Particulate matter10-induced airway inflammation and fibrosis can be regulated by chitinase-1 suppression.

BACKGROUND: Particulate matter10 (PM10) can induce airway inflammation and fibrosis. Recently, chitinase-1 has been shown to play key roles in inflammation and fibrosis. We aimed to investigate the effects of chitinase-1 inhibitor in PM10-treated murine mice models. METHODS: In female BALB/c mice, PM10 was intranasally administered six times over 3 weeks, and ovalbumin (OVA) was intraperitoneally injected and then intranasally administered. Chitinase-1 inhibitor (CPX) 6 times over 3 weeks or dexamethasone 3 times in the last week were intraperitoneally administered. Two days after the last challenges, mice were euthanized. Messenger RNA sequencing using lung homogenates was conducted to evaluate signaling pathways. RESULTS: PM10 and/or OVA-induced airway inflammation and fibrosis murine models were established. CPX and dexamethasone ameliorated PM10 or PM10/OVA-induced airway hyper-responsiveness, airway inflammation, and fibrosis. CPX and dexamethasone also reduced levels of various inflammatory markers in lung homogenates. PM10 and OVA also induced changes in mRNA expression across an extreme range of genes. CPX and dexamethasone decreased levels of mRNA expression especially associated with inflammation and immune regulation. They also significantly regulated asthma and asthma-related pathways, including the JACK-STAT signaling pathway. CONCLUSIONS: Chitinase-1 suppression by CPX can regulate PM10- and OVA-induced and aggravated airway inflammation and fibrosis via an asthma-related signaling pathway.

Early Bactericidal Activity of Delpazolid (LCB01-0371) in Patients with Pulmonary Tuberculosis.

Delpazolid, an oxazolidinone, has been studied in non-clinical studies of efficacy and toxicity and Phase 1 clinical studies. Delpazolid has in vitro activity against Gram-positive bacteria, including Mycobacterium tuberculosis. This study evaluated the bactericidal activity, safety, and pharmacokinetics of delpazolid in patients with pulmonary tuberculosis (TB). Seventy-nine subjects, aged 19 to 75 years with newly diagnosed smear-positive TB with no prior treatment for the current episode and no confirmed resistance to rifampin or isoniazid, were randomized to receive delpazolid 800 mg once a day (QD), 400 mg twice a day (BID), 800 mg BID or 1,200 mg QD or an active control of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) or linezolid 600 mg BID. The primary endpoint was the average daily reduction in log transformed bacterial load, assessed on 7H11 solid-media culture, from days 0 to 14. The average daily decline in log-CFU was 0.044 ± 0.016, 0.053 ± 0.017, 0.043 ± 0.016, and 0.019 ± 0.017, for the delpazolid 800 mg QD, 400 mg BID, 800 mg BID, and the 1,200 mg QD groups, respectively. The average daily decline in log-CFU was 0.192 ± 0.028 for the HRZE group and 0.154 ± 0.023 for the linezolid 600 mg BID group. Three serious adverse events (SAE) were reported, one each in the delpazolid 400 mg BID group (death due to worsening of TB at day 2), the HRZE group (hospitalization due to pleural effusion) and the linezolid group (hyperkalemia); none of the SAEs were assessed as related to study drugs. This study has been registered at ClinicalTrials.gov with registration number NCT02836483.

Effect of asthma and asthma medication on the prognosis of patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread worldwide rapidly. However, the effects of asthma, asthma medication and asthma severity on the clinical outcomes of COVID-19 have not yet been established. METHODS: The study included 7590 de-identified patients, who were confirmed to have COVID-19 using the severe acute respiratory syndrome coronavirus 2 RNA-PCR tests conducted up to May 15, 2020; we used the linked-medical claims data provided by the Health Insurance Review and Assessment Service. Asthma and asthma severity (steps suggested by the Global Initiative for Asthma) were defined using the diagnostic code and history of asthma medication usage. RESULTS: Among 7590 COVID-19 patients, 218 (2.9%) had underlying asthma. The total medical cost associated with COVID-19 patients with underlying asthma was significantly higher than that of other patients. Mortality rate for COVID-19 patients with underlying asthma (7.8%) was significantly higher than that of other patients (2.8%; p<0.001). However, asthma was not an independent risk factor for the clinical outcomes of COVID-19 after adjustment, nor did asthma medication use and asthma severity affect the clinical outcomes of COVID-19. However, use of oral short-acting ß2-agonists was an independent factor to increase the total medical cost burden. Patients with step 5 asthma showed significant prolonged duration of admission compared to those with step 1 asthma in both univariate and multivariate analysis. CONCLUSIONS: Asthma led to poor outcomes of COVID-19; however, underlying asthma, use of asthma medication and asthma severity were not independent factors for poor clinical outcomes of COVID-19, generally.

Effects of e-cigarettes and vaping devices on cardiac and pulmonary physiology.

E-cigarette aerosols are exceedingly different from conventional tobacco smoke, containing dozens of chemicals not found in cigarette smoke. It is highly likely that chronic use of e-cigarettes will induce pathological changes in both the heart and lungs. Here we review human and animal studies published to date and summarize the cardiopulmonary physiological changes caused by vaping. In terms of cardiac physiology, acute exposure to e-cigarette aerosols in human subjects led to increased blood pressure and heart rate, similar to traditional cigarettes. Chronic exposure to e-cigarette aerosols using animal models caused increased arterial stiffness, vascular endothelial changes, increased angiogenesis, cardiorenal fibrosis and increased atherosclerotic plaque formation. Pulmonary physiology is also affected by e-cigarette aerosol inhalation, with increased airway reactivity, airway obstruction, inflammation and emphysema. Research thus far demonstrates that the heart and lung undergo numerous changes in response to e-cigarette use, and disease development will depend on how those changes combine with both environmental and genetic factors. E-cigarettes have been advertised as a healthy alternative to cigarette smoking, and users are under the impression that vaping of e-cigarettes is harmless, but these claims that e-cigarettes are safer and healthier are not based on evidence. Data from both humans and animal models are consistent in demonstrating that vaping of e-cigarettes causes health effects both similar to and disparate from those of cigarette smoking. Further work is needed to define the long-term cardiopulmonary effects of e-cigarette use in humans.

Cigarette Smoke Exposure Promotes Virulence of Pseudomonas aeruginosa and Induces Resistance to Neutrophil Killing.

It is widely known that cigarette smoke damages host defenses and increases susceptibility to bacterial infections. Pseudomonas aeruginosa, a Gram-negative bacterium that commonly colonizes the airways of smokers and patients with chronic lung disease, can cause pneumonia and sepsis and can trigger exacerbations of lung diseases. Pseudomonas aeruginosa colonizing airways is consistently exposed to inhaled cigarette smoke. Here, we investigated whether cigarette smoke alters the ability of this clinically significant microbe to bypass host defenses and cause invasive disease. We found that cigarette smoke extract (CSE) exposure enhances resistance to human neutrophil killing, but this increase in pathogenicity was not due to resistance to neutrophil extracellular traps. Instead, Pseudomonas aeruginosa exposed to CSE (CSE-PSA) had increased resistance to oxidative stress, which correlated with increased expression of tpx, a gene essential for defense against oxidative stress. In addition, exposure to CSE induced enhanced biofilm formation and resistance to the antibiotic levofloxacin. Finally, CSE-PSA had increased virulence in a model of pneumonia, with 0% of mice infected with CSE-PSA alive at day 6, while 28% of controls survived. Altogether, these data show that cigarette smoke alters the phenotype of P. aeruginosa, increasing virulence and making it less susceptible to killing by neutrophils and more capable of causing invasive disease. These findings provide further explanation of the refractory nature of respiratory illnesses in smokers and highlight cigarette smoking as a potential driver of virulence in this important airway pathogen.

Lung Adenocarcinoma Invasiveness Risk in Pure Ground-Glass Opacity Lung Nodules Smaller than 2 cm.

