one comorbidities previously suspected to be associated with NTM disease were selected, and the prevalence of these comorbidities compared between cases and controls. Result Overall, 419 NTM patients (134 males and 285 females) and 4190 non-NTM controls were identified from the JMDC database. Aspergillosis, asthma, chronic heart failure, diffuse panbronchiolitis, gastroesophageal reflux, interstitial pneumonia, lung cancer, cancer other than breast, lung, ovary, or prostate cancer, and rheumatoid arthritis were associated with NTM disease in both males and females. Chronic obstructive pulmonary disease was associated with NTM in males while chronic kidney disease, osteoporosis, and Sjögren syndrome were associated with NTM in females. Conclusion NTM disease was associated with multiple comorbidities that should be considered when providing medical care to individuals with NTM disease.

1652. Diagnoses of Non- Tuberculosis Mycobacterium (NTM) in patients with granuloma on lung biopsy

Background The prevalence of non-Tuberculous mycobacteria (NTM) lung disease has increased from 8.7 to 13.9/100,000 from 2008-2013 making NTM lung disease a rising public health problem. Patterns of infection include fibrocavitary, bronchiectatic or nodular. Diagnosis of NTM may be incidental after surgical resection performed during malignancy work up. We aimed to identify the proportion of NTM in resected lung lesions (both nodules and masses) with granulomas (GL) both necrotizing (NGL) and non-necrotizing (n-NGL) on pathology and to compare differences in characteristics of patients with NTM versus those without NTM. Methods This was a retrospective chart review of patients who underwent resection of lung nodules and/or a lung mass during malignancy work up from January 2013 through March 2019 including only those with granulomatous inflammation on pathology. 497 patients met these criteria and their electronic medical records were reviewed. Findings of culture-confirmed NTM on tissue, bronchoalveolar lavage or sputum (at time of resection) were classified as “NTM” group; and those with no NTM diagnoses were classified as “Non-NTM” group. Patients with NTM and another diagnoses were classified within the NTM group. Study variables were compared by the dichotomous NTM group using Chi-square test for categorical variables and T-test for continuous variables. Results Among all patients, the most common diagnosis was lung cancer (21.93%). There were 81 (16.3%) patients with NTM (Table 1). Within the NTM group, percentage of Asians, presence of NGL, placement on airborne precautions and prior history of tuberculosis were significantly higher. The NTM group also had a higher proportion of both COPD and lung cancer as their underlying condition (Table 2). 161 patients had non-diagnostic biopsies. Table 1 Table 2 Table 2 Conclusion Mycobacterial infections made up a significant percentage of resected lung nodules and/or lung masses for malignancy evaluation. NTM were isolated with greater frequency than M. Tuberculosis even with NGL on lung pathology. This reflects the changing epidemiology of NTM. The significant proportion of Asians with NTM compared with GL found during a malignancy work up without NTM is interesting and deserves further investigation. Disclosures All Authors: No reported disclosures

Comorbidities associated with nontuberculous mycobacterial disease in Japanese adults: A claims-data analysis

Background: Nontuberculous mycobacterial (NTM) lung disease is one of a growing number of chronic health problems that is difficult to cure in aging societies. While it is important to be vigilant about associated comorbidities in order to provide better patient care, data on the prevalence of comorbidities stratified by country or region are scarce. We aimed to elucidate the comorbidities associated with NTM disease based on Japanese health insurance claims data. Methods: Cross-sectional analyses were performed using the claims data for 2014 provided by the Japan Medical Data Center Co., Ltd. Patients aged 20–75 years with ≥3 claims associated with NTM disease were identified and matched to 10 sex-and-age-matched controls that had never made a claim for NTM disease. Thirty-one comorbidities previously suspected to be associated with NTM disease were selected, and the prevalence of these comorbidities compared between cases and controls. Result: Overall, 419 NTM patients (134 males and 285 females) and 4190 non-NTM controls were selected from the JMDC database. Aspergillosis, asthma, bronchiectasis, chronic heart failure, diffuse panbronchiolitis, gastroesophageal reflux, interstitial pneumonia, lung cancer, cancer other than breast, lung, ovary, or prostate cancer, and rheumatic arthritis were associated with NTM disease in both males and females. Chronic obstructive pulmonary disease was associated with NTM in males while chronic kidney disease, osteoporosis, and Sjögren syndrome were associated with NTM in females. Conclusion: NTM disease was associated with multiple comorbidities that should be considered when providing medical care to individuals with NTM disease.

Comorbidities associated with nontuberculous mycobacterial disease in Japanese adults: A claims-data analysis

Background: Nontuberculous mycobacterial (NTM) lung disease is one of a growing number of chronic health problems that is difficult to cure in aging societies. While it is important to be vigilant about associated comorbidities in order to provide better patient care, data on the prevalence of comorbidities stratified by country or region are scarce. We aimed to elucidate the comorbidities associated with NTM disease based on Japanese health insurance claims data.Methods: Cross-sectional analyses were performed using the claims data for 2014 provided by the Japan Medical Data Center Co., Ltd. Patients aged 20–75 years with ≥3 claims associated with NTM disease were identified and matched to 10 sex-and-age-matched controls that had never made a claim for NTM disease. Thirty-one comorbidities previously suspected to be associated with NTM disease were selected, and the prevalence of these comorbidities compared between cases and controls.Result: Overall, 419 NTM patients (134 males and 285 females) and 4190 non-NTM controls were selected from the JMDC database. Aspergillosis, asthma, bronchiectasis, chronic heart failure, diffuse panbronchiolitis, gastroesophageal reflux, interstitial pneumonia, lung cancer, cancer other than breast, lung, ovary, or prostate cancer, and rheumatic arthritis were associated with NTM disease in both males and females. Chronic obstructive pulmonary disease was associated with NTM in males while chronic kidney disease, osteoporosis, and Sjögren syndrome were associated with NTM in females.Conclusion: NTM disease was associated with multiple comorbidities that should be considered when providing medical care to individuals with NTM disease.