A prospective, open-label, randomized clinical trial to evaluate the efficacy and safety of remimazolam in patients undergoing EBUS-TBNA: REST trial design.

BACKGROUND: Remimazolam is safe and effective for moderate sedation during flexible bronchoscopy, but its safety and efficacy during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) remains undetermined. The REST trial (NCT06275594) will be a prospective randomized study of remimazolam in patients undergoing EBUS-TBNA with conscious sedation. The primary aim is to evaluate whether remimazolam is safe and effective for moderate sedation during EBUS-TBNA compared to real-world midazolam and on-label midazolam. METHODS: The REST trial will recruit 330 patients from four university hospitals with mediastinal lesions suspected of being lung cancer who are eligible for EBUS-TBNA under moderate sedation. The participants will be randomized into groups using remimazolam, real-world midazolam, and on-label midazolam (US prescribing information dosage) to perform EBUS-TBNA for procedural sedation. The primary endpoint will be procedural success using composite measures. DISCUSSION: The REST trial will prospectively evaluate the efficacy and safety of remimazolam during EBUS-TBNA under moderate sedation. It will provide information for optimizing sedation modalities and contribute to practical benefits in patients undergoing EBUS-TBNA. TRIAL REGISTRATION: ClinicalTrials.gov (NCT06275594). Prospectively registered on 15 February 2024.

Increased Lung Cancer Risk and Associated Risk Factors in Tuberculosis Survivors: A Korean Population-Based Study.

BACKGROUND: Few studies have comprehensively evaluated the risk of lung cancer in tuberculosis survivors with consideration of smoking status and chronic obstructive pulmonary disease (COPD). Furthermore, little is known about lung cancer risk factors in tuberculosis survivors. METHODS: This population-based cohort study enrolled tuberculosis survivors (n = 75 467) between 2010 and 2017 and 1:1 age- and sex-matched controls. Subjects were followed up for 1 year from the date of tuberculosis diagnosis to the date of the incident lung cancer, death, or December 2018, whichever came first. The risk of lung cancer was evaluated according to smoking and COPD status. We also evaluated the risk factors for lung cancer and developed an individualized lung cancer prediction model for tuberculosis survivors. RESULTS: During a median follow-up duration of 4.8 years, the incident lung cancer risk was 1.72-fold higher in tuberculosis survivors than in the controls. Among tuberculosis survivors, those who were current smokers with ≥20 pack-years showed the highest risk of lung cancer (adjusted hazard ratio, 6.78) compared with never-smoker, non-tuberculosis-infected controls. tuberculosis survivors with COPD had a higher risk (2.43) than non-COPD, non-tuberculosis-infected controls. Risk factors for lung cancer in tuberculosis survivors were pulmonary tuberculosis, age >60 years, smoking, and the presence of COPD or asthma. The individualized lung cancer risk model showed good discrimination (concordance statistic = 0.827). CONCLUSIONS: Previous tuberculosis infection is an independent risk factor regardless of smoking status or amount and COPD. Closer monitoring of tuberculosis survivors, especially heavy smokers or those with COPD, is needed for early lung cancer diagnosis.

Chronic cavitary pulmonary aspergillosis: Serial clinical and CT findings correlated with antifungal treatment and patient response.

BACKGROUND: Chronic cavitary pulmonary aspergillosis (CCPA) is the most common form of chronic pulmonary aspergillosis. OBJECTIVE: We hypothesise that by observing serial clinical and CT findings of CCPA patients with antifungal therapy, factors helping predict responses to antifungal therapy could be withdrawn. METHODS: A total of 31 patients with CCPA who received antifungal therapy for greater than six months and who had serial CT studies were included. Clinical finding analyses were performed at initial and last follow-up CT acquisition dates. Clinical characteristics and CT features were compared between clinically improving or stable and deteriorating groups. RESULTS: With antifungal therapy, neutrophil-to-lymphocyte ratio (2.66 vs. 5.12, p = .038) and serum albumin (4.40 vs. 3.85 g/dl, p = .013) and CRP (1.10 vs. 42.80 mg/L, p = .007) were different between two groups. With antifungal therapy, meaningful CT change, regardless of clinical response grouping, was decrease in cavity wall thickness (from 13.70 mm to 8.28 mm, p < .001). But baseline (p = .668) and follow-up (p = .278) cavity wall thickness was not different between two groups. In univariate analysis, initial maximum diameter of cavity (p = .028; HR [0.983], 95% CI [0.967-0.998]) and concurrent NTM infection (p = .030; HR [0.20], 95% CI [0.05-0.86]) were related factors for poor clinical response. CONCLUSIONS: With antifungal therapy, cavities demonstrate wall thinning. Of all clinical and radiological findings and their changes, initial large cavity size and concurrent presence of NTM infection are related factors to poor response to antifungal therapy.

