Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection.

Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject's bacterial isolate. In the setting of compassionate use, the evidence of phage-induced lysis was observed using molecular and metabolic assays combined with clinical assessments. M. abscessus isolates pre and post-phage treatment demonstrated genetic stability, with a general decline in diversity and no increased resistance to phage or antibiotics. The anti-phage neutralizing antibody titers to one phage increased with time but did not prevent clinical improvement throughout the course of treatment. The subject received lung transplantation on day 379, and systematic culturing of the explanted lung did not detect M. abscessus. This study describes the course and associated markers of a successful phage treatment of M. abscessus in advanced lung disease.

Incremental mortality associated with nontuberculous mycobacterial lung disease among US Medicare beneficiaries with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with nontuberculous mycobacterial lung disease (NTMLD). Both conditions are associated with increased morbidity and mortality, but data are lacking on the additional burden associated with NTMLD among patients with COPD. Thus, the goal of this study was to assess the incremental mortality risk associated with NTMLD among older adults with COPD. METHODS: A retrospective cohort study was conducted using the US Medicare claims database (2010-2017). Patients with preexisting COPD and NTMLD (cases) were matched 1:3 by age and sex with patients with COPD without NTMLD (control patients). Patients were followed up until death or data cutoff (December 31, 2017). Incremental risk of mortality was evaluated by comparing the proportions of death, annualized mortality rate, and mortality hazard rate between cases and control patients using both univariate and multivariate analyses adjusting for age, sex, comorbidities, and COPD severity. RESULTS: A total of 4,926 cases were matched with 14,778 control patients. In univariate analyses, a higher proportion of cases (vs. control patients) died (41.5% vs. 26.7%; P < 0.0001), unadjusted annual mortality rates were higher among cases (158.5 vs. 86.0 deaths/1000 person-years; P < 0.0001), and time to death was shorter for cases. This increased mortality risk was also reflected in subsequent multivariate analyses. Patients with COPD and NTMLD were more likely to die (odds ratio [95% CI], 1.39 [1.27-1.51]), had higher mortality rates (rate ratio [95% CI], 1.36 [1.28-1.45]), and had higher hazard of death (hazard ratio [95% CI], 1.37 [1.28-1.46]) than control patients. CONCLUSIONS: The substantial incremental mortality burden associated with NTMLD in patients with COPD highlights the importance of developing interventions targeting this high-risk group and may indicate an unmet need for timely and appropriate management of NTMLD.

Distinguishing nontuberculous mycobacterial lung disease and Mycobacterium tuberculosis lung disease on X-ray images using deep transfer learning.

BACKGROUND: Nontuberculous mycobacterial lung disease (NTM-LD) and Mycobacterium tuberculosis lung disease (MTB-LD) have similar clinical characteristics. Therefore, NTM-LD is sometimes incorrectly diagnosed with MTB-LD and treated incorrectly. To solve these difficulties, we aimed to distinguish the two diseases in chest X-ray images using deep learning technology, which has been used in various fields recently. METHODS: We retrospectively collected chest X-ray images from 3314 patients infected with Mycobacterium tuberculosis (MTB) or nontuberculosis mycobacterium (NTM). After selecting the data according to the diagnostic criteria, various experiments were conducted to create the optimal deep learning model. A performance comparison was performed with the radiologist. Additionally, the model performance was verified using newly collected MTB-LD and NTM-LD patient data. RESULTS: Among the implemented deep learning models, the ensemble model combining EfficientNet B4 and ResNet 50 performed the best in the test data. Also, the ensemble model outperformed the radiologist on all evaluation metrics. In addition, the accuracy of the ensemble model was 0.85 for MTB-LD and 0.78 for NTM-LD on an additional validation dataset consisting of newly collected patients. CONCLUSIONS: In previous studies, it was known that it was difficult to distinguish between MTB-LD and NTM-LD in chest X-ray images, but we have successfully distinguished the two diseases using deep learning methods. This study has the potential to aid clinical decisions if the two diseases need to be differentiated.

Real-world treatment patterns in patients with nontuberculous mycobacterial lung disease in the Netherlands based on medication dispensing data.

