Endobronchial valves for emphysema and persistent air-leak: 10-year experience in an Asian country.

BACKGROUND: Endobronchial valve (EBV) therapy, a validated method for bronchoscopic lung volume reduction (BLVR) in severe emphysema, has been explored for persistent air-leak (PAL) management. However, its effectiveness and safety in the Asian population require further real-world evaluation. In this study, we assessed the outcomes of treatment with EBV within this demographic. METHODS: We conducted a retrospective analysis of medical records from 11 Korean centers. For the emphysema cohort, inclusion criteria were patients diagnosed with emphysema who underwent bronchoscopy intended for BLVR. We assessed these patients for clinical outcomes of chronic obstructive pulmonary disease. All patients with PAL who underwent treatment with EBV were included. We identified the underlying causes of PAL and evaluated clinical outcomes after the procedure. RESULTS: The severe emphysema cohort comprised 192 patients with an average age of 70.3 years, and 95.8% of them were men. Ultimately, 137 underwent treatment with EBV. Three months after the procedure, the BLVR group demonstrated a significant improvement in forced expiratory volume in 1 s (+160 mL vs. +30 mL; P = 0.009). Radiographic evidence of lung volume reduction 6 months after BLVR was significantly associated with improved survival (adjusted hazard ratio 0.020; 95% confidence interval 0.038-0.650; P = 0.010). Although pneumothorax was more common in the BLVR group (18.9% vs. 3.8%; P = 0.018), death was higher in the no-BLVR group (38.5% vs. 54.5%, P = 0.001), whereas other adverse events were comparable between the groups. Within the subset of 18 patients with PAL, the predominant causes of air-leak included spontaneous secondary pneumothorax (44.0%), parapneumonic effusion/empyema (22.2%), and post-lung resection surgery (16.7%). Following the treatment, the majority (77.8%) successfully had their chest tubes removed. Post-procedural complications were minimal, with two incidences of hemoptysis and one of empyema, all of which were effectively managed. CONCLUSIONS: Treatment with EBV provides substantial clinical benefits in the management of emphysema and PAL in the Asian population, suggesting a favorable outcome for this therapeutic approach.

Fine particulate matter aggravates smoking induced lung injury via NLRP3/caspase-1 pathway in COPD.

BACKGROUND: Exposure to noxious particles, including cigarette smoke and fine particulate matter (PM2.5), is a risk factor for chronic obstructive pulmonary disease (COPD) and promotes inflammation and cell death in the lungs. We investigated the combined effects of cigarette smoking and PM2.5 exposure in patients with COPD, mice, and human bronchial epithelial cells. METHODS: The relationship between PM2.5 exposure and clinical parameters was investigated in patients with COPD based on smoking status. Alveolar destruction, inflammatory cell infiltration, and pro-inflammatory cytokines were monitored in the smoking-exposed emphysema mouse model. To investigate the mechanisms, cell viability and death and pyroptosis-related changes in BEAS-2B cells were assessed following the exposure to cigarette smoke extract (CSE) and PM2.5. RESULTS: High levels of ambient PM2.5 were more strongly associated with high Saint George's respiratory questionnaire specific for COPD (SGRQ-C) scores in currently smoking patients with COPD. Combined exposure to cigarette smoke and PM2.5 increased mean linear intercept and TUNEL-positive cells in lung tissue, which was associated with increased inflammatory cell infiltration and inflammatory cytokine release in mice. Exposure to a combination of CSE and PM2.5 reduced cell viability and upregulated NLRP3, caspase-1, IL-1ß, and IL-18 transcription in BEAS-2B cells. NLRP3 silencing with siRNA reduced pyroptosis and restored cell viability. CONCLUSIONS: PM2.5 aggravates smoking-induced airway inflammation and cell death via pyroptosis. Clinically, PM2.5 deteriorates quality of life and may worsen prognosis in currently smoking patients with COPD.

Stellera chamaejasme L. extract inhibits adipocyte differentiation through activation of the extracellular signal-regulated kinase pathway.

Stellera chamaejasme L. (SCL) is a perennial herb with demonstrated bioactivities against inflammation and metabolic dysfunction. Adipocyte differentiation is a critical regulator of metabolic homeostasis and a promising target for the treatment of metabolic diseases, so we examined the effects of SCL on adipogenesis. A methanol extract of SCL dose-dependently suppressed intracellular lipid accumulation in adipocyte precursors cultured under differentiation induction conditions and reduced expression of the adipogenic transcription factors PPARγ and C/EBPα as well as the downstream lipogenic genes fatty acid binding protein 4, adiponectin, fatty acid synthase, and stearoyl-CoA desaturase. The extract also promoted precursor cell proliferation and altered expression of the cell cycle regulators cyclin-dependent kinase 4, cyclin E, and cyclin D1. In addition, SCL extract stimulated extracellular signal-regulated kinase (ERK) phosphorylation, while pharmacological inhibition of ERK effectively blocked the inhibitory effects of SCL extract on preadipocyte differentiation. These results suggest that SCL extract contains bioactive compounds that can suppress adipogenesis through modulation of the ERK pathway.

Ubiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates.

In mammals, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) execute sequential thermogenesis to maintain body temperature during cold stimuli. BAT rapidly generates heat through brown adipocyte activation, and further iWAT gradually stimulates beige fat cell differentiation upon prolonged cold challenges. However, fat depot-specific regulatory mechanisms for thermogenic activation of two fat depots are poorly understood. Here, we demonstrate that E3 ubiquitin ligase RNF20 orchestrates adipose thermogenesis with BAT- and iWAT-specific substrates. Upon cold stimuli, BAT RNF20 is rapidly downregulated, resulting in GABPα protein elevation by controlling protein stability, which stimulates thermogenic gene expression. Accordingly, BAT-specific Rnf20 suppression potentiates BAT thermogenic activity via GABPα upregulation. Moreover, upon prolonged cold stimuli, iWAT RNF20 is gradually upregulated to promote de novo beige adipogenesis. Mechanistically, iWAT RNF20 mediates NCoR1 protein degradation, rather than GABPα, to activate PPARγ. Together, current findings propose fat depot-specific regulatory mechanisms for temporal activation of adipose thermogenesis.

Unique adipose tissue invariant natural killer T cell subpopulations control adipocyte turnover in mice.

Adipose tissue invariant natural killer T (iNKT) cells are a crucial cell type for adipose tissue homeostasis in obese animals. However, heterogeneity of adipose iNKT cells and their function in adipocyte turnover are not thoroughly understood. Here, we investigate transcriptional heterogeneity in adipose iNKT cells and their hierarchy using single-cell RNA sequencing in lean and obese mice. We report that distinct subpopulations of adipose iNKT cells modulate adipose tissue homeostasis through adipocyte death and birth. We identify KLRG1+ iNKT cells as a unique iNKT cell subpopulation in adipose tissue. Adoptive transfer experiments showed that KLRG1+ iNKT cells are selectively generated within adipose tissue microenvironment and differentiate into a CX3CR1+ cytotoxic subpopulation in obese mice. In addition, CX3CR1+ iNKT cells specifically kill enlarged and inflamed adipocytes and recruit macrophages through CCL5. Furthermore, adipose iNKT17 cells have the potential to secrete AREG, and AREG is involved in stimulating adipose stem cell proliferation. Collectively, our data suggest that each adipose iNKT cell subpopulation plays key roles in the control of adipocyte turnover via interaction with adipocytes, adipose stem cells, and macrophages in adipose tissue.

Lifestyle practices that reduce seasonal PM2.5 exposure and their impact on COPD.

Particulate matter (PM) is a major air pollutant that has led to global health concerns and can cause and exacerbate chronic obstructive pulmonary disease (COPD). We asked patients with COPD to complete a detailed questionnaire about their lifestyle practices to reduce PM2.5 exposure and analyzed the relationship between ambient PM2.5 concentrations and lifestyle practices. We prospectively enrolled 104 COPD patients from four hospitals in different areas of Korea. They completed detailed questionnaires twice (at enrollment and the end of the study) and Internet of Things-based sensors were installed in their homes to continuously measure PM2.5 for 1 year. The relationship between PM2.5 concentrations, lifestyle practices, and COPD exacerbations were analyzed in each season. The PM2.5 concentration was higher outdoors than indoors in all seasons except summer, and the difference was largest in winter. The six lifestyle practices that significantly lowered the annual indoor PM2.5 concentration compared with the outdoors. The higher the economic status and educational level of patients, the lower the indoor PM2.5 concentration. Some lifestyle practices were associated with reduced small airway resistance, presented as R5-R20 determined by impulse oscillometry, and scores of the St. George's Respiratory Questionnaire. Some lifestyle practices are associated with reduced indoor PM2.5 concentrations and can even affect clinical outcomes, including small airway resistance and quality of life of COPD patients.