Relationship between Resistance to Ethambutol and Rifampin and Clinical Outcomes in Mycobacterium avium Complex Pulmonary Disease.

We evaluated the associations between the in vitro activities of ethambutol and rifampin and clinical outcomes of Mycobacterium avium complex (MAC) pulmonary disease (PD). Among 158 patients with MAC-PD, there was no relationship between high MICs for ethambutol and/or rifampin and treatment failure for MAC-PD. Ethambutol and rifampin resistance was common among MAC isolates (rates of 87% and 59%, respectively), but mutations in embB, rpoB, and rpoC were rare, with detection in only 4% of the drug-resistant MAC isolates.

Comparative Study on the Effect of Cidofovir Treatment for Severe Adenovirus Pneumonia.

BACKGROUND: Adenovirus infection can cause severe pneumonia even in immunocompetent adults. However, there is limited data on the benefits of cidofovir treatment in severe adenovirus pneumonia. The objective of this study was to evaluate the association of cidofovir treatment with clinical improvement in immunocompetent adult patients with severe adenovirus pneumonia. METHODS: We evaluated 22 male patients who admitted to intensive care unit (ICU) with severe adenovirus pneumonia between January 2014 and December 2019. The patients were divided into 2 groups, patients treated with cidofovir or not. Clinical outcomes including time to defervescence and stopping of oxygen supplement, length of stay in ICU and hospital, and the need for mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) were compared between the 2 groups. RESULTS: Among 22 patients, 13 patients (59%) were treated with cidofovir and 9 (41%) were not. The difference in mean time (95% confidence interval [CI]) to defervescence and stopping of oxygen supplement between cidofovir group and no cidofovir group was 2.1 (-5.7 to 10.0) and 1.0 (-14.9 to 16.8) days, respectively. The difference in mean length of stay (95% CI) in ICU and hospital between the 2 groups was 0.2 (-7.1 to 7.5) and -0.4 (-18.3 to 17.5) days, respectively. The differences in proportion of patients requiring MV and ECMO between the 2 groups was 28.2 (-17.4 to 73.8) % and -10.3 (-52.2 to 31.7) %, respectively. CONCLUSIONS: The treatment with cidofovir for severe adenovirus pneumonia in immunocompetent patients did not improve clinical outcomes. Further studies with larger samples with prospective design are warranted.

Translation and validation of the Korean version of the clinical frailty scale in older patients.

BACKGROUND: Frailty is a multidimensional syndrome that leads to an increase in vulnerability. Previous studies have suggested that frailty is associated with poor health-related outcomes. For frailty screening, the Clinical Frailty Scale (CFS) is a simple tool that is widely used in various translated versions. We aimed to translate the CSF into Korean and evaluated its contents and concurrent validity. METHODS: Translations and back-translations of the CFS were conducted independently. A multidisciplinary team decided the final CFS-K. Between August 2019 and April 2020, a total of 100 outpatient and inpatient participants aged ≥65 years were enrolled prospectively. The clinical characteristics were evaluated using the CFS-K. The CFS-K scores were compared with those of other frailty screening tools using Pearson's correlation coefficient and Spearman's rank correlation. The area under curve (AUC) for identifying the Eastern Cooperative Oncology Group Performance Status (ECOG PS) grade 3 or more was calculated for the CFS-K and other screening tools. RESULTS: The mean age of the participants was 76.5 years (standard deviation [SD], 7.0), and 63 (63%) participants were male. The mean CFS-K was 4.8 (SD, 2.5). Low body mass index (p = 0.013) and low score on the Korean version of the Mini-Mental State Examination (p < 0.001) were significantly associated with high CFS-K scores, except for those assigned to scale 9 (terminally ill). The CFS-K showed a significant correlation with other frailty screening tools (R = 0.7742-0.9190; p < 0.01), except in the case of those assigned to scale 9 (terminally ill). In comparison with other scales, the CFS-K identified ECOG PS grade 3 or more with the best performance (AUC = 0.99). Patients assigned to scale 9 on the CFS-K (terminally ill) had similar frailty scores to those assigned to scale 4 (vulnerable) or 5 (mildly frail). CONCLUSIONS: In conclusion, the CFS-K is a valid scale for measuring frailty in older Korean patients. The CFS-K scores were significantly correlated with the scores of other scales. To evaluate the predictive and prognostic value of this scale, further larger-scale studies in various clinical settings are warranted.

Prognostic factors associated with long-term mortality in 1445 patients with nontuberculous mycobacterial pulmonary disease: a 15-year follow-up study.

Limited data are available regarding the prognostic factors for patients with nontuberculous mycobacterial pulmonary disease (NTM-PD). We investigated the prognostic factors associated with long-term mortality in NTM-PD patients after adjusting for individual confounders, including aetiological organism and radiological form.A total of 1445 patients with treatment-naïve NTM-PD who were newly diagnosed between July 1997 and December 2013 were included. The aetiological organisms were as follows: Mycobacterium avium (n=655), M. intracellulare (n=487), M. abscessus (n=129) and M. massiliense (n=174). The factors associated with mortality in NTM-PD patients were analysed using a multivariable Cox model after adjusting for demographic, radiological and aetiological data.The overall 5-, 10- and 15-year cumulative mortality rates for the NTM-PD patients were 12.4%, 24.0% and 36.4%, respectively. On multivariable analysis, the following factors were significantly associated with mortality in NTM-PD patients: old age, male sex, low body mass index, chronic pulmonary aspergillosis, pulmonary or extrapulmonary malignancy, chronic heart or liver disease and erythrocyte sedimentation rate. The aetiological organism was also significantly associated with mortality: M. intracellulare had an adjusted hazard ratio (aHR) of 1.40, 95% CI 1.03-1.91; M. abscessus had an aHR of 2.19, 95% CI 1.36-3.51; and M. massiliense had an aHR of 0.99, 95% CI 0.61-1.64, compared to M. avium Mortality was also significantly associated with the radiological form of NTM-PD for the cavitary nodular bronchiectatic form (aHR 1.70, 95% CI 1.12-2.59) and the fibrocavitary form (aHR 2.12, 95% CI 1.57-3.08), compared to the non-cavitary nodular bronchiectatic form.Long-term mortality in patients with NTM-PD was significantly associated with the aetiological NTM organism, cavitary disease and certain demographic characteristics.

Epidemiology of Nontuberculous Mycobacterial Infection, South Korea, 2007-2016.

The prevalence and incidence of nontuberculous mycobacterial (NTM) infections increased in South Korea from 2007 to 2016. Annual prevalence of NTM infection increased to 39.6 cases/100,000 population in 2016 and annual incidence to 19.0 cases/100,000 population. Overall prevalence for the study period was higher in the elderly, in females, and in cities.

Intermittent Treatment with Azithromycin and Ethambutol for Noncavitary Mycobacterium avium Complex Pulmonary Disease.

We evaluated the efficacy of intermittent azithromycin and ethambutol therapy for noncavitary Mycobacterium avium complex pulmonary disease (MAC-PD). Twenty-nine (76%) of 38 patients achieved sputum culture conversion after 12 months of treatment, and sputum smear positivity was an independent factor for failure to achieve culture conversion (adjusted odds ratio, 26.7; 95% confidence interval, 2.1 to 339.9; P = 0.011). Intermittent azithromycin and ethambutol may be an optional treatment regimen for noncavitary MAC-PD.

Species Distribution and Macrolide Susceptibility of Mycobacterium fortuitum Complex Clinical Isolates.

The understanding of species distribution and inducible macrolide resistance in the Mycobacterium fortuitum complex (MFC) is limited. Of 90 mostly respiratory MFC clinical isolates, half were M. fortuitum, followed by M. peregrinum, M. porcinum, M. septicum, and M. conceptionense Most M. fortuitum, M. porcinum, and M. septicum isolates were inducibly resistant to clarithromycin, whereas two-thirds of the M. peregrinum isolates were clarithromycin susceptible. Clarithromycin-resistant M. fortuitum isolates exhibited common mutations of erm(39), potentially involved in clarithromycin resistance.

In Vitro Activity of Bedaquiline and Delamanid against Nontuberculous Mycobacteria, Including Macrolide-Resistant Clinical Isolates.

We evaluated the in vitro activities of the antimicrobial drugs bedaquiline and delamanid against the major pathogenic nontuberculous mycobacteria (NTM). Delamanid showed high MIC values for all NTM except Mycobacterium kansasii However, bedaquiline showed low MIC values for the major pathogenic NTM, including Mycobacterium avium complex, Mycobacterium abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. kansasii Bedaquiline also had low MIC values with macrolide-resistant NTM strains and warrants further investigation as a potential antibiotic for NTM treatment.

Development of Macrolide Resistance and Reinfection in Refractory Mycobacterium avium Complex Lung Disease.

RATIONALE: Patients with refractory Mycobacterium avium complex lung disease (MAC-LD) undergo long-term macrolide therapy, but macrolide resistance develops infrequently. OBJECTIVES: The aim of this study was to determine whether reinfection was a factor in the low incidence of macrolide resistance in patients with refractory MAC-LD. METHODS: Among 481 patients with treatment-naive MAC-LD who started antibiotic treatment between January 2002 and December 2013, we identified 72 patients with refractory disease, characterized by persistently positive sputum cultures despite ≥12 months of treatment. Molecular analyses of the 23S ribosomal RNA gene responsible for macrolide resistance and serial mycobacterial genotyping were performed using stored MAC isolates. MEASUREMENTS AND MAIN RESULTS: The median duration of treatment was 32 months (interquartile range, 24-41 mo) in 72 patients. After treatment for a median of 33 months (interquartile range, 21-44 mo), macrolide resistance developed in 16 (22%) patients. Molecular analysis of isolates from 15 patients revealed that 80% (12 of 15) had a point mutation at position 2,058 or 2,059 of the 23S ribosomal RNA gene. Of the 49 patients who had stored pre- and post-treatment isolates, mycobacterial genotyping revealed that reinfection by new MAC strains occurred in 36 (73%) patients. New MAC strains were found in 24 (49%) patients, and mixed infections with original and new strains occurred in 12 (24%) patients. Only 13 (27%) patients had persistent infections with their original MAC strains. CONCLUSIONS: Refractory MAC-LD is commonly caused by reinfection with new strains rather than persistence of the original strain, which may explain the infrequent development of macrolide resistance in refractory MAC-LD. Clinical trial registered with www.clinicaltrials.gov (NCT00970801).

Intermittent Antibiotic Therapy for Recurrent Nodular Bronchiectatic Mycobacterium avium Complex Lung Disease.

Intermittent, three-times-weekly oral antibiotic therapy is recommended for the initial treatment of noncavitary nodular bronchiectatic (NB) Mycobacterium avium complex (MAC) lung disease. However, intermittent therapy is not recommended for patients who have been previously treated. We evaluated 53 patients with recurrent noncavitary NB MAC lung disease who underwent antibiotic treatment for ≥12 months with daily therapy (n = 26) or intermittent therapy (n = 27) between January 2008 and December 2015. Baseline characteristics were comparable between daily therapy and intermittent therapy groups. Sputum culture conversion rates did not differ between daily therapy (21/26, 81%) and intermittent therapy (22/27, 82%) groups. Compared to the etiologic organism at the time of previous treatment, recurrent MAC lung disease was caused by the same MAC species in 38 patients (72%) and by a different MAC species in 15 patients (28%). Genotype analysis in patients with sequenced paired isolates revealed that 86% (12/14) of cases with same species recurrence were due to reinfection with a new MAC genotype. In conclusion, most recurrent noncavitary NB MAC lung disease cases were caused by reinfection rather than relapse. Intermittent antibiotic therapy is a reasonable treatment strategy for recurrent noncavitary NB MAC lung disease.

Mutations in gyrA and gyrB in Moxifloxacin-Resistant Mycobacterium avium Complex and Mycobacterium abscessus Complex Clinical Isolates.

Data on the frequency of gyrA and gyrB mutations in fluoroquinolone-resistant isolates of the Mycobacterium avium complex (MAC) and the Mycobacterium abscessus complex (MABC) are limited. In our analysis, we did not find any resistance-associated mutations in gyrA or gyrB in 105 MAC or MABC clinical isolates, including 72 moxifloxacin-resistant isolates. Our findings suggest that mechanisms other than gyrA and gyrB mutations contribute to moxifloxacin resistance in these organisms.

Amikacin Inhalation as Salvage Therapy for Refractory Nontuberculous Mycobacterial Lung Disease.

Although guidelines recommend amikacin (AMK) inhalation therapy for difficult-to-treat nontuberculous mycobacterial lung disease (NTM-LD), data are limited regarding the safety and clinical efficacy of this salvage therapy. We retrospectively evaluated the treatment outcomes of 77 patients with refractory NTM-LD caused by Mycobacterium abscessus complex (MABC) or M. avium complex (MAC) who initiated AMK inhalation therapy between February 2015 and June 2016. MABC was the most common etiology (n = 48, 62%), followed by MAC (n = 20, 26%) and mixed infections (n = 9, 12%). Isolates with macrolide resistance and baseline AMK resistance were identified in 63 (82%) patients and 5 (6%) patients, respectively. At 12 months after AMK inhalation therapy, 49% of patients had symptomatic improvement, whereas 42% had radiological improvement. Conversion to a negative sputum culture occurred in 14 (18%) patients, and the culture conversion rate was higher in patients infected with macrolide-susceptible isolates (7/14, 50%) than in those infected with macrolide-resistant isolates (7/63, 11%) (P = 0.003). Significant decreases in sputum semiquantitative culture positivity occurred after AMK inhalation therapy (P < 0.001). On multivariate analysis, conversion to a negative sputum culture was associated with mixed infections (P = 0.009), a forced expiratory volume in 1 s of greater than 60% (P = 0.008), and the absence of macrolide resistance (P = 0.003). Thirty-eight percent of patients experienced adverse effects, with ototoxicity (n = 15) being the most common. AMK inhalation salvage therapy may improve the treatment responses in some patients with refractory NTM-LD. However, considering the common adverse effects, further evaluation of the optimal dosage and intervals for AMK inhalation therapy is needed.

Differences in drug susceptibility pattern between Mycobacterium avium and Mycobacterium intracellulare isolated in respiratory specimens.

Mycobacterium avium complex (MAC) is the most common etiologic organisms of nontuberculous mycobacteria (NTM) lung disease. In this study, we aimed to retrospectively investigate the differences in drug susceptibility patterns of two major MAC species; Mycobacterium avium and Mycobacterium intracellulare. A total of 1883 major two MAC isolates (1060 M. avium and 823 M. intracellulare) from respiratory specimens were included in this study during the period 2011─2016. The minimum inhibitory concentrations (MICs) were determined by broth microdilution method and MIC50/MIC90 values were derived from MIC distribution. M. intracellulare had generally low susceptible rates than M. avium for almost all tested antimicrobials except ethambutol and amikacin. The susceptible rate to clarithromycin was >94% of the MAC without significant differences between the two species. The MIC50 values of ciprofloxacin, clarithromycin, linezolid, moxifloxacin, and rifampicin were higher in M. intracellulare than in M. avium, contrary to the results of ethambutol with a higher MIC50 in M. avium. In general, M. intracellulare showed a higher resistance rate and higher MIC50 values than M. avium. Differences between this study and previous reports suggest regional differences in drug susceptibility profile of MAC species.

Changing Epidemiology of Nontuberculous Mycobacterial Lung Diseases in a Tertiary Referral Hospital in Korea between 2001 and 2015.