PURPOSE: Real-world data on antibiotic management of nontuberculous mycobacterial lung disease (NTM-LD) is limited for many countries. This study aimed to evaluate real-world treatment practices of NTM-LD in the Netherlands using medication dispensing data. METHODS: A retrospective longitudinal real-world study was conducted using IQVIA's Dutch pharmaceutical dispensing database. The data are collected monthly and include approximately 70% of all outpatient prescriptions in the Netherlands. Patients initiated on specific NTM-LD treatment regimens between October 2015 and September 2020 were included. The main areas of investigation were initial treatment regimens, persistence on treatment, treatment switching, treatment compliance in terms of medication possession rate (MPR) and restarts of treatment. RESULTS: The database included 465 unique patients initiated on triple- or dual-drug regimens for the treatment of NTM-LD. Treatment switches were common and occurred approximately 1.6 per quarter throughout the treatment period. The average MPR of patients initiated on triple-drug therapy was 90%. The median time on therapy for these patients was 119 days; after six months and one year, 47% and 20% of the patients, respectively, were still on antibiotic therapy. Of 187 patients initiated on triple-drug therapy, 33 (18%) patients restarted antibiotic therapy after the initial treatment had been stopped. CONCLUSION: When on therapy, patients were compliant with the NTM-LD treatment; however, many patients stopped their therapy prematurely, treatment switches often occurred, and part of patients had to restart their therapy after a longer treatment gap. NTM-LD management should be improved through greater guideline adherence and appropriate involvement of expert centers.

Inhaled Corticosteroids Increase Risk of Nontuberculous Mycobacterial Lung Disease: A Nested Case-Control Study and Meta-analysis.

Studies on use of inhaled corticosteroids (ICS) and the risk of nontuberculous mycobacterial lung disease (NTM-LD) are limited and have some conflicting results. We recruited 1235 NTM-LD patients and found that ICS use within 1 year was associated with increased NTM-LD, and the risk increased with elevated ICS dose and cumulative duration. Discontinuation of ICS use for more than 120 days could reduce the risk of NTM-LD to an insignificant level. For NTM species, the development of NTM-LD by ICS was highest for Mycobacterium kansasii lung disease. The pooled results of the meta-analysis showed that ICS use might increase the risk of NTM-LD with dose response in medium and high dose of daily ICS. In addition, budesonide had a smaller impact on the risk of NTM-LD than other ICS medications. The present study and meta-analysis provide evidence for ICS adjustment, including dose, discontinuation effect, and medications to possibly reduce the risk of NTM-LD.

Disease Progression in Patients With Nontuberculous Mycobacterial Lung Disease of Nodular Bronchiectatic (NB) Pattern: The Roles of Cavitary NB and Soluble Programmed Death Protein-1.

BACKGROUND: In patients with nodular bronchiectatic (NB) nontuberculous mycobacterial lung disease (NTM-LD), risk factors for disease progression have not been clearly investigated. The roles of cavitary NB and soluble programmed death protein-1 (sPD-1), an immune-related biomarker, in the disease course of NB NTM-LD remain unknown. METHODS: Patients with NB NTM-LD were enrolled from 2 medical centers in 2014-2020. We identified cavitary NB, measured sPD-1 levels, and analyzed factors associated with cavitary NB and predictors for disease progression of NB NTM-LD. RESULTS: Of 120 cases of NB NTM-LD, 87 (72.5%) were caused by Mycobacterium avium complex. sPD-1 levels were lower in 13 (10.8%) patients with cavitary NB than in noncavitary patients (P = .020). Over 1.41 ± 1.43 years of follow-up, 12 (92.3%) patients in the cavitary and 66 (61.7%) in the noncavitary group developed disease progression (P = .032). In multivariable analysis, body mass index (BMI [kg/m2]; adjusted hazard ratio [aHR], .895 [95% confidence interval, .811-.988]), sputum smear grade (aHR, 1.247 [1.014-1.534]), cavitary NB (aHR, 2.008 [1.052-3.834]), and sPD-1 (per 10-pg/mL increase; aHR, .889 [.816-.967]) were predictive for disease progression. Notably, sPD-1 showed a dose-dependent association with disease progression (sPD-1 ≤23.5 pg/mL; aHR, 3.306 [1.664-6.567]; sPD-1: 23.6-53.7 pg/mL; aHR, 2.496 [1.390-4.483]) compared with the reference (sPD-1 >53.7 pg/mL). CONCLUSIONS: Patients with NB NTM-LD and low sPD-1, low BMI, high smear grade, and cavitary NB were at high risk for disease progression. sPD-1 was low in patients with cavitary NB phenotype and dose-responsively associated with disease progression.

