Chest Radiograph Screening for Detecting Subclinical Tuberculosis in Asymptomatic Household Contacts, Peru.

The World Health Organization's end TB strategy promotes the use of symptom and chest radiograph screening for tuberculosis (TB) disease. However, asymptomatic early states of TB beyond latent TB infection and active disease can go unrecognized using current screening criteria. We conducted a longitudinal cohort study enrolling household contacts initially free of TB disease and followed them for the occurrence of incident TB over 1 year. Among 1,747 screened contacts, 27 (52%) of the 52 persons in whom TB subsequently developed during follow-up had a baseline abnormal radiograph. Of contacts without TB symptoms, persons with an abnormal radiograph were at higher risk for subsequent TB than persons with an unremarkable radiograph (adjusted hazard ratio 15.62 [95% CI 7.74-31.54]). In young adults, we found a strong linear relationship between radiograph severity and time to TB diagnosis. Our findings suggest chest radiograph screening can extend to detecting early TB states, thereby enabling timely intervention.

Detecting circulating microbial cell-free DNA by next-generation sequencing in patients with Mycobacterium avium complex-lung disease: A pilot study.

Objectives: Determining a diagnosis for non-Tuberculous mycobacterium (NTM)-lung disease (LD) remains difficult. The value of circulating cell-free DNA (cfDNA) secreted from microbes has been established in the detection of pathogens in septic patients. However, it is unknown whether NTM-derived cfDNA is detectable in plasma from patients with NTM-LD and whether this is associated with the disease status of NTM-LD, especially in patients with Mycobacterium avium complex (MAC)-LD. Materials and Methods: In this pilot study, from 2018 to 2019, we enrolled adult patients with MAC-LD at Taipei Veterans General Hospital in Taiwan for the detection of circulating cfDNA. We performed cfDNA extraction from plasma, next-generation sequencing (NGS) for nonhuman cfDNA, and sequence matching to a microbial database and then assessed the association between pathogen cfDNA and MAC-LD. Results: Two (40%) plasma samples from MAC-LD patients had detectable MAC-specific cfDNA, namely one instance of DNA polymerase III alpha subunit and one instance of ATP-binding cassette transporters permease. The plasma samples from the three other MAC-LD cases and the one tuberculosis control were negative for either NTM-derived cfDNA or tuberculosis-related cfDNA. In addition to MAC-specific cfDNA, Ralstonia solanacearum, Staphylococcus aureus, and Pasteurella multocida were the most observed bacteria in our patients. The two patients with MAC-cfDNA positivity yielded higher radiographic scores (P = 0.076) and presented a higher number of nonhuman reads than those without MAC-cfDNA positivity (P = 0.083). Conclusion: Using NGS method, we demonstrated MAC-cfDNA was detectable in patients with MAC-LD. Further large-scale research is warranted to assess the clinical value of detecting MAC-specific cfDNA in MAC-LD patients.

Comparative cardiovascular safety of LABA/LAMA FDC versus LABA/ICS FDC in patients with chronic obstructive pulmonary disease: a population-based cohort study with a target trial emulation framework.

BACKGROUND: Use of combinations of long-acting ß2 agonists/long-acting muscarinic antagonists (LABA/LAMA) in patients with chronic obstructive pulmonary disease (COPD) is increasing. Nevertheless, existing evidence on cardiovascular risk associated with LABA/LAMA versus another dual combination, LABA/inhaled corticosteroids (ICS), was limited and discrepant. AIM: The present cohort study aimed to examine comparative cardiovascular safety of LABA/LAMA and LABA/ICS with a target trial emulation framework, focusing on dual fixed-dose combination (FDC) therapies. METHODS: We identified patients with COPD who initiated LABA/LAMA FDC or LABA/ICS FDC from a nationwide Taiwanese database during 2017-2020. The outcome of interest was a hospitalized composite cardiovascular events of acute myocardial infarction, unstable angina, heart failure, cardiac dysrhythmia, and ischemic stroke. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for composite and individual cardiovascular events after matching up to five LABA/LAMA FDC initiators to one LABA/ICS FDC initiator using propensity scores (PS). RESULTS: Among 75,926 PS-matched patients, use of LABA/LAMA FDC did not show a higher cardiovascular risk compared to use of LABA/ICS FDC, with a HR of 0.89 (95% CI, 0.78-1.01) for the composite events, 0.80 (95% CI, 0.61-1.05) for acute myocardial infarction, 1.48 (95% CI, 0.68-3.25) for unstable angina, 1.00 (95% CI, 0.80-1.24) for congestive heart failure, 0.62 (95% CI, 0.37-1.05) for cardiac dysrhythmia, and 0.82 (95% CI, 0.66-1.02) for ischemic stroke. The results did not vary substantially in several pre-specified sensitivity and subgroup analyses. CONCLUSION: Our findings provide important reassurance about comparative cardiovascular safety of LABA/LAMA FDC treatment among patients with COPD.

Predicting stringent QuantiFERON-TB Gold Plus conversions in contacts of tuberculosis patients.

OBJECTIVES: To assess associations between disease severity in index TB patients and QuantiFERON-TB Gold Plus (QFT-Plus) results in contacts, and predictors for QFT-Plus conversion in contacts over 6-12 months. METHODS: TB patients (n = 295) and the contacts (n = 1051) were enrolled during 2018-2021 with QFT-Plus performed at baseline and months 6 and 12. A strong CD8 response was defined as TB2 interferon gamma (IFN-γ) response minus TB1 >0.6 IU/ml and stringent conversion as change from QFT-plus negative to high-positive QFT-Plus (TB1 or TB2 IFN-γ responses >0.7 IU/ml). RESULTS: Contacts with index TB patients with sputum smear >1+ was associated with positive QFT-Plus compared to those without (p < 0.001). Contacts with index TB patients with bilateral lung disease were more likely to have strong CD8 responses than those without (p = 0.038). QFT-Plus stringent conversion occurred in 9.7% of contacts over 6-12 months. A TB1 IFN-γ response ≥0.03 IU/ml combined with a TB2 ≥0.06 IU/ml was predictive of a 19-fold increased risk for QFT-Plus stringent conversion in contacts (odd ratio 19.565 [8.484-45.116], p < 0.001). CONCLUSION: Bacterial burden and bilateral lung disease of index TB patients were associated with positive QFT-Plus and strong CD8 responses in contacts. TB1 and TB2 IFN-γ responses were synergistically predictive of stringent conversion in contacts.

Prescription Patterns of New Use of Fixed-Dose Combination Inhalers in Patients with Chronic Obstructive Pulmonary Disease: Long-Acting ß2 Agonists Plus Long-Acting Muscarinic Antagonists versus Long-Acting ß2 Agonists Plus Inhaled Corticosteroids.

Background: The clinical guideline recommends use of long-acting ß2 agonists/long-acting muscarinic antagonists (LABA/LAMA) or long-acting ß2 agonists/inhaled corticosteroids (LABA/ICS) combination therapies for patients with severe chronic obstructive pulmonary disease (COPD). The fixed-dose combination (FDC) inhalers of LABA/LAMA and LABA/ICS were reimbursed in Taiwan in 2015 and in 2002, respectively. This study aimed to examine prescription patterns of new use of either FDC therapy in real-world practice. Methods: We identified COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC between 2015 and 2018 from a population-based Taiwanese database with 2 million, randomly sampled beneficiaries enrolled in a single-payer health insurance system. We compared number of LABA/LAMA FDC and LABA/ICS FDC initiators in each calendar year, from different hospital accreditation levels, and cared for by different physician specialties. We also compared baseline patient characteristics between LABA/LAMA FDC and LABA/ICS FDC initiators. Results: A total of 12,455 COPD patients who initiated LABA/LAMA FDC (n=4019) or LABA/ICS FDC (n=8436) were included. Number of LABA/LAMA FDC initiators increased apparently (n=336 in 2015 versus n=1436 in 2018), but number of LABA/ICS FDC initiators decreased obviously (n=2416 in 2015 versus n=1793 in 2018) over time. The preference of use of LABA/LAMA FDC varied across clinical environments. The proportions of LABA/LAMA FDC initiators were more than 30% in the setting of non-primary care clinics (eg, medical centers) and in the services of chest physicians; but were only less than 10% in primary care clinics and non-chest physicians' services (eg, family medicine physicians). LABA/LAMA FDC initiators appeared to be older, male, to have more comorbidities, and to utilize resources more frequently compared to LABA/ICS FDC initiators. Conclusion: This real-world study found evident temporal trends, variations in healthcare provider, and differences in patient characteristics among COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC.

Role of nebulized colistin as a substitutive strategy against nosocomial pneumonia caused by CR-GNB in intensive care units: a retrospective cohort study.

BACKGROUND: Adverse reactions, especially nephrotoxicity, are great concerns of intravenous colistin treatment. The role of substitutive nebulized colistin in treating nosocomial pneumonia caused by carbapenem-resistant Gram-negative bacterial (CR-GNB) in critically ill patients remains unknown. METHODS: This retrospective study enrolled patients with nosocomial pneumonia caused by colistin-susceptible CRGNB in the intensive care unit (ICU) without intravenous colistin treatment. Patients were categorized based on whether substitutive nebulized colistin was used alongside other intravenous antibiotics. Clinical responses and mortality rates were compared between the two groups in the original and propensity score (PS)-matched cohorts. This study aimed to investigate the clinical effectiveness of substitutive nebulized colistin in treatment outcomes of nosocomial pneumonia caused by CR-GNB. The impact of dosing strategy of nebulized colistin was also explored. RESULTS: In total, 343 and 214 patients with and without substitutive nebulized colistin, respectively, were enrolled for analysis. In the PS-matched cohort, clinical failure rates on day 7 (22.6 vs. 42.6%, p = 0.001), day 14 (27.0 vs. 42.6%, p = 0.013), and day 28 (27.8 vs. 41.7%, p = 0.027) were significantly lower in patients with nebulized colistin. In multivariate analysis, nebulized colistin was an independent factor associated with lower day 14 clinical failure (Original cohort: adjusted odds ratio (aOR) 0.45, 95% confidence interval (CI) 0.30-0.67; PS-matched cohort: aOR 0.48, 95% CI 0.27-0.87). There were no differences in clinical failure rate and mortality rate between patients receiving high (> 6 MIU/day) and low (≤ 6 MIU/day) dose nebulized colistin in the PS-matched cohort. CONCLUSIONS: In ICU-admitted patients with nosocomial pneumonia caused by colistin-susceptible CRGNB, substitutive nebulized colistin was associated with better clinical outcomes.

Sex-Specific Associations Between Susceptibility to Mycobacterium avium Complex Lung Disease and Programmed Cell Death 1 Gene Polymorphisms.

BACKGROUND: Mycobacterium avium complex lung disease (MAC-LD) preferentially occurs in postmenopausal women and may have immune exhaustion involving the programmed cell death 1 (PD-1) pathway. It is still unknown whether sex-specific associations between susceptibility to MAC-LD and programmed cell death 1 gene (PDCD1) polymorphisms exist. METHODS: Adult patients with MAC-LD (n = 152) and controls (n = 167) were included at 2 medical centers in Taiwan. Five single-nucleotide polymorphisms in PDCD1 genes were genotyped, and their associations with MAC-LD and soluble PD-1 protein were analyzed, especially in sex subgroups. RESULTS: PDCD1 rs2227982 polymorphism was associated with increased risk of MAC-LD in women (adjusted odds ratio for AA vs AG vs GG, 2.205 [95% confidence interval, 1.108-4.389]; P = .02), and the rs10204525 TT genotype was associated with low risk in men (TT vs TC and CC, 0.396 [.176-.890]; P = .02). Compared with men with rs10204525 TT, women with rs2227982 AG and with AA had 2.7- and 5.0-fold increased risks, respectively. Soluble PD-1 levels were lower in the female subgroup with rs2227982 AG and AA than in the remainder (median level [interquartile range], 46.7 [33.7-71.5] pg/mL vs 66.2 [48.6-101.5] pg/mL; P < .001). CONCLUSIONS: PDCD1 genetic polymorphisms were associated with the risk of MAC-LD in a sex-specific pattern, possibly through regulation of PD-1 expression.

Circulating mitochondrial cell-free DNA dynamics in patients with mycobacterial pulmonary infections: Potential for a novel biomarker of disease.

Objectives: Human mitochondrial cell-free DNA (Mt-cfDNA) may serve as a useful biomarker for infectious processes. We investigated Mt-cfDNA dynamics in patients with pulmonary mycobacterial infections to determine if this novel biomarker could be used to differentiate disease states and severity. Methods: Patients with pulmonary tuberculosis (PTB), latent tuberculosis infection (LTBI), and nontuberculous mycobacterial-lung disease (NTM-LD) were enrolled at a tertiary care hospital in Taiwan between June 2018 and August 2021. Human Mt-cfDNA and nuclear-cfDNA (Nu-cfDNA) copy numbers were estimated by quantitative polymerase chain reaction. Variables associated with PTB and 2-month sputum culture-positivity, indicating poor treatment response, were assessed using logistic regression. Results: Among 97 patients with PTB, 64 with LTBI, and 51 with NTM-LD, Mt-cfDNA levels were higher in patients with PTB than in LTBI (p=0.001) or NTM-LD (p=0.006). In the Mycobacterium tuberculosis-infected population, Mt-cfDNA levels were highest in smear-positive PTB patients, followed by smear-negative PTB (p<0.001), and were lowest in LTBI persons (p=0.009). A Mt-cfDNA, but not Nu-cfDNA, level higher than the median helped differentiate culture-positive PTB from culture-negative PTB and LTBI (adjusted OR 2.430 [95% CI 1.139-5.186], p=0.022) and differentiate PTB from NTM-LD (adjusted OR 4.007 [1.382-12.031], p=0.011). Mt-cfDNA levels decreased after 2 months of treatment in PTB patients (p=0.010). A cutoff Mt-cfDNA level greater than 62.62 x 106 copies/µL-plasma was associated with a 10-fold risk of 2-month culture-positivity (adjusted OR 9.691 [1.046-89.813], p=0.046). Conclusion: Elevated Mt-cfDNA levels were associated with PTB disease and failed sputum conversion at 2 months in PTB patients, and decreased after treatment.

Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified, Randomized, Controlled Trial

Introduction: Chronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation represents a distinct phenotype that might respond to treatment with inhaled corticosteroids. Fractional exhaled nitric oxide (FENO) might predict eosinophilic inflammation and guide treatment option. We hypothesized that COPD patients with different baseline levels of FENO might have differentiated response to treatment with salmeterol/fluticasone (SFC) or tiotropium (TIO). Methods: This open-label, randomized-controlled trial enrolled treatment-naïve COPD patients who were stratified into high- (≥23.5ppb) and low-FENO group, followed by 12-week treatment with SFC or TIO. A linear mixed model with repeated measures was applied to analyze the changes in FENO (primary outcome), COPD assessment test (CAT) score, FEV1, and parameters in induced sputum and blood after treatment. Results: 134 patients were divided into 4 subgroups: low-FENO/SFC (n=30), low-FENO/TIO (n=29), high-FENO/SFC (n=37), and high-FENO/TIO (n=38). At baseline, FENO 23.5ppb clearly differentiated between eosinophilic and non-eosinophilic inflammation groups based on the eosinophils in induced sputum and blood. FENO significantly correlated with sputum and blood eosinophils at baseline. High-FENO/SFC (vs. high-FENO/TIO) subgroup had significant reduction in FENO and sputum inflammation profiles (including eosinophils, macrophages, matrix metalloproteinase-9, and interlukin-8) after treatment. These differences were not replicated between low-FENO/SFC and low-FENO/TIO subgroups. The improvement in CAT and FEV1 after treatment was indiscriminate between SFC and TIO in the low- and high-FENO groups. Conclusion: High baseline FENO can serve as an indicator of eosinophilic airway inflammation in COPD patients who may respond favorably to treatment with inhaled corticosteroids/long-acting β2-agonists. (AU)

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.

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. (AU)

Treatment Outcome in Patients with Mycobacterium abscessus Complex Lung Disease: The Impact of Tigecycline and Amikacin.

BACKGROUND: The contemporary guidelines have recommended multiple antimicrobial therapies along with oral macrolides for the treatment of Mycobacterium abscessus complex lung disease (MABC-LD). However, there is little evidence supporting the parenteral tigecycline-containing regimens against MABC-LD. Therefore, we conducted this study to evaluate the effect of intravenous tigecycline-containing regimens on the treatment of MABC-LD. METHODS: A retrospective study was conducted in 6 medical centers. Patients with MABC-LD that were followed up at ≥12 months were enrolled. Mycobacterium abscessus subspecies were identified by hsp65, rpoB, secA1 gene PCR, and sequencing. Antimicrobial susceptibility was determined for 34 patients using broth microdilution methods following the Clinical and Laboratory Standards Institute (CLSI) guideline. The microbiology and treatment outcomes were defined as either success or failure. The impacts of tigecycline and amikacin were adjusted for age, comorbidities, surgical resection, and radiologic scores. RESULTS: During the study period, seventy-one patients were enrolled for final analysis. The microbiology failure rate was 61% (43/71) and the treatment failure rate was 62% (44/71). For M. abscessus complex, 97% (33/34) of tigecycline MIC were ≤1 mg/L. Amikacin also demonstrated great susceptibility (94.1%; 32/34). Treatment with regimens containing tigecycline plus amikacin provided better microbiology success (adjusted OR 17.724; 95% CI 1.227-267.206) and treatment success (adjusted OR 14.085; 95% CI 1.103-166.667). CONCLUSION: The outcome of MABC-LD is always unsatisfactory. Treatment regimens with oral macrolide in combination with tigecycline and amikacin were correlated with increased microbiology success and less treatment failure.

Using an ATR-FTIR Technique to Detect Pathogens in Patients with Urinary Tract Infections: A Pilot Study.

Urinary tract infections (UTIs) are a leading hospital-acquired infection. Although timely detection of causative pathogens of UTIs is important, rapid and accurate measures assisting UTI diagnosis and bacterial determination are poorly developed. By reading infrared spectra of urine samples, Fourier-transform infrared spectroscopy (FTIR) may help detect urine compounds, but its role in UTI diagnosis remains uncertain. In this pilot study, we proposed a characterization method in attenuated total reflection (ATR)-FTIR spectra to evaluate urine samples and assessed the correlation between ATR-FTIR patterns, UTI diagnosis, and causative pathogens. We enrolled patients with a catheter-associated UTI in a subacute-care unit and non-UTI controls (total n = 18), and used urine culture to confirm the causative pathogens of the UTIs. In the ATR-FTIR analysis, the spectral variation between the UTI group and non-UTI, as well as that between various pathogens, was found in a range of 1800-900 cm-1, referring to the presence of specific constituents of the bacterial cell wall. The results indicated that the relative ratios between different area zones of vibration, as well as multivariate analysis, can be used as a clue to discriminate between UTI and non-UTI, as well as different causative pathogens of UTIs. This warrants a further large-scale study to validate the findings of this pilot research.

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.

Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified, Randomized, Controlled Trial.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation represents a distinct phenotype that might respond to treatment with inhaled corticosteroids. Fractional exhaled nitric oxide (FENO) might predict eosinophilic inflammation and guide treatment option. We hypothesized that COPD patients with different baseline levels of FENO might have differentiated response to treatment with salmeterol/fluticasone (SFC) or tiotropium (TIO). METHODS: This open-label, randomized-controlled trial enrolled treatment-naïve COPD patients who were stratified into high- (≥23.5ppb) and low-FENO group, followed by 12-week treatment with SFC or TIO. A linear mixed model with repeated measures was applied to analyze the changes in FENO (primary outcome), COPD assessment test (CAT) score, FEV1, and parameters in induced sputum and blood after treatment. RESULTS: 134 patients were divided into 4 subgroups: low-FENO/SFC (n=30), low-FENO/TIO (n=29), high-FENO/SFC (n=37), and high-FENO/TIO (n=38). At baseline, FENO 23.5ppb clearly differentiated between eosinophilic and non-eosinophilic inflammation groups based on the eosinophils in induced sputum and blood. FENO significantly correlated with sputum and blood eosinophils at baseline. High-FENO/SFC (vs. high-FENO/TIO) subgroup had significant reduction in FENO and sputum inflammation profiles (including eosinophils, macrophages, matrix metalloproteinase-9, and interlukin-8) after treatment. These differences were not replicated between low-FENO/SFC and low-FENO/TIO subgroups. The improvement in CAT and FEV1 after treatment was indiscriminate between SFC and TIO in the low- and high-FENO groups. CONCLUSION: High baseline FENO can serve as an indicator of eosinophilic airway inflammation in COPD patients who may respond favorably to treatment with inhaled corticosteroids/long-acting ß2-agonists. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02546349.

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.

PD-L1 Expression in Monocytes Correlates with Bacterial Burden and Treatment Outcomes in Active Pulmonary Tuberculosis.

The PD-1/PD-L1 pathway is critical in T cell biology; however, the role of the PD-1/PD-L1 pathway in clinical characteristics and treatment outcomes in pulmonary tuberculosis (PTB) patients is unclear. We prospectively enrolled PTB, latent TB infection (LTBI), and non-TB, non-LTBI subjects. The expression of PD-1/PD-L1 on peripheral blood mononuclear cells (PBMCs) was measured and correlated with clinical characteristics and treatment outcomes in PTB patients. Immunohistochemistry and immunofluorescence were used to visualize PD-1/PD-L1-expressing cells in lung tissues from PTB patients and from murine with heat-killed MTB (HK-MTB) treatment. A total of 76 PTB, 40 LTBI, and 28 non-TB, non-LTBI subjects were enrolled. The expression of PD-1 on CD4+ T cells and PD-L1 on CD14+ monocytes was significantly higher in PTB cases than non-TB subjects. PTB patients with sputum smear/culture unconversion displayed higher PD-L1 expression on monocytes. PD-L1-expressing macrophages were identified in lung tissue from PTB patients, and co-localized with macrophages in murine lung tissues. Mycobacterium tuberculosis (MTB) whole cell lysate/EsxA stimulation of human and mouse macrophages demonstrated increased PD-L1 expression. In conclusion, increased expression of PD-L1 on monocytes in PTB patients correlated with higher bacterial burden and worse treatment outcomes. The findings suggest the involvement of the PD-1/PD-L1 pathway in MTB-related immune responses.

Cavitary Mycobacterium avium Complex Lung Disease Developed After Immunotherapy / Enfermedad pulmonar cavitaria por complejo Mycobacterium avium desarrollada tras inmunoterapia

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