This study investigated the changes in the major etiologic organisms and clinical phenotypes of nontuberculous mycobacterial lung disease (NTM-LD) over a recent 15-year period in Korea. The increase of number of patients with NTM-LD was primarily due to an increase of Mycobacterium avium complex (MAC) lung disease (LD). Among MAC cases, the proportion of M. avium increased compared with M. intracellulare, whereas the incidence of M. abscessus complex and M. kansasii LD remained relatively stable. The proportion of cases of the nodular bronchiectatic form increased compared with the fibrocavitary form of NTM-LD.

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease.

Patients with lung disease caused by Mycobacterium abscessus subsp. abscessus (here M. abscessus) typically have poor treatment outcomes. Although clofazimine (CFZ) has been increasingly used in the treatment of M. abscessus lung disease in clinical practice, there are no reported data on its effectiveness for this disease. This study sought to evaluate the clinical efficacy of a CFZ-containing regimen for the treatment of M. abscessus lung disease. We performed a retrospective review of the medical records of 42 patients with M. abscessus lung disease who were treated with CFZ-containing regimens between November 2013 and January 2015. CFZ was administered in combination with other antibiotics as an initial antibiotic regimen in 15 (36%) patients (initial treatment group), and it was added to an existing antibiotic regimen for refractory M. abscessus lung disease in 27 (64%) patients (salvage treatment group). Overall, there was an 81% treatment response rate based on symptoms and a 31% response rate based on radiographic findings. Conversion to culture-negative sputum samples was achieved in 10 (24%) patients after CFZ-containing antibiotic treatment, and during treatment, there were significant decreases in the positivity of semiquantitative sputum cultures for acid-fast bacilli in both the initial (P = 0.018) and salvage (P = 0.001) treatment groups. Our study suggests that CFZ-containing regimens may improve treatment outcomes in patients with M. abscessus lung disease and that a prospective evaluation of CFZ in M. abscessus lung disease is warranted.

Outcomes of Mycobacterium avium complex lung disease based on clinical phenotype.

The effect of the clinical phenotype of Mycobacterium avium complex (MAC) lung disease on treatment outcome and redevelopment of nontuberculous mycobacterial (NTM) lung disease after treatment completion has not been studied systematically.We evaluated 481 treatment-naïve patients with MAC lung disease who underwent antibiotic treatment for ≥12 months between January 2002 and December 2013.Out of 481 patients, 278 (58%) had noncavitary nodular bronchiectatic (NB) disease, 80 (17%) had cavitary NB disease and 123 (25%) had fibrocavitary disease. Favourable outcome was higher in patients with noncavitary disease (88%) than in patients with cavitary disease (76% for fibrocavitary and 78% for cavitary NB disease; p<0.05). Cavitary disease was independently associated with unfavourable outcomes (p<0.05). Out of 402 patients with favourable outcomes, 118 (29%) experienced redevelopment of NTM lung disease, with the same MAC species recurring in 65 (55%) patients. The NB form was an independent risk factor for redevelopment of NTM lung disease (p<0.05). In patients with recurrent MAC lung disease due to the same species, bacterial genotyping revealed that 74% of cases were attributable to reinfection and 26% to relapse.Treatment outcomes and redevelopment of NTM lung disease after treatment completion differed by clinical phenotype of MAC lung disease.

Effect of a 150 mg dose of rifabutin on serum itraconazole levels in patients with coexisting chronic pulmonary aspergillosis and Mycobacterium avium complex lung disease.

Patients with coexisting chronic pulmonary aspergillosis and nontuberculous mycobacterial lung disease may undergo treatment with both the antifungal itraconazole and the antimycobacterial rifamycin. However, rifamycins interact with itraconazole. We examined the effects of a 150 mg dose of rifabutin on serum itraconazole levels and found significantly lower levels in 28 patients receiving itraconazole with rifabutin (median, 0.65 µg/ml) compared with 65 patients receiving itraconazole alone (median 3.45 µg/ml, P < 0.001). One-third of patients receiving itraconazole and rifabutin reached the therapeutic range of serum itraconazole concentration. Therapeutic drug monitoring is strongly recommended during concomitant use of rifabutin and itraconazole.