Reduced phagocytic activity of human alveolar macrophages infected with Mycobacterium avium complex.

INTRODUCTION: Co-infection of nontuberculous mycobacteria (NTM) with other bacteria is associated with increased frequency of hospitalization and reduced quality of life. However, the clinical significance of co-infection with NTM and other bacteria remains unclear. Here, we investigated the distribution of alveolar macrophage populations, characterized their phagocytic function in bronchoalveolar lavage fluid (BALF), and assessed the bactericidal function of macrophages infected with NTM using cell lines. METHODS: BALF samples were prospectively obtained from 30 patients with suspected NTM lung disease to evaluate phagocytic activities of macrophages using immunostaining. Bactericidal activities of Staphylococcus aureus (S. aureus) and Mycobacterium intracellulare (M. intracellulare)-infected or -non-infected macrophages were evaluated using macrophage cell lines. RESULTS: Eleven patients with Mycobacterium avium complex (MAC) infection and 19 patients with chronic lower respiratory tract infections except for NTM infection (controls) were enrolled. The percentage of non-polarized (HLA-DR+, CD40-, and CD163-) macrophages in patients infected with MAC was significantly higher than that in controls; non-polarized macrophages demonstrated an impaired ability to phagocytose S. aureus. In vitro experiments revealed higher intracellular S. aureus colony-forming unit counts and proinflammatory cytokine levels in M. intracellulare-infected macrophages than in non-NTM-infected macrophages. Electron microscopy showed morphologically damaged macrophages and M. intracellulare and S. aureus growing in the same phagosome. CONCLUSION: The proportion of alveolar macrophages (HLA-DR+, CD40-, and CD163-) with impaired phagocytosis increased in MAC-infected individuals. M. intracellulare-infected macrophages reduced bactericidal activity in vitro. Dysfunction of alveolar macrophages may contribute to persistent infection by other bacteria, leading to MAC lung disease progression.

Impact of initiation of amikacin liposome inhalation suspension on hospitalizations and other healthcare resource utilization measures: a retrospective cohort study in real-world settings.

BACKGROUND: Mycobacterium avium complex lung disease (MAC-LD) is an infection that is increasing in frequency, associated with substantial disease burden, and often refractory to treatment. Amikacin liposome inhalation suspension (ALIS) is the first therapy approved for refractory MAC-LD. In the CONVERT study of adult patients with refractory MAC-LD, adding ALIS to a multidrug background regimen showed evidence of MAC infection elimination in sputum by month 6, which was maintained in most patients through the end of treatment (≤ 12 months post-conversion). This study assessed changes in healthcare resource utilization (HCRU) among patients initiating ALIS in real-world settings. METHODS: This retrospective cohort study of the All-Payer Claims Database (October 2018-April 2020) included patients aged ≥ 18 years with ≥ 1 pharmacy claim for ALIS and ≥ 12 months of continuous health plan enrollment pre- and post-ALIS initiation. Respiratory disease-related (and all-cause) HCRU (hospitalizations, length of stay [LOS], emergency department [ED] visits, and outpatient office visits) were compared 12 months pre- and post-ALIS initiation. Outcomes were reported at 6-month intervals; 0-6 months pre-ALIS initiation was the reference period for statistical comparisons. RESULTS: A total of 331 patients received ALIS, with HCRU highest in the 6 months pre-ALIS initiation. Compared with 26.9% during the reference period, respiratory-related hospitalizations decreased to 19.3% (P < 0.01) and 15.4% (P < 0.0001) during 0-6 and 7-12 months post-ALIS initiation, respectively. Mean number of respiratory disease-related hospitalizations per patient/6-month period decreased from 1.0 (reference period) to 0.6 (P < 0.0005) at both timepoints post-ALIS initiation. A similar pattern was observed for all-cause hospitalizations and hospitalizations per patient/6-month period (both P < 0.005). Reductions in all-cause and respiratory disease-related LOS post-ALIS initiation were significant (both P < 0.05). ED visits were few and unchanged during the study. Significant reductions per patient/6-month period in all-cause and respiratory-related outpatient office visits were observed post-ALIS initiation (all P < 0.01). CONCLUSIONS: In this first real-world study of ALIS, respiratory disease-related (and all-cause) hospitalizations and outpatient visits were reduced in the 12 months following ALIS initiation. The results of this study provide HCRU-related information to better understand the impact of initiating ALIS treatment. TRIAL REGISTRATION: Not appliable.

[Association between early peripheral lung cancer and nontuberculous mycobacterial lung disease]. / Assotsiatsiya rannego perifericheskogo raka i netuberkuleznoi mikobakterial'noi bolezni legkikh.

Mycobacteriosis is an infectious disease caused by nontuberculous mycobacteria, with granulomatous inflammation in the affected organs and tissues. The association of mycobacteriosis and lung cancer in one patient is quite rarely observed and is of interest to the medical community. A 63-year-old male patient was admitted to the hospital with a diagnosis of infiltrative tuberculosis in SI-SII of both lungs in the lung cavitation phase on the right, peripheral mass in SIII on the right in order to make a decision about a surgical intervention. Morphological examination of the material obtained during upper lobectomy revealed mucinous adenocarcinoma concurrent with mycobacterium-associated inflammation with cavern formation. A bacteriological study confirmed the presence of the pathogen Mycobacterium avium. This study reports a case of association of the diseases with successful surgical intervention without complications in the early postoperative period.

Incremental Shuttle Walk Distance as an Indicator for Functional Exercise Capacity of Pre-Surgical Patients with Nontuberculous Mycobacterial Lung Disease.

The incidence of nontuberculous mycobacterial lung disease (NTMLD) is increasing worldwide, the number of lung surgeries is increasing accordingly. The disease is progressive and is characterized by exertional intolerance, respiratory dysfunctions, and impaired health-related quality of life (HRQOL). Treatment comprises multidrug antibiotic treatment combined with lung resection. The incremental shuttle walk distance (ISWD) is a standard tool for assessing the patients' tolerance to lung resection. The exertional tolerance, physical functions and HRQOL among pre-surgical patients with NTMLD are clinically important, but not fully studied yet from the viewpoint of physiotherapy. The purpose of this study was to explore the clinical significance of ISWD for assessing the exercise capacity of pre-surgical patients with NTMLD. For peripheral muscle evaluation, the strength of the quadriceps femoris muscle was measured. HRQOL was evaluated using scores of the St. George's Respiratory Questionnaire (SGRQ). Thirty-three patients (mean age 54.9 ± 13 years) were enrolled. The mean ISWD was 505 ± 134 m, shorter than the reference values (ISWD %predicted: 96 ± 27%). Regression analysis showed significant associations between ISWD and percent-predicted vital capacity (r = 0.38, p = 0.03) and percent quadriceps force/body weight (r = 0.54, p = 0.001). HRQOL assessed by SGRQ scores was correlated with ISWD (r < -0.4, p < 0.05). Multiple regression analysis showed that ISWD was significantly associated with leg muscle strength and with HRQOL. In conclusion, ISWD is useful to evaluate the exercise capacity among pre-surgical patients with NTMLD.

Nonpharmacological treatment for patients with nontuberculous mycobacterial lung disease.

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.

Gut microbiota dysbiosis-related susceptibility to nontuberculous mycobacterial lung disease.

The role of gut microbiota in host defense against nontuberculous mycobacterial lung disease (NTM-LD) was poorly understood. Here, we showed significant gut microbiota dysbiosis in patients with NTM-LD. Reduced abundance of Prevotella copri was significantly associated with NTM-LD and its disease severity. Compromised TLR2 activation activity in feces and plasma in the NTM-LD patients was highlighted. In the antibiotics-treated mice as a study model, gut microbiota dysbiosis with reduction of TLR2 activation activity in feces, sera, and lung tissue occurred. Transcriptomic analysis demonstrated immunocompromised in lung which were closely associated with increased NTM-LD susceptibility. Oral administration of P. copri or its capsular polysaccharides enhanced TLR2 signaling, restored immune response, and ameliorated NTM-LD susceptibility. Our data highlighted the association of gut microbiota dysbiosis, systematically compromised immunity and NTM-LD development. TLR2 activation by P. copri or its capsular polysaccharides might help prevent NTM-LD.

Dipeptidyl peptidase IV inhibitors and the risk of mycobacterial pulmonary infections in type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (DM) is a risk factor for mycobacterial pulmonary infections (MPI), including tuberculosis (TB) and nontuberculous mycobacterial lung disease (NTM-LD). Dipeptidyl peptidase IV inhibitor (DPP4i), a common DM medication, has an immune-modulation effect that raises concerns about developing MPI. However, there is scarce research on the topic. METHODS: This retrospective study was conducted in a tertiary-referral center in Taiwan from 2009 to 2016. Patients with type 2 DM who were receiving any DM medication were enrolled. TB and NTM-LD were defined by microbiological criteria. We analyzed the risk of MPI in DPP4i users using Cox proportional hazard regression with adjusted inverse probability of treatment weighting. RESULTS: A total of 9963 patients were included. Among them, 3931 were classified as DPP4i users, and 6032 patients were DPP4i nonusers. DPP4i users had no increase in incidences of MPI (604 vs. 768 per 100,000 person-years, p = 0.776), NTM-LD (174 vs. 255 per 100,000 person-years, p = 0.228), and TB (542 vs. 449 per 100,000 person-years, p = 0.663) relative to those of DPP4i nonusers. After adjustment, the adjusted hazard ratios for MPI (aHR: 1.07, 95% CI: 0.79-1.45), TB (aHR: 1.15, 95% CI: 0.81-1.64) and NTM-LD (aHR: 0.85, 95% CI: 0.49-1.47) were not significantly increased relative to those of nonusers. The subgroup analysis also showed that DPP4i use did not increase the risk of MPI in different DM severities and comorbidities. CONCLUSIONS: According to our large cohort study, DPP4i use is safe for patients with type 2 DM and might not increase the risk of MPI.

Nontuberculous mycobacteria by metagenomic next-generation sequencing: Three cases reports and literature review.

Background: The increasing worldwide incidence of nontuberculous mycobacterial lung disease (NTM-LD) and the similarity of its manifestations to those of tuberculosis (TB) pose huge challenges in the diagnosis and treatment of NTM-LD, which is commonly misdiagnosed and mistreated as TB. Proper diagnosis and treatment at an early stage can greatly improve patient outcomes. Case presentation: Mycobacterium avium was identified by mNGS in lung tissue of case 1 and bronchioalveolar fluid from case 2 that was not identified using conventional microbiological methods. Multiple NTM species were detected in the blood mNGS samples from case 3 who had disseminated NTM infection. Although NTM was isolated from blood culture, conventional methods failed to identify the organisms to the level of species. All three patients were suffering from and being treated for myelodysplastic syndrome, rheumatoid arthritis, systemic lupus erythematosus, or acute lymphoblastic leukemia, making them immunosuppressed and susceptible to NTM infections. Case 1 and Case 2 significantly improved after anti-NTM treatment, but case 3 succumbed to the infection due to her underlying medical illness despite aggressive treatment. Conclusions: The cases in this study demonstrate the effectiveness of mNGS in facilitating and improving the clinical diagnosis of NTM infections. We propose combining mNGS with traditional diagnostic methods to identify pathogens at the early stages of the disease so that targeted treatment can be implemented.

Prevalence of Latent Tuberculous Infection in Patients With Nontuberculous Mycobacterial Lung Disease and Colonization: A Prospective Study in an Intermediate Tuberculosis Burden Country.

BACKGROUND: Controlling latent tuberculosis infection (LTBI) is important in eliminating tuberculosis (TB); however, the prevalence of LTBI has rarely been studied in patients with nontuberculous mycobacterial (NTM) lung disease (LD) and colonization (LC). METHODS: We prospectively recruited subjects with NTM isolated from sputum mycobacterial cultures from December 2011 to June 2019. NTM-LD and NTM-LC were defined according to the American Thoracic Society guidelines. Patients with negative cultures were recruited as controls. Patients with a history of active TB or positive TB cultures were excluded. LTBI was confirmed using a QuantiFERON-TB Gold In-tube test. The prevalence and factors associated with LTBI were analyzed. RESULTS: A total of 406 participants were enrolled, including 171 in the NTM-LD group, 153 in the NTM-LC group, and 82 in the control group. The prevalence of LTBI was higher in the NTM-LD and NTM-LC groups than in the controls (21.6%, 20.9%, and 6.1%; P = .006). Multivariable analysis showed that old age (adjusted odds ratio [aOR], 1.021, per year increment; P = .042), NTM-LD (aOR, 4.030; P = .005), NTM-LC (aOR, 3.610; P = .011, compared with the controls), and pulmonary cavitary lesions (aOR, 3.393; P = .034) were independently associated with LTBI. CONCLUSIONS: The prevalence of LTBI was higher in the patients with NTM-LD and NTM-LC than in the controls. Old age, pulmonary cavitation, and NTM isolated from sputum were associated with a higher risk of LTBI.

High diversity of clinical Mycobacterium intracellulare in China revealed by whole genome sequencing.

Mycobacterium intracellulare is the most common cause of nontuberculous mycobacterial lung disease, with a rapidly growing prevalence worldwide. In this study, we performed comparative genomic analysis and antimicrobial susceptibility characteristics analysis of 117 clinical M. intracellulare strains in China. Phylogenetic analysis showed that clinical M. intracellulare strains had high genetic diversity and were not related to the geographical area. Notably, most strains (76.07%, 89/117) belonged to Mycobacterium paraintracellulare (MP) and Mycobacterium indicus pranii (MIP) in the genome, and we named them MP-MIP strains. These MP-MIP strains may be regarded as a causative agent of chronic lung disease. Furthermore, our data demonstrated that clarithromycin, amikacin, and rifabutin showed strong antimicrobial activity against both M. intracellulare and MP-MIP strains in vitro. Our findings also showed that there was no clear correlation between the rrs, rrl, and DNA gyrase genes (gyrA and gyrB) and the aminoglycosides, macrolides, and moxifloxacin resistance, respectively. In conclusion, this study highlights the high diversity of M. intracellulare in the clinical setting and suggests paying great attention to the lung disease caused by MP-MIP.

Role of Soluble T-Cell Immunoglobulin Mucin Domain-3 in Differentiating Nontuberculous Mycobacterial Lung Disease from Pulmonary Colonization.

BACKGROUND: Differentiating between nontuberculous mycobacterial lung disease (NTM-LD) and pulmonary NTM colonization (NTM-Col) is difficult. Compared with healthy controls, patients with NTM-LD generally present immune tolerance along with increased expressions of T-cell immunoglobulin mucin domain-3 (TIM-3) and programmed cell death-1 (PD-1) on T lymphocytes. However, the role of soluble TIM-3 (sTIM-3) and soluble PD-1 (sPD-1) in differentiating NTM-LD from NTM colonization (NTM-Col) remains unclear. METHODS: Patients with NTM-positive respiratory samples and controls were enrolled from 2016 to 2019. Patients were classified into NTM-Col and NTM-LD groups. Levels of sTIM-3, sPD-1, soluble PD-ligand-1 (sPD-L1), and TIM-3 expression were measured. Factors associated with NTM-LD were analyzed by logistical regression. RESULTS: TIM-3 expression on CD4+ and CD8+ T lymphocytes were highest in NTM-LD group, followed by NTM-Col, and control (P=.017 and P=.011 for trend). sTIM-3 elevated in the NTM-Col group compared with the NTM-LD and control groups (856.3±518.7 vs. 595.3±352.6pg/mL, P=.009; vs. 437.0±267.4pg/mL, P<.001). Levels of soluble PD-1 and its ligand were similar among groups. Among the 79 NTM-positive patients, sTIM-3 was associated with NTM-LD (100-pg/mL increase, adjusted odds ratio (aOR) 0.658 [95% CI, 0.502-0.864], P=.003). Patients with ≥2 risk factors (sTIM-3≤530pg/mL, BMI≤22.5, and radiographic score ≥5) were 13 times more likely to exhibit NTM-LD than those without (aOR 13.234 [2.983-58.709], P=.001). CONCLUSIONS: sTIM-3 was an independent factor for differentiating NTM-LD from NTM-Col, suggesting the immunologic role of sTIM-3 in NTM-LD pathogenesis. By assessing sTIM-3 levels and other risk factors, physicians may be able to identify NTM-LD cases in a simplified manner.

Is the Leicester Cough Questionnaire useful for nontuberculous mycobacterial lung disease?

BACKGROUND: Although the incidence of nontuberculous mycobacterial lung disease (NTM-LD) is increasing worldwide, there is no established standard of care leading to eradication. Therefore, research on health-related quality of life (HRQOL) is important for patients with NTM-LD. HRQOL is commonly evaluated using the St. George's Respiratory Questionnaire (SGRQ), developed for chronic obstructive pulmonary disease (COPD). However, NTM-LD differs from COPD in that few patients complain of dyspnea or wheezing, and cough and sputum are their main symptoms. The Leicester Cough Questionnaire (LCQ) is an HRQOL questionnaire dedicated to cough, but few studies have used it for NTM-LD. This study evaluated HRQOL in patients with NTM-LD using the SGRQ and LCQ and clarified the usefulness of the LCQ. METHODS: Information on age, height, weight, lung function, percent ideal body weight, laboratory data, radiological scores, exercise capacity, SGRQ, and LCQ were collected from the medical records of 81 patients. Correlations between SGRQ and LCQ domains were assessed using Spearman's rank correlation coefficients. Multivariate analysis was performed with SGRQ and LCQ total scores. RESULTS: Statistically significant correlations were observed between all domains, and the correlation between the total scores was -0.67 (p < 0.01). Multivariate analysis with total scores as the dependent variable showed that the explanatory variables were lung function (p < 0.05) and radiological score (p < 0.05) in the SGRQ, and radiological score (p < 0.05) and C-reactive protein level (p < 0.05) in the LCQ. CONCLUSION: The LCQ, which evaluates an inflammatory response involved in the diagnosis of NTM-LD, may be useful to assess HRQOL in patients with NTM-LD.

Symptom Burden and Medication Use Among Patients with Nontuberculous Mycobacterial Lung Disease.

PURPOSE: Respiratory diseases caused by nontuberculous mycobacteria (NTM) have become a significant concern for patients and health care providers. We aimed to compare symptoms experienced during the 2 week period, at a single point in time, by patients with NTM lung disease (NTMLD) who were currently on any medication to treat their NTMLD versus those not on any therapies. METHODS: We analyzed responses to a "Burden of NTM Survey" developed by the COPD Foundation. The study population included 266 individuals with NTMLD. Using adjusted penalized logistic regression models, we determined associations between the self-reported symptoms and the use of any medication to treat NTMLD. RESULTS: Based on available data, most respondents were aged 50 and older (95.1%), of female gender (93.1%), and had been living with NTMLD for more than 5 years (55.7%). Many respondents reported symptoms that bother them very often or daily. After adjustment for age and gender, duration of living with NTMLD, and other respiratory illnesses, patients on medication had significantly larger odds of reporting difficulty in walking 500 meters without stopping, difficulty in interacting with others, fatigue or lack of energy, feelings of sadness or depression related to illness, and shortness of breath, wheezing or other difficulties. CONCLUSION: In this study, patients currently on any medication to treat their NTMLD reported more symptoms associated with their NTMLD. Further investigations are needed to explore whether increased symptoms are related to differences in disease severity and/or medication effects.

Nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex - disease burden, unmet needs, and advances in treatment developments.

INTRODUCTION: Nontuberculous mycobacterial (NTM) lung disease (LD) is the most common clinical manifestation of NTM infection and is a growing health concern. Up to 85% of NTM-LD cases are caused by Mycobacterium avium complex (MAC). Increased awareness of NTM-LD caused by MAC is needed as patients with this disease experience substantial burden and unmet treatment needs. AREAS COVERED: This review provides clinicians and regulatory and healthcare decision makers an overview of the clinical, economic, and humanistic burden of NTM-LD and the unmet treatment needs faced by patients and clinicians. The review focuses on NTM-LD caused by MAC. A summary of the 2020 NTM guidelines specifically for MAC-LD and an overview of novel treatment options, including amikacin liposome inhalation suspension (ALIS) as the first approved therapy for refractory MAC-LD, and investigational drugs in testing phase are provided. EXPERT OPINION: Key advancements in NTM-LD management include recent updates to clinical practice guidelines, approval of ALIS for the treatment of refractory MAC-LD, and ongoing clinical trials of investigational treatments. Yet opportunities still exist to improve patient outcomes, including development of better screening tools, such as reliable and responsive biomarkers to help identify high-risk patients, and addressing unmet treatment needs.