BACKGROUND: We aimed to identify clinicopathologic characteristics and risk of invasiveness of lung adenocarcinoma in surgically resected pure ground-glass opacity lung nodules (GGNs) smaller than 2 cm. METHODS: Among 755 operations for lung cancer or tumors suspicious for lung cancer performed from 2012 to 2016, we retrospectively analyzed 44 surgically resected pure GGNs smaller than 2 cm in diameter on computed tomography (CT). RESULTS: The study group was composed of 36 patients including 11 men and 25 women with a median age of 59.5 years (range, 34-77). Median follow-up duration of pure GGNs was 6 months (range, 0-63). Median maximum diameter of pure GGNs was 8.5 mm (range, 4-19). Pure GGNs were resected by wedge resection, segmentectomy, or lobectomy in 27 (61.4%), 10 (22.7%), and 7 (15.9%) cases, respectively. Pathologic diagnosis was atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma (MIA), or invasive adenocarcinoma (IA) in 1 (2.3%), 18 (40.9%), 15 (34.1%), and 10 (22.7%) cases, respectively. The optimal cutoff value for CT-maximal diameter to predict MIA or IA was 9.1 mm. In multivariate analyses, maximal CT-maximal diameter of GGNs ≥10 mm (odds ratio, 24.050; 95% confidence interval, 2.6-221.908; p = 0.005) emerged as significant independent predictor for either MIA or IA. Estimated risks of MIA or IA were 37.2, 59.3, 78.2, and 89.8% at maximal GGN diameters of 5, 10, 15, and 20 mm, respectively. CONCLUSION: Pure GGNs were highly associated with lung adenocarcinoma in surgically resected cases, while estimated risk of GGNs invasiveness gradually increased as maximal diameter increased.

Significant predictors of medically diagnosed chronic obstructive pulmonary disease in patients with preserved ratio impaired spirometry: a 3-year cohort study.

BACKGROUND: Preserved ratio impaired spirometry (PRISm) is an incompletely understood respiratory condition. We investigated the incidence and significant predictive factors of chronic obstructive pulmonary disease (COPD) in PRISm patients. METHODS: From 11,922 subjects registered in the Korea National Health and Nutrition Examination Survey, never or light smokers, young subjects, and those already medically diagnosed with COPD (defined by ICD-10 code and prescribed medication) were excluded. The 2666 remaining subjects were categorized into PRISm (normal forced expiratory volume in the first second [FEV1]/force vital capacity [FVC] [≥ 0.7] and low FEV1 (< 80%); n = 313); normal (n = 1666); and unrevealed COPD groups (FEV1/FVC ratio <  0.7; n = 687). These groups were compared using matched Health Insurance Review and Assessment Service data over a 3-year follow-up. RESULTS: COPD incidence in PRISm patients (17/1000 person-year [PY]) was higher than that in normal subjects (4.3/1000 PY; P <  0.001), but lower than that in unrevealed COPD patients (45/1000 PY; P < 0.001). PRISm patients visited hospitals, took COPD medication, and incurred hospitalization costs more frequently than normal subjects, but less frequently than unrevealed COPD patients. In the overall sample, age, FVC, FEV1, dyspnea, and wheezing were significant predictors of COPD, but in PRISm patients, only age (OR, 1.14; P = 0.002) and wheezing (OR, 4.56; P = 0.04) were significant predictors. CONCLUSION: PRISm patients are likely to develop COPD, and should be monitored carefully, especially older patients and those with wheezing, regardless of lung function.

History of pulmonary tuberculosis affects the severity and clinical outcomes of COPD.

BACKGROUND AND OBJECTIVE: Although an association between pulmonary tuberculosis (TB) and chronic obstructive pulmonary disease (COPD) has been suggested, studies on the effect of TB in COPD patients have not been conducted. We aimed to investigate the severity and clinical outcomes of COPD in patients with and without a history of TB. METHODS: We retrospectively reviewed the data of 1784 patients with COPD in the Korean COPD Subtype Study cohort collected from December 2011 to January 2017 and followed up for 3 years. RESULTS: Among the 1784 patients at baseline, the COPD assessment test (CAT) scores and total St George's Respiratory Questionnaire for COPD (SGRQc) scores were significantly higher in the prior TB group (n = 468) than in the non-TB group (n = 1316). Lung function and exacerbation prevalence were significantly poorer and higher, respectively, in the prior TB group than in the non-TB group. In a small-sized follow-up study, CAT scores (n = 318), SGRQc scores (n = 295) and lung function (n = 182) remained poorer, and exacerbation prevalence (n = 256) remained higher in the prior TB group over 3 years. The forced expiratory volume in 1 s in the prior TB group declined (-0.57%/year), whereas it improved (+0.93%/year) in the non-TB group (P for changes between the groups = 0.076). In the prior TB group, patients showed poorer lung function compared with the non-TB group regardless of having lung lesions visible or not on chest radiographs. CONCLUSION: TB history negatively affected the severity of COPD, and a small-sized follow-up study showed that the changes were sustained for several years.

Longitudinal analysis of retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness in ethambutol-induced optic neuropathy.

PURPOSE: The aim of the study was to evaluate longitudinal analysis of peripapillary retinal nerve fiber layer (RNFL) and perifoveal ganglion cell-inner plexiform layer (GCIPL) thickness in patients being treated with ethambutol (EMB). METHODS: This prospective longitudinal cohort study enrolled 37 patients who were treated with EMB for pulmonary tuberculosis. Best-corrected visual acuity, color vision test, automated perimetry, fundus photography, and RNFL and GCIPL thickness were measured at baseline and at 4 and 6 months after the start of EMB treatment, using Cirrus optical coherence tomography. RESULTS: Among 37 patients, EMB-induced optic neuropathy occurred in one patient (2.7 %). In this patient, thickening of the RFNL and thinning of the GCIPL were noted at the onset of symptoms. After discontinuation of EMB, RNFL and GCIPL thickness progressively normalized. Changes in RNFL and GCIPL thickness were not statistically significant in the 36 patients who did not exhibit EMB-induced optic neuropathy-related symptoms during follow-up (all P values > 0.05). CONCLUSIONS: Thickening of the peripapillary RNFL and thinning of the perifoveal GCIPL is an effective quantitative and early marker for diagnosis of EMB-induced optic neuropathy.

Roles of Inflammatory Biomarkers in Exhaled Breath Condensates in Respiratory Clinical Fields.

BACKGROUND: Exhaled condensates contain inflammatory biomarkers; however, their roles in the clinical field have been under-investigated. METHODS: We prospectively enrolled subjects admitted to pulmonology clinics. We collected exhaled breath condensates (EBC) and analysed the levels of six and 12 biomarkers using conventional and multiplex enzyme-linked immunosorbent assay, respectively. RESULTS: Among the 123 subjects, healthy controls constituted the largest group (81 participants; 65.9%), followed by the preserved ratio impaired spirometry group (21 patients; 17.1%) and the chronic obstructive pulmonary disease (COPD) group (21 patients; 17.1%). In COPD patients, platelet derived growth factor-AA exhibited strong positive correlations with COPD assessment test (ρ=0.5926, p=0.0423) and COPD-specific version of St. George's Respiratory Questionnaire (SGRQ-C) score (total, ρ=0.6725, p=0.0166; activity, ρ=0.7176, p=0.0086; and impacts, ρ=0.6151, p=0.0333). Granzyme B showed strong positive correlations with SGRQ-C score (symptoms, ρ=0.6078, p=0.0360; and impacts, ρ=0.6007, p=0.0389). Interleukin 6 exhibited a strong positive correlation with SGRQ-C score (activity, ρ=0.4671, p=0.0378). The absolute serum eosinophil and basophil counts showed positive correlations with pro-collagen I alpha 1 (ρ=0.6735, p=0.0164 and ρ=0.6295, p=0.0283, respectively). In healthy subjects, forced expiratory volume in 1 second (FEV1)/forced vital capacity demonstrated significant correlation with CC chemokine ligand 3 (CCL3)/macrophage inflammatory protein 1 alpha (ρ=0.3897 and p=0.0068). FEV1 exhibited significant correlation with CCL11/eotaxin (ρ=0.4445 and p=0.0017). CONCLUSION: Inflammatory biomarkers in EBC might be useful to predict quality of life concerning respiratory symptoms and serologic markers. Further studies are needed.

Low Skeletal Muscle Mass and Clinical Outcomes in Chronic Obstructive Pulmonary Disease.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), decreased muscle mass is a frequently encountered comorbidity in clinical practice. However, the evaluation of muscle mass in patients with COPD in real-world practice is rare. METHODS: We retrospectively reviewed the electronic medical records of all patients with COPD who underwent bioelectrical impedance analysis at least once between January 2011 and December 2021 in three hospitals. Then, we analyzed the performance rate of muscle mass measurement in the patients and the correlation between muscle mass, clinical parameters, and COPD prognosis. RESULTS: Among the 24,502 patients with COPD, only 270 (1.1%) underwent muscle mass measurements. The total skeletal muscle mass index was significantly correlated with albumin, alanine transaminase, and creatinine to cystatin C ratio in patients with COPD (r=0.1614, p=0.011; r=0.2112, p=0.001; and r=0.3671, p=0.001, respectively). Acute exacerbation of COPD (AE COPD) was significantly correlated with muscle mass, especially the truncal skeletal muscle mass index (TSMI) in males (r=-0.196, p=0.007). In the multivariate analysis, TSMI and cystatin C were significant risk factors for AE COPD (hazard ratio, 0.200 [95% confidence interval, CI, 0.048 to 0.838] and 4.990 [95% CI, 1.070 to 23.278], respectively). CONCLUSION: Low muscle mass negatively affects the clinical outcomes in patients with COPD. Despite its clinical significance, muscle mass measurement is performed in a small proportion of patients with COPD. Therefore, protocols and guidelines for the screening of sarcopenia in patients with COPD should be established.

Long-Term Clinical Outcomes of Patients with Chronic Obstructive Pulmonary Disease with Sarcopenia.

BACKGROUND AND OBJECTIVE: Sarcopenia with muscle wasting and weakness is a common occurrence among patients with chronic obstructive pulmonary disease (COPD). We aimed to evaluate the clinical outcomes of sarcopenia in patients with COPD. METHODS: We reviewed the electronic medical records of 71 patients with COPD between 1 January 2012, and 31 December 2018. We longitudinally analyzed clinical outcomes in patients with COPD with and without sarcopenia. RESULTS: Compared to the non-sarcopenia group COPD, the sarcopenia group showed a higher rate of acute exacerbation events of COPD (AE COPD, 84.6% vs. 31.0%, p = 0.001), all-cause mortality (30.8% vs. 5.2%, p = 0.022), and pneumonia occurrence per year (median [first quartile-third quartile]; 0.2 [0.0-1.6] vs. 0.0 [0.0-0.2], p = 0.025). Sarcopenia was an independent risk factor for AE COPD in Cox regression analysis (hazard ratio, 5.982; 95% confidence interval, 1.576-22.704). Hand grip strength was associated with the COPD Assessment Test (CAT) score and annual Charlson's comorbidity index score change. Total skeletal muscle mass index (SMMI) was associated with the modified medical research council dyspnea scale score, CAT score, body mass index, airflow obstruction, dyspnea, and exercise (BODE) index, and alanine transaminase. Trunk SMMI was significantly associated with AE COPD, while appendicular SMMI was associated with BODE index and annual intensive care unit admissions for AE COPD. CONCLUSIONS: Sarcopenia is associated with clinical prognosis, pneumonia occurrence, and the acute exacerbation of COPD requiring intensive care in patients with COPD. Therefore, it is important to carefully monitor sarcopenia development as well as recommend appropriate exercise and nutritional supplementation in patients with COPD.

Airflow obstruction and chronic obstructive pulmonary disease are common in pulmonary tuberculosis even without sequelae findings on chest X-ray.

PURPOSE: Pulmonary tuberculosis (TB) is a well-known risk factor for airflow obstruction and chronic obstructive pulmonary disease (COPD). The prognosis of TB without sequelae on chest X-ray (CXR) remains uncertain. METHODS: We used the 2008-2009 Korea National Health and Nutrition Examination Survey (KNHANES) data and 2007-2012 KNHANES-matched Health Insurance Review and Assessment Service cohort data. Airflow obstruction was assessed using a pulmonary function test. COPD was defined using diagnostic codes and the use of COPD medication for 3-year. We classified subjects into three groups based on TB history and sequelae on CXR. RESULTS: In 4911 subjects, the CXR(-) (no TB sequelae on CXR) post-TB group (n = 134) showed similar characteristics and normal lung function compared to that of the control group (n = 4,405), while the CXR(+) (TB sequelae on CXR) post-TB group (n = 372) showed different characteristics and reduced lung function. The prevalence of airflow obstruction was 9.3%, 13.4%, and 26.6% in control, CXR(-) post-TB, and CXR(+) post-TB groups, respectively. COPD was more common in the post-TB with CXR(+) (6.5%) or without CXR (-) (4.5%) groups, than in the control group (1.8%). Compared to the CXR(-) post-TB group, the control group showed a lower risk for airflow obstruction (OR, 0.774; p = .008). The CXR(+) post-TB group showed a higher risk for airflow obstruction (OR, 1.456; p = .011). The Control group also showed a lower risk for the development of COPD than the CXR(-) post-TB group (OR, 0.496; p = .011). CONCLUSIONS: We need to educate TB patients that airway obstruction and COPD can easily develop, even if TB sequelae are not observed on CXR.

Characteristic Chest Computed Tomography Findings for Birt-Hogg-Dube Syndrome Indicating Requirement for Genetic Evaluation.

Background: Chest computed tomography (CT) findings are important for identifying Birt−Hogg−Dube (BHD) syndrome. However, the predictive power of classical criteria for chest CT findings is weak. Here, we aimed to identify more specific chest CT findings necessitating genetic examination for FLCN gene mutations. Methods: From June 2016 to December 2017, we prospectively enrolled 21 patients with multiple bilateral and basally located lung cysts on chest CT with no other apparent cause, including cases with and without spontaneous primary pneumothorax. All enrolled patients underwent FLCN mutation testing for diagnosis confirmation. Results: BHD was diagnosed in 10 of 21 enrolled patients (47.6%). There were no differences in clinical features between the BHD and non-BHD groups. Maximal cyst diameter was significantly greater in the BHD group (mean ± standard deviation; 4.1 ± 1.1 cm) than in the non-BHD group (1.6 ± 0.9 cm; p < 0.001). Diversity in cyst size was observed in 100.0% of BHD cases and 18.2% of non-BHD cases (p = 0.001). Morphological diversity was observed in 100.0% of BHD cases and 54.6% of non-BHD cases (p = 0.054). Areas under the receiver operating characteristic curves for predicting FLCN gene mutations were 0.955 and 0.909 for maximal cyst diameter and diversity in size, respectively. The optimal cut-off value for maximal diameter FLCN mutations prediction was 2.1 cm (sensitivity: 99%; specificity: 82%). Conclusions: Reliable chest CT features suggesting the need for FLCN gene mutations screening include variations in cyst size and the presence of cysts > 2.1 cm in diameter, predominantly occurring in the bilateral basal lungs.

Effects of chitinase-1 inhibitor in obesity-induced and -aggravated asthma in a murine model.

AIMS: Despite recent investigations on the role of chitinase in asthma, its role in obesity-induced asthma has not been evaluated. Therefore, we investigated the roles of chitin, chitinase-1, and a chitinase-1 inhibitor (compound X, CPX) in a murine model. MAIN METHODS: We assigned C57BL/6 mice to the ovalbumin (OVA) model or obesity model group. In the OVA model, mice received intraperitoneal OVA twice within a 2-week interval and intranasal OVA for 3 consecutive days. Additionally, chitin was intranasally administered for 3 consecutive days, and CPX was intraperitoneally injected three times over 5 days. In the obesity model, a high-fat diet (HFD) was maintained for 13 weeks, and CPX was intraperitoneally injected eight times over 4 weeks. KEY FINDINGS: In the OVA model, chitin aggravated OVA-induced airway hyper-responsiveness (AHR), increased bronchoalveolar lavage fluid (BALF) cell proliferation, increased fibrosis, and increased the levels of various inflammatory cytokines (including chitinase-1, TGF-ß, TNF-α, IL-1 ß, IL-6, IL-4, and IL-13). CPX treatment significantly ameliorated these effects. In the obesity model, HFD significantly increased AHR, BALF cell proliferation, fibrosis, and the levels of various inflammatory cytokines. Particularly, compared to the control group, the mRNA expression of chitinase, chitinase-like molecules, and other molecules associated with inflammation and the immune system was significantly upregulated in the HFD and HFD/OVA groups. Immunofluorescence analysis also showed increased chitinase-1 expression in these groups. CPX significantly ameliorated all these effects in this model. SIGNIFICANCE: This study showed that CPX can be an effective therapeutic agent in asthma, especially, obesity-induced and -aggravated asthma to protect against the progression to airway remodeling and fibrosis.

Outstanding Characteristics of Birt-Hogg-Dube Syndrome in Korea.

Birt-Hogg-Dube (BHD) is a rare genetic disorder characterized by multiple lung cysts, typical skin manifestations, and renal tumors. We prospectively enrolled thirty-one subjects from four South Korean institutions with typical lung cysts, and next-generation sequencing was conducted. We prospectively enrolled thirty-one subjects from four Korean institutions with typical lung cysts. Next-generation sequencing was performed to investigate mutations in the following genes: FLCN, TSC1, TSC2, CFTR, EFEMP2, ELN, FBLN5, LTBP4, and SERPINA1. BHD was diagnosed in 11 of the 31 enrolled subjects (35.5%; FLCN mutations). Notably, we identified three novel mutations (c.1098G>A, c.139G>T, and c.1335del) that have not been previously reported. In addition to FLCN mutations, we also observed mutations in CFTR (16.1%), LTBP4 (9.7%), TSC2 (9.7%), TSC1 (3.2%), ELN (3.2%), and SERPINA1 (3.2%). According to a systematic review of 45 South Korean patients with BHD, the prevalence of pneumothorax (72.7%) was greater in South Korea than in the rest of the world (50.9%; p = 0.003). The prevalence of skin manifestations (13.6%) and renal tumors (9.1%) was lower in Korea than in the rest of the world, at 47.9% [p < 0.001] and 22.5% [p = 0.027], respectively). This study confirmed a significant prediction model for BHD based on age, number of lung cysts (>40), and maximal diameter of lung cysts (>2 cm) regardless of skin manifestations and renal tumors. Importantly, three novel mutations (c.1098G>A, c.139G>T, and c.1335del) were identified. In conclusion, South Korean patients with BHD display characteristics that are different from those observed in patients of other nationalities. Detailed characterization of lung cysts is needed to define BHD, especially in South Korea, even if patients do not present with skin or renal lesions.

Fiberoptic bronchoscopy for the rapid diagnosis of smear-negative pulmonary tuberculosis.

BACKGROUND: This study was aimed to investigate the diagnostic value of fiberoptic bronchoscopy (FOB) with chest high-resolution computed tomography (HRCT) for the rapid diagnosis of active pulmonary tuberculosis (PTB) in patients suspected of PTB but found to have a negative sputum acid-fast bacilli (AFB) smear. METHODS: We evaluated the diagnostic accuracy of results from FOB and HRCT in 126 patients at Gangnam Severance Hospital (Seoul, Korea) who were suspected of having PTB. RESULTS: Of 126 patients who had negative sputum AFB smears but were suspected of having PTB, 54 patients were confirmed as having active PTB. Hemoptysis was negatively correlated with active PTB. Tree-in-bud appearance on HRCT was significantly associated with active PTB. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FOB alone was 75.9%, 97.2%, 95.3%, and 84.3%, respectively, for the rapid diagnosis of active PTB. The combination of FOB and HRCT improved the sensitivity to 96.3% and the NPV to 96.2%. CONCLUSIONS: FOB is a useful tool in the rapid diagnosis of active PTB with a high sensitivity, specificity, PPV and NPV in sputum smear-negative PTB-suspected patients. HRCT improves the sensitivity of FOB when used in combination with FOB in sputum smear-negative patients suspected of having PTB.

Effects of Asthma Medication Type on Asthma Exacerbation in a Real-World Setting.

PURPOSE: Currently, there are multiple options for the pharmacological treatment of asthma. This study aimed to compare the effects of different asthma medications on exacerbation in a real-world setting. MATERIALS AND METHODS: We retrospectively reviewed electronic medical records of asthma patients who visited the hospital from November 1, 2016 to October 31, 2019. The number of asthma exacerbations requiring administration of systemic steroids was the primary outcome. A time-varying Cox regression analysis was used to reflect the real-world setting: variable usage times, discontinuation, and switching of medication. RESULTS: Among 937 patients with asthma, 228 (24.3%) experienced asthma exacerbation during the study period. Asthma exacerbation was observed in patients using short-acting ß2-agonists (SABA) alone (50.4% vs. 28.6%, p<0.001) as well as in patients not using inhaled corticosteroids (ICS) (58.8% vs. 40.3%, p<0.001), long-acting ß2-agonists (LABA) (54.8% vs. 36.1%, p<0.001), and leukotriene receptor antagonists (71.5% vs. 50.8%, p<0.001). A time-varying Cox regression analysis of asthma exacerbations according to the duration of asthma medication showed that SABA alone increased the risk of asthma exacerbation [hazard ratio (HR), 1.834; 95% confidence interval (CI), 1.299-2.588; p=0.001], whereas ICS-LABA decreased the risk (HR, 0.733; 95% CI, 0.538-0.997; p=0.048). However, in the subgroup analysis according to medication type, specific ingredients showed no significant differences. CONCLUSION: In the real world, asthma medications affect asthma exacerbation variably according to the medication type.

Acute and chronic effects of vaping electronic devices on lung physiology and inflammation.

The impact of e-cigarette use on the inflammatory state and function of the lungs is not well understood. Here we review the latest studies on the impact of short and long term e-cigarette aerosol inhalation on molecular pathways, cellular recruitment, gas exchange and airway physiology. Inflammatory cytokines IL-6 and IL-8 were increased by e-cigarette exposures, and a variety of immune cells were recruited to the parenchyma and airways across models. While there are few consistent signals across in vitro, in vivo and human studies, due to the multitude of different e-devices and the combination of chemicals within different aerosols generated, it is clear that use of e-cigarettes does alter the inflammatory state and function of the lungs with both acute and chronic use. This is evidenced by the multitude of inflammatory lung diseases already tied to e-cigarette use, but the causal chemicals are primarily remain at large.

Low alanine aminotransferase as a risk factor for chronic obstructive pulmonary disease in males.

Alanine aminotransferase (ALT) levels reflect skeletal muscle volume and general performance, which are associated with chronic obstructive pulmonary disease (COPD) development and prognosis. This study aimed to investigate ALT levels as a risk factor for COPD development. This 13-year population-based retrospective observational cohort study included 422,452 participants for analysis. We classified groups according to the baseline ALT levels (groups 1-5: ALT (IU/L) < 10; 10-19; 20-29; 30-39; and ≥ 40, respectively). The incidence of COPD was the highest in group 1, decreasing as the group number increased in males, but not in females. The Cox regression analysis in males revealed that a lower ALT level, as a continuous variable, was a significant risk factor for COPD development [univariable, hazard ratio (HR): 0.992, 95% confidence interval (CI): 0.991-0.994; multivariable, HR: 0.998, 95% CI: 0.996-0.999]. In addition, COPD was more likely to develop in the lower ALT level groups (groups 1-4; < 40 IU/L), than in the highest ALT level group (group 5; ≥ 40 IU/L) (univariable, HR: 1.341, 95% CI: 1.263-1.424; multivariable, HR: 1.097, 95% CI: 1.030-1.168). Our findings suggest that males with low ALT levels should be carefully monitored for COPD development.