Safety and outcomes of "at-home self-provocation tests" in patients with mild nonsteroidal anti-inflammatory drug-induced urticaria/angioedema.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity is common; however, many patients do not receive an accurate diagnosis and are using unnecessary alternative drugs or have medication restrictions. OBJECTIVE: To establish a protocol for provocation tests that can be performed safely and effectively at home to give patients an accurate diagnosis, whereas also delabeling NSAID hypersensitivity. METHODS: We retrospectively analyzed the medical records of 147 patients with NSAID hypersensitivity. All patients had NSAID-induced urticaria/angioedema with less than 10% body surface area skin involvement. One specialist developed the protocol through history taking and chart review. If NSAID hypersensitivity was confirmed, an oral provocation test was performed to confirm the safe alternative medications (group A). If it was undetermined, an oral provocation test was performed to confirm the diagnosis and alternative medications (group B). All oral provocation tests were performed by patients in their homes according to the protocol. RESULTS: Approximately 26% of group A patients had urticaria or angioedema symptoms with alternative drugs, whereas the remaining 74% was safe. In group B, 34% of the patients were diagnosed with having NSAID hypersensitivity. However, 61% did not respond to the culprit drug; therefore, NSAID hypersensitivity had been misdiagnosed. During this at-home self-provocation test, no severe hypersensitivity reactions occurred. CONCLUSION: Many patients originally suspected of having NSAID hypersensitivity were confirmed to have been misdiagnosed. We successfully conducted an effective and safe at-home self-provocation test.

Clinical Characteristics of Post-COVID-19 Persistent Cough in the Omicron Era.

Cough is one of the most common symptoms of acute coronavirus disease 2019, but cough may persist for weeks or months. This study aimed to examine the clinical characteristics of patients with post-coronavirus disease (COVID) persistent cough in the Omicron era. We conducted a pooled analysis comparing 3 different groups: 1) a prospective cohort of post-COVID cough (> 3 weeks; n = 55), 2) a retrospective cohort of post-COVID cough (> 3 weeks; n = 66), and 3) a prospective cohort of non-COVID chronic cough (CC) (> 8 weeks; n = 100). Cough and health status was assessed using patient-reported outcomes (PROs). Outcomes, including PROs and systemic symptoms, were longitudinally evaluated in the prospective post-COVID cough registry participants receiving usual care. A total of 121 patients with post-COVID cough and 100 with non-COVID CC were studied. Baseline cough-specific PRO scores did not significantly differ between post-COVID cough and non-COVID CC groups. There were no significant differences in chest imaging abnormality or lung function between groups. However, the proportions of patients with fractional exhaled nitric oxide (FeNO) ≥ 25 ppb were 44.7% in those with post-COVID cough and 22.7% in those with non-COVID CC, which were significantly different. In longitudinal assessment of the post-COVID registry (n = 43), cough-specific PROs, such as cough severity or Leicester Cough Questionnaire (LCQ) scores, significantly improved between visits 1 and 2 (visit interval: median 35 [interquartile range, IQR: 23-58] days). In the LCQ score, 83.3% of the patients showed improvement (change ≥ +1.3), but 7.1% had worsened (≤ -1.3). The number of systemic symptoms was median 4 (IQR: 2-7) at visit 1 but decreased to median 2 (IQR: 0-4) at visit 2. In summary, post-COVID persistent cough was similar in overall clinical characteristics to CC. Current cough guideline-based approaches may be effective in most patients with post-COVID cough. Measurement of FeNO levels may also be useful for cough management.

Efficacy and safety of combination therapy with pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis.

Background: Recent studies have suggested that combination therapy with pirfenidone and nintedanib is safe and tolerable in patients with idiopathic pulmonary fibrosis (IPF). However, data from real-world practice are limited. Thus, we aimed to investigate the safety and efficacy of this combination therapy in patients with IPF in a real-world setting. Methods: A multicenter retrospective cohort study was conducted to investigate the safety and efficacy of combination therapy with pirfenidone and nintedanib in 45 patients with IPF. Incidences of adverse events and rates of lung function decline were compared before and after the combination therapy. Propensity score matching was performed to compare the outcomes between the combination and monotherapy groups. Results: The mean age of the patients was 68.8 years, and 82.2% of them were male. The median follow-up duration after combination therapy was 12.1 months. The majority of the patients (97.8%) received nintedanib as an add-on to pirfenidone. The most common adverse events after the combination therapy were diarrhea and anorexia. Pirfenidone or nintedanib was stopped in 12 patients owing to gastrointestinal AEs, lung transplantation, or financial problems. In patients with serial lung function data, the rate of decline in the forced vital capacity was significantly reduced after the combination therapy. In the matched analysis, the combination group had a higher incidence of diarrhea than the monotherapy group without an increase in serious adverse events; however, the two groups had similar changes in forced vital capacity (FVC). Conclusion: The combination of pirfenidone and nintedanib in patients with IPF has the potential to reduce the rate of FVC decline. However, in the matched analysis, FVC decline was comparable between the patients on combination therapy and those on monotherapy. The incidence of certain adverse events, particularly diarrhea, was higher with combination therapy, but serious adverse events were similar between the groups.

