Nontuberculous Mycobacterial Lung Disease Research Articles

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

IntroductionCo-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. MethodsBALF 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. ResultsEleven 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. ConclusionThe 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.

The Impact of Nontuberculous Mycobacteria Species on Mortality in Patients With Nontuberculous Mycobacterial Lung Disease.

Patients with nontuberculous mycobacterial lung disease (NTM-LD) have increased mortality. The impact of NTM species on the risk of mortality remains unclear, especially that of death by non-cancer causes. We conducted a retrospective cohort study from 2006 to 2018 in a tertiary-care hospital in Taiwan. We enrolled patients who fulfilled the microbiological diagnostic criteria of NTM-LD. The mortality causes within 8 years after diagnosis were identified, and the Cox proportional hazard regression was performed for risk factors of mortality. A total of 1,652 subjects with NTM-LD were included. Among them, 723 (43.8%) were infected by Mycobacterium avium complex (MAC), 408 (24.7%) by M. abscessus complex (MABC), 120 (7.3%) by Mycobacterium kansasii (MK), 304 (18.4%) by other rapid-growing mycobacteria (RGM), and 97 (5.9%) by other slow-growing mycobacteria (SGM) groups. The 8-year all-cause mortality was 45.2% for all and the highest in the MK-LD group (59.2%), followed by the MABC-LD and MAC-LD groups. The adjusted hazard ratios were 2.20 (95% confidence interval: 1.40–3.46) in the MK-LD, 1.85 (1.54–2.22) in the MABC-LD, and 1.65 (1.12–2.41) in the MAC-LD groups for all-cause mortality, compared with the SGM group. Kaplan–Meier survival curves showed that all-cause mortality, non-cancer mortality, and mortality due to chronic airway diseases were significantly correlated with NTM species (log-rank p = 0.0031, < 0.001, and 0.001, respectively). High 8-year mortality rates were found in patients with NTM-LDs according to different NTM species. Notably, the difference was significant in non-cancer mortality causes, especially in chronic airway diseases.

Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system

BackgroundIn Japan, Mycobacterium avium complex lung disease (MAC-LD) is the most common in nontuberculous mycobacterial lung disease. Patients often experience adverse events, resulting in the discontinuation of treatment, which causes treatment failure. The JADER (Japanese Adverse Drug Event Report) database is a database of adverse events that allows us to collect real-world data on adverse events. We can collect large-scale data cost-effectively and detect signals of potential adverse events such as reporting odds ratio (ROR) by using spontaneous reporting systems. In this study, we aimed to elucidate the adverse events of clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) using the JADER database.MethodsWe included cases of MAC-LD between April 2004 and June 2017. We investigated sex, age, and medications that may have caused the adverse events, outcomes, and time of onset. We calculated the safety signal index as the ROR. Time-to-event analysis was performed using the Weibull distribution.ResultsThe total number of adverse events of CAM, EB, and RFP was 2780, with 806 patients. In the overall adverse events, hematologic and lymphatic disorders were the most common adverse events, with 17.3%, followed by eye disorders (16.6%), and hepatobiliary disorders (14.0%). The outcomes were as follows: recovery, 40.0%; remission, 27.1%; non-recovery, 11.2%; and death, 7.1%. Regarding the most common onset time of CAM, EB, and RFP was within 120 days at 40%, 181–300 days at 43.6%, and within 120 days at 88.5%. For CAM, the RORs of infections and infestations, hepatobiliary system disorders, and immune system disorders were 4.13 (95% confidence interval [CI], 2.3–7.44), 2.61 (95% CI, 1.39–4.91), and 2.38 (95% CI, 1.04–5.44). For EB, the ROR of eye disorders was 215.79 (95% CI, 132.62–351.12). For RFP, the RORs of renal and urinary tract disorders and investigations were 7.03 (95% CI, 3.35–14.77) and 6.99 (95% CI, 3.22–15.18). The β value of EB was 2.07 (95% CI, 1.48–2.76), which was classified as a wear-out failure type.ConclusionsFor MAC-LD, the adverse event which has the highest ROR is infections and infestations in CAM, eye disorders in EB, renal and urinary tract disorders in RFP. Adverse events of EB occur after 180 days, whereas the adverse events of CAM and RFP occur early in the course of treatment.

Molecular Characterization of Mycobacterium species Isolates from Patients with Pulmonary Tuberculosis in Sabah, Malaysia

Tuberculosis (TB) is one of the deadliest diseases worldwide, caused by members of Mycobacterium tuberculosis complex (MTBC), commonly by Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis. In Malaysia, Sabah is one of the states of public health concern with the highest TB cases. Clinical presentations of TB and non-tuberculous mycobacteria (NTM) lung disease are similar, and mycobacteria appear to be identical under standard diagnosis with sputum smear microscopy, causing difficulty to diagnose TB. Identification of Mycobacterium species is essential for effective management of mycobacterial diseases treatment and their control strategy. Thus, this study aimed to identify the Mycobacterium species from suspected TB patients in Sabah using molecular methods. Sputum samples (n=595) were screened with GeneXpert MTB/RIF (Xpert), and positive TB samples (n=67) were processed and cultured in BACTEC MGIT. Forty-five isolates were successfully recovered in MGIT and characterisation of the mycobacterial isolates using PCR and/or sequencing with rpoB, RD9, hsp65, and 16S rRNA genes confirmed the presence of Mtb in 41 samples, and four non-mycobacteria, i.e. Microbacterium laevaniformans, Streptomyces sp., Streptomyces misionensis and Gordonia sp. These non-mycobacteria isolates showed negative results when tested directly with Xpert. In conclusion, Mtb is the predominant species of MTBC circulating in Sabah. The presence of non-mycobacteria in this study was due to bacterial contamination in MGIT, not bacterial cross-reactivity in Xpert, implying the high sensitivity and specificity of Xpert for diagnosis of TB.

Innate and Adaptive Lymphocytes in Non-Tuberculous Mycobacteria Lung Disease: A Review.

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental microorganisms capable of a wide range of infections that primarily involve the lymphatic system and the lower respiratory tract. In recent years, cases of lung infection sustained by NTM have been steadily increasing, due mainly to the ageing of the population with underlying lung disease, the enlargement of the cohort of patients undergoing immunosuppressive medications and the improvement in microbiologic diagnostic techniques. However, only a small proportion of individuals at risk ultimately develop the disease due to reasons that are not fully understood. A better understanding of the pathophysiology of NTM pulmonary disease is the key to the development of better diagnostic tools and therapeutic targets for anti-mycobacterial therapy. In this review, we cover the various types of interactions between NTM and lymphoid effectors of innate and adaptive immunity. We also give a brief look into the mechanism of immune exhaustion, a phenomenon of immune dysfunction originally reported for chronic viral infections and cancer, but recently also observed in the setting of mycobacterial diseases. We try to set the scene to postulate that a better knowledge of immune exhaustion can play a crucial role in establishing prognostic/predictive factors and enabling a broader investigation of immune-modulatory drugs in the experimental treatment of NTM pulmonary disease.

Nontuberculous Mycobacterial Lung Disease in the Patients with Cystic Fibrosis-A Challenging Diagnostic Problem.

Background: Cystic fibrosis (CF) is an autosomal, recessive genetic disorder, caused by a mutation in the cystic fibrosis transmembrane conductance receptor regulator (CFTR) gene. Dysregulated mucous production, and decreased bronchial mucociliary clearance, results in increased susceptibility to bacterial and fungal infections. Recently, nontuberculous mycobacteria (NTM) infections were identified as an emerging clinical problem in CF patients. Aim: The aim of the present study was to assess the frequency of NTM isolations in CF patients hospitalized in the pulmonary department, serving as a hospital CF center, and to describe challenges concerning the recognition of NTMLD (nontuberculous mycobacterial lung disease) in those patients. Methods: Consecutive CF patients, who were hospitalized due to pulmonary exacerbations (PEX), in a single CF center, between 2010 and 2020, were retrospectively assessed for the presence of NTM in respiratory specimens. Clinical and radiological data were retrospectively reviewed. Results: Positive respiratory specimen cultures for NTM were obtained in 11 out of 151 patients (7%), mean age—35.7 years, mean BMI—20.2 kg/m2, mean FEV1—58.6% pred. Cultures and phenotyping revealed the presence of Mycobacterium avium (M. avium)—in six patients, Mycobacterium chimaera (M. chimaera) in two, Mycobacterium kansasii (M. kansasii)—in one, Mycobacterium abscessus (M. abscessus)—in one, Mycobacterium lentifavum (M. lentiflavum)—in one. Simultaneously, respiratory cultures were positive for fungi in 91% of patients: Candida albicans (C. albicans)—in 82%, Aspergillus fumigatus (A. fumigatus)—in 45%. Clinical signs of NTMLD were non—specific, chest CT indicated NTMLD in five patients only. Conclusion: Due to non-specific clinical presentation, frequent sputum cultures for NTM and analysis of serial chest CT examinations are crucial for NTMLD recognition in CF patients. Further studies concerning the predictive role of fungal pathogens for NTMLD development in CF patients are needed.

Clinical Deterioration and Lung Function Change in Patients With Concomitant Asthma and Bronchiectasis

Only limited data are available regarding the effects of bronchiectasis on the clinical course of asthma. This study evaluated longitudinal clinical outcomes according to bronchiectasis status in patients with asthma. This retrospective study included patients with asthma who underwent chest computed tomography and pulmonary function tests between January 2013 and December 2019. The annual incidence of episodes of moderate-to-severe acute clinical deterioration (exacerbations) and longitudinal changes in lung function were evaluated. Of 667 patients with asthma, 251 had bronchiectasis. Patients with bronchiectasis had significantly more history of tuberculosis and nontuberculous mycobacterial lung disease, and lower forced expiratory volume in 1 second and forced vital capacity, compared with patients without bronchiectasis, although there was no difference in smoking intensity and inhaled corticosteroid treatment. Bronchiectasis was significantly associated with higher annual rates of severe and moderate-to-severe acute exacerbations; it was also associated with greater risk of acute exacerbation during follow-up. The severity and progression of bronchiectasis were independent risk factors for acute exacerbation. There were no significant differences in annual decline of lung function according to bronchiectasis status or bronchiectasis progression. In patients with asthma, the presence and progression of bronchiectasis were significantly associated with increased risk of moderate-to-severe acute exacerbation, but they were not associated with longitudinal changes in lung function.

Drug development challenges in nontuberculous mycobacterial lung disease: TB to the rescue.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is treated with multiple repurposed drugs. Chemotherapy is long and often toxic, includes parenteral drugs, and suffers from poor cure rates. There is an urgent need for more efficacious, tolerated, and oral antibiotics optimized towards the treatment of NTM-PD, adapted to the spectrum of disease. In contrast to the empty NTM pipeline, drug development for the related tuberculosis lung disease has experienced a renaissance. Here, we argue that applying lessons learned from tuberculosis will facilitate the discovery of curative oral regimens for NTM-PD.

Treatment of Nontuberculous Mycobacterial Lung Disease Is Complex; Thus, Shared Decision Making Is Critical.

Treatment of Nontuberculous Mycobacterial Lung Disease Is Complex; Thus, Shared Decision Making Is Critical.

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

BackgroundControlling 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).MethodsWe 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.ResultsA 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.ConclusionsThe 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.

A Rabbit Model to Study Antibiotic Penetration at the Site of Infection for Nontuberculous Mycobacterial Lung Disease: Macrolide Case Study.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a potentially fatal infectious disease requiring long treatment duration with multiple antibiotics and against which there is no reliable cure. Among the factors that have hampered the development of adequate drug regimens is the lack of an animal model that reproduces the NTM lung pathology required for studying antibiotic penetration and efficacy. Given the documented similarities between tuberculosis and NTM immunopathology in patients, we first determined that the rabbit model of active tuberculosis reproduces key features of human NTM-PD and provides an acceptable surrogate model to study lesion penetration. We focused on clarithromycin, a macrolide and pillar of NTM-PD treatment, and explored the underlying causes of the disconnect between its favorable potency and pharmacokinetics and inconsistent clinical outcome. To quantify pharmacokinetic-pharmacodynamic target attainment at the site of disease, we developed a translational model describing clarithromycin distribution from plasma to lung lesions, including the spatial quantitation of clarithromycin and azithromycin in mycobacterial lesions of two patients on long-term macrolide therapy. Through clinical simulations, we visualized the coverage of clarithromycin in plasma and four disease compartments, revealing heterogeneous bacteriostatic and bactericidal target attainment depending on the compartment and the corresponding potency against nontuberculous mycobacteria in clinically relevant assays. Overall, clarithromycin's favorable tissue penetration and lack of bactericidal activity indicated that its clinical activity is limited by pharmacodynamic, rather than pharmacokinetic, factors. Our results pave the way toward the simulation of lesion pharmacokinetic-pharmacodynamic coverage by multidrug combinations to enable the prioritization of promising regimens for clinical trials.

Mycobacterial skin infection.

Purpose of reviewThe aim of this article is to review the most recent evidences concerning mycobacterial skin infections, limiting the period of literature research to 2020--2021.Recent findingsMycobacterial skin infections include a heterogeneous group of cutaneous diseases.Cutaneous tuberculosis is usually the result of hematogenous dissemination or spread from underlying foci and it must be distinguished from tuberculids, resulting from the immunological reaction to Mycobacterium tuberculosis antigens. Leprosy prevalence was drastically reduced after introduction of multidrug therapy in the 1980 s, but cases are still reported due to underdiagnosis, and animal and environmental reservoirs. Recent advances concentrate in the diagnostic field. Specific guidelines for the treatment of nontuberculous mycobacteria skin infections are missing and surgical procedures may be required. Prognosis is better as compared to nontuberculous mycobacteria lung disease. Rapid laboratory-confirmed diagnosis of Buruli ulcer may be achieved by the IS2404 PCR. Among new drugs, telacebec is promising in terms of potency, shorter duration and tolerability in animal studies. A clinical trial in humans is planned.SummaryMycobacterial cutaneous lesions are nonpathognomonic and clinical suspicion must be confirmed by culture or molecular detection. Long-course multidrug treatment is required based on susceptibility tests. Surgical intervention may also be required. Rehabilitation and psychosocial support reduce long-term physical and mental consequences mostly in Buruli ulcer and leprosy.

CT Imaging Characteristics of Nontuberculous Mycobacteria Lung Disease, Active Tuberculosis and Multi-Drug Resistant Tuberculosis.

The differential diagnosis of nontuberculous mycobacteria (NTM) lung disease, active tuberculosis (ATB) and multi-drug resistant tuberculosis (MDR-TB) remains difficult. To explore the CT imaging characteristics of NTM lung disease, ATB and MDR-TB for differential diagnosis. Patients with NTM lung disease (n=200), ATB (n=200) and MDR-TB (n=200) who were examined and treated from August 2013 to May 2021 were included. Their chest CT imaging results were retrospectively analyzed, and the imaging characteristics were compared. The proportion of cases complicated with underlying lung disease, cough and hemoptysis was significantly higher in NTM group than those in ATB and MDR-TB groups (P<0.05). Compared with ATB and MDR-TB groups, NTM group had significantly more cases of nodule-bronchus dilation type, but significantly fewer cases of nodule-mass type and other types (P<0.05). In NTM group, the cases of thin-wall cavity, bronchiectasis and centrilobular nodules increased, but the detection rate of thick-wall cavity, lung consolidation, atelectasis, lung damage, lung volume reduction, intrapulmonary calcification, hilar and mediastinal lymph node calcification, acinar nodules, pleural thickening and pleural effusion declined compared with ATB and MDR-TB groups (P<0.05). The detection rates of lesions, cavities and bronchiectasis in the lingual lobe of left lung and middle lobe of right lung were significantly higher in NTM group than those in ATB and MDR-TB groups (P<0.05). The imaging characteristics of NTM lung disease are quite similar to those of ATB and MDR-TB, but they can be differentially diagnosed through the types of cavities and nodules, incidence rate of bronchiectasis, and differences in lung consolidation, lung damage, calcification, pleural thickening and pleural effusion.

Characterization of Immune Cells From the Lungs of Patients With Chronic Non-Tuberculous Mycobacteria or Pseudomonas aeruginosa Infection.

Little is known of the lung cellular immunophenotypes in patients with non-tuberculous mycobacterial lung disease (NTM-LD). Flow-cytometric analyses for the major myeloid and lymphoid cell subsets were performed in less- and more-diseased areas of surgically resected lungs from six patients with NTM-LD and two with Pseudomonas aeruginosa lung disease (PsA-LD). Lymphocytes, comprised mainly of NK cells, CD4+ and CD8+ T cells, and B cells, accounted for ~60% of all leukocytes, with greater prevalence of T and B cells in more-diseased areas. In contrast, fewer neutrophils were found with decreased number in more-diseased areas. Compared to NTM-LD, lung tissues from patients with PsA-LD demonstrated relatively lower numbers of T and B lymphocytes but similar numbers of NK cells. While this study demonstrated a large influx of lymphocytes into the lungs of patients with chronic NTM-LD, further analyses of their phenotypes are necessary to determine the significance of these findings.

1396. The Incremental Hospitalization Burden Associated with Nontuberculous Mycobacterial Lung Disease(NTMLD) among Patients with Chronic Obstructive Pulmonary Disease (COPD) in Japan

BackgroundNTMLD is a life-threatening pulmonary infection with increasing incidence and prevalence in Japan. It is associated with progressive lung damage and increased healthcare use. Many patients with NTMLD have comorbid respiratory conditions such as COPD. Treatment of NTMLD in patients with COPD is difficult, however there is limited data on the incremental burden that NTMLD adds to underlying COPD. We assessed the incremental burden associated with NTMLD in Japanese patients with COPD by comparing their hospitalizations to matched COPD patients without NTMLD.MethodsA retrospective cohort study was conducted using claims data provided by the Japan Medical Data Center (2015-2020). COPD patients with NTMLD were matched 1:3 to COPD patients without NTMLD (controls). Hospitalizations (all-cause, respiratory-related, and COPD-related) were accrued over a 1-year follow-up period after NTMLD diagnosis (index). Incremental burden of NTMLD was assessed by comparing hospitalizations between COPD patients with NTMLD and controls with univariate and multivariate analyses adjusting for comorbidities during 1-year pre-index period.ResultsA total of 492 COPD patients with NTMLD were matched by age and sex to 1476 controls. Mean (SD) age on index date was 56.6 (10.3) years and 61.4% were females. Compared to controls, NTMLD patients had higher prevalence of some pulmonary symptoms and comorbidities such as hemoptysis (11% vs 2%), dyspnea (1.6% vs 0.6%) and lung cancer (7% vs 4%). In univariate analyses, a higher percent of COPD patients with NTMLD had hospitalizations compared to controls (Fig 1A); the unadjusted annual hospitalization rates were also higher among patients with NTMLD (Fig 2A). Multivariate regressions after adjusting for pre-index comorbidities showed COPD patients with NTMLD were 1.9 times more likely to have an all-cause hospitalization, 2.8 times more likely to have a respiratory hospitalization, and 3.0 times more likely to have a COPD-related hospitalization (Fig 1B).ConclusionCOPD patients with NTMLD had a higher burden of hospitalization than COPD patients without NTMLD. The statistically significantly incremental burden associated with NTMLD in patients with COPD highlights the acute need for appropriate management of NTMLD in Japan. Disclosures Naoki Hasegawa, MD, PhD, Insmed Incorporated (Consultant, Scientific Research Study Investigator)Janssen Pharmaceuticals Inc (Consultant, Scientific Research Study Investigator) Kozo Morimoto, MD, Insmed Incorporated (Consultant) Ping Wang, PhD, Insmed Incorporated (Employee) Lu Zhang, PhD, Panalgo (Employee, Other Financial or Material Support, Lu Zhang is an employee of Panalgo which provides the analytic platform Instant Health Data that is used by Insmed) Mariam Hassan, PhD, B. Pharm, Insmed Incorporated (Employee) Anjan Chatterjee, MD, MPH, Insmed Incorporated (Employee)

Sputum Proteomics in Nontuberculous Mycobacterial Lung Disease

Nontuberculous mycobacterial (NTM) infections are difficult to diagnose and treat. Biomarkers to identify patients with active infection or at risk of disease progression would have clinical utility. Sputum is the most frequently used matrix for the diagnosis of NTM lung disease. Can sputum proteomics be used to identify NTM-associated inflammatory profiles in sputum? Patients with NTM lung disease and a matched cohort of patients with COPD, bronchiectasis (BE), and cystic fibrosis (CF) without NTM lung disease were enrolled from two hospitals in the United Kingdom. Liquid chromatography-tandem mass spectrometry was used to identify proteomic biomarkers associated with underlying diagnosis (COPD, BE, and CF), the presence of NTM lung disease defined according to American Thoracic Society/Infectious Diseases Society of America criteria, and severity of NTM. A subset of patients receiving guideline-concordant NTM treatment were studied to identify protein changes associated with treatment response. This study analyzed 95 sputum samples from 55 subjects (BE, n= 21; COPD, n= 19; CF, n= 15). Underlying disease and infection with Pseudomonas aeruginosa were the strongest drivers of sputum protein profiles. Comparing protein abundance in COPD, BE, and CF found that 12 proteins were upregulated in CF compared with COPD, including MPO, AZU1, CTSG, CAT, and RNASE3, with 21 proteins downregulated, including SCGB1A1, IGFBP2, SFTPB, GC, and CFD. Across CF, BE, and COPD, NTM infection (n= 15) was not associated with statistically significant differences in sputum protein profiles compared with those without NTM. Two proteins associated with iron chelation were significantly downregulated in severe NTM disease. NTM treatment was associated with heterogeneous changes in the sputum protein profile. Patients with NTM and a decrease in immune response proteins had a subjective symptomatic improvement. Sputum proteomics identified candidate biomarkers of NTM severity and treatment response. However, underlying lung disease and typical bacterial pathogens such as P aeruginosa are also key determinants of the sputum proteomic profile.

The Trend of TIM3 Expression on T Cells in Patients With Nontuberculous Mycobacterial Lung Disease: From Immune Cell Dysfunction to Clinical Severity.

BackgroundThe incidence of nontuberculous mycobacterial lung disease (NTM-LD) is increasing worldwide. Immune exhaustion has been reported in NTM-LD, but T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a co-inhibitory receptor on T cells, has been scarcely studied.MethodsPatients with NTM-LD and healthy controls were prospectively recruited from July 2014 to August 2019 at three tertiary referral centers in Taiwan. We examined TIM3 expression on the T cells from the participants using flow cytometry. TIM3 expression was analyzed for different disease statuses and after treatment. The apoptosis and cytokine profiles were analyzed according to the TIM3 expression.ResultsAmong enrolled subjects (47 patients and 46 controls), TIM3 on CD4+ cells (6.44% vs. 4.12%, p = 0.028) and CD8+ cells (18.47% vs. 9.13%, p = 0.003) were higher in NTM-LD patients than in the controls. The TIM3 level on CD4+ and CD8+ T cells was positively associated with T-cell apoptosis in the NTM-LD patients. In stimulating peripheral blood mononuclear cells using PMA plus ionomycin, a high TIM3 level on T cells correlated with low interleukin-2 and tumor necrosis factor-alpha (TNF-α) on CD4+ cells and interferon-gamma and TNF-α on CD8+ T cells. For clinical manifestation, low body mass index (BMI), positive sputum acid-fast smear, and high radiographic score correlated with high TIM3 expression on T cells. After NTM treatment, TIM3+ decreased significantly on CD4+ and CD8+ T cells.ConclusionsIn patients with NTM-LD, TIM3+ expression increased over CD4+ and CD8+ T cells and correlated with cell apoptosis and specific cytokine attenuation. Clinically, TIM3+ T cells increased in patients with low BMI, high disease extent, and high bacilli burden but decreased after treatment.

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.

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. 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. 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). 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.

O7‐5: The role of increasing TIM3 on T cells in patients with nontuberculous mycobacterial lung disease: From immune cell dysfunction to clinical severity

O7‐5: The role of increasing TIM3 on T cells in patients with nontuberculous mycobacterial lung disease: From immune cell dysfunction to clinical severity

P6‐7: Is nontuberculous mycobacterial lung disease a risk factor of latent tuberculous infection? ‐ A prospective study in a medical center

P6‐7: Is nontuberculous mycobacterial lung disease a risk factor of latent tuberculous infection? ‐ A prospective study in a medical center