VLDL-VLDLR axis facilitates brown fat thermogenesis through replenishment of lipid fuels and PPARß/δ activation.

In mammals, brown adipose tissue (BAT) is specialized to conduct non-shivering thermogenesis for survival under cold acclimation. Although emerging evidence suggests that lipid metabolites are essential for heat generation in cold-activated BAT, the underlying mechanisms of lipid uptake in BAT have not been thoroughly understood. Here, we show that very-low-density lipoprotein (VLDL) uptaken by VLDL receptor (VLDLR) plays important roles in thermogenic execution in BAT. Compared with wild-type mice, VLDLR knockout mice exhibit impaired thermogenic features. Mechanistically, VLDLR-mediated VLDL uptake provides energy sources for mitochondrial oxidation via lysosomal processing, subsequently enhancing thermogenic activity in brown adipocytes. Moreover, the VLDL-VLDLR axis potentiates peroxisome proliferator activated receptor (PPAR)ß/δ activity with thermogenic gene expression in BAT. Accordingly, VLDL-induced thermogenic capacity is attenuated in brown-adipocyte-specific PPARß/δ knockout mice. Collectively, these data suggest that the VLDL-VLDLR axis in brown adipocytes is a key factor for thermogenic execution during cold exposure.

Incidence and risk factors associated with progression to severe pneumonia among adults with non-severe Legionella pneumonia.

BACKGROUND: Legionella species are important causative organisms of severe pneumonia. However, data are limited on predictors of progression to severe Legionella pneumonia (LP). Therefore, the risk factors for LP progression from non-severe to the severe form were investigated in the present study. METHODS: This was a retrospective cohort study that included adult LP patients admitted to a 2,700-bed referral center between January 2005 and December 2019. RESULTS: A total of 155 patients were identified during the study period; 58 patients (37.4%) initially presented with severe pneumonia and 97 (62.6%) patients with non-severe pneumonia. Among the 97 patients, 28 (28.9%) developed severe pneumonia during hospitalization and 69 patients (71.1%) recovered without progression to severe pneumonia. Multivariate logistic regression analysis showed platelet count ≤150,000/mm3 (odds ratio [OR], 2.923; 95% confidence interval [CI], 1.100-8.105; P=0.034) and delayed antibiotic treatment >1 day (OR, 3.092; 95% CI, 1.167-8.727; P=0.026) were significant independent factors associated with progression to severe pneumonia. CONCLUSIONS: A low platelet count and delayed antibiotic treatment were significantly associated with the progression of non-severe LP to severe LP.

Sarcoid-like reaction in patients with malignant tumors: Long-term clinical course and outcomes.

Background: The development of non-caseating epithelioid cell granulomas in cancer patients who do not fulfill the systemic sarcoidosis criteria is termed sarcoid-like reaction (SLR). Little is known about this condition's natural course and impact on the prognosis of malignancy. We aimed to investigate the natural course and prognostic value of cancer-associated SLR. Methods: Clinical data were retrospectively analyzed in 32 patients with biopsy-proven cancer-associated SLR. Among patients with non-small cell lung cancer (NSCLC), SLR cases (n = 8) were matched with non-SLR cases (n = 78) for survival analysis. Results: Among the included patients, the mean age was 59.7 years, and 68.8% were female. The median follow-up period was 35.6 months [interquartile range (IQR): 14.0-61.4 months]. Of all the included malignancies (n = 32), breast cancer (25.0%) and NSCLC (25.0%) were the most common, with stage I being the most frequent tumor stage (59.4%). During follow-up, SLR progression to overt sarcoidosis was not observed. In the 28 patients with available follow-up computed tomography images (median interval: 24.9 months; IQR: 14.4-41.7), 4 patients received corticosteroids (n = 4), resulting to a decrease of SLR lesions. Meanwhile, among those who did not receive treatment (n = 24), the extent of SLR decreased or did not change in 85.7% of them, whereas 3.6% had increased SLR extent. Furthermore, among patients with NSCLC, SLR was not associated with overall survival [hazard ratio (HR) = 1.28, 95% confidence interval (CI): 0.02-67.71, P = 0.882] and recurrence of malignancy (HR = 1.27, 95% CI 0.21-7.51, P = 0.793) in the Cox proportional hazard regression model. Conclusions: During the follow-up of cancer-related SLR, we found no further evidence for systemic sarcoidosis, and most of the lesions decreased or did not change. Development of SLR was also not associated with overall survival or disease-free survival in patients with NSCLC.

Foreign body aspirations in dental clinics: a narrative review.

Foreign body aspiration can produce a medical emergency. Obstruction of the airways can be life-threatening, and complications may develop in less-severe cases if it is left untreated. Although it is more prevalent in children by approximately three times, adults can still experience it, and it is more frequently related to healthcare in adults. Objects used in dental treatment are usually placed in the oral cavity and can be ingested or inhaled by accident. Dental treatment has been identified as an important cause of the misplacement of foreign bodies in the airway. However, few reports have been published on dentistry-related foreign body aspiration. This paper discusses the disease course, management, and clinical outcomes of foreign body aspiration, especially those associated with dentistry. The patient must be examined for respiratory distress. If the patient is unstable, urgent airway management and the maneuvers for removal should be performed. Radiographs and computed tomography can help identify and locate the object. The treatment of choice is often bronchoscopy, and both flexible and rigid endoscopes can be used depending on the situation. Preventive measures need to be implemented to avoid inhalation accidents given the potential consequences. Though the incidence is rare, healthcare levels need to be enhanced to avert morbidity and mortality. Radiological evaluation and bronchoscopy are vital for management.

Hepatic GSK3ß-Dependent CRY1 Degradation Contributes to Diabetic Hyperglycemia.

Excessive hepatic glucose production (HGP) is a key factor promoting hyperglycemia in diabetes. Hepatic cryptochrome 1 (CRY1) plays an important role in maintaining glucose homeostasis by suppressing forkhead box O1 (FOXO1)-mediated HGP. Although downregulation of hepatic CRY1 appears to be associated with increased HGP, the mechanism(s) by which hepatic CRY1 dysregulation confers hyperglycemia in subjects with diabetes is largely unknown. In this study, we demonstrate that a reduction in hepatic CRY1 protein is stimulated by elevated E3 ligase F-box and leucine-rich repeat protein 3 (FBXL3)-dependent proteasomal degradation in diabetic mice. In addition, we found that GSK3ß-induced CRY1 phosphorylation potentiates FBXL3-dependent CRY1 degradation in the liver. Accordingly, in diabetic mice, GSK3ß inhibitors effectively decreased HGP by facilitating the effect of CRY1-mediated FOXO1 degradation on glucose metabolism. Collectively, these data suggest that tight regulation of hepatic CRY1 protein stability is crucial for maintaining systemic glucose homeostasis.

Antimicrobial effects of microwave plasma-activated water with skin protective effect for novel disinfectants in pandemic era.

Skin antiseptics have important implications for public health and medicine. Although conventional antiseptics have considerable antimicrobial activity, skin toxicity and the development of resistance are common problems. Plasma-treated water has sterilization and tissue-regenerative effects. Therefore, the aim of this study was to identify whether plasma-activated water (PAW) manufactured by our microwave plasma system can be used as a novel antiseptic solution for skin protection. PAW was produced by dissolving reactive nitrogen oxide gas using microwave plasma in deionized water. The antibacterial effects of PAW against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Bacillus cereus, and Salmonella typhimurium and effective concentrations were investigated by a solid agar plate assay. The factors mediating the effects of PAW were evaluated by the addition of reactive species scavengers. Cytotoxicity and cell viability assays were performed to examine the protective effect of PAW on normal skin cells. PAW exhibited excellent sterilization and no toxicity in normal skin cells. Experiments also confirmed the potential of PAW as a sanitizer for SARS-CoV-2. Our findings support the use of PAW as an effective skin disinfectant with good safety in the current situation of a global pandemic.

Comparative efficacy of inhalers in mild-to-moderate asthma: systematic review and network meta-analysis.

The comparative effectiveness of different inhaler therapies in mild-to-moderate asthma remains unclear. To assess this, we performed a systematic review and network meta-analysis of randomized controlled trials on the use of inhalers for mild-to-moderate asthma by searching PubMed, Cochrane, and Embase. A total of 29 trials including 43,515 patients and 12 types of inhaler therapies were included. For the prevention of severe and moderate-to-severe exacerbations, inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) as maintenance and reliever (SMART) showed the highest rank for effectiveness. As-needed ICS/LABA or short-acting ß2-agonist (SABA) was similar to low-dose ICS and superior to as-needed SABA or LABA for the prevention of severe and moderate-severe exacerbations. As for lung function (FEV1), low-dose ICS/LABA had the highest rank; as-needed ICS/LABA was inferior to regular low-dose ICS but superior to placebo. Higher-dose ICS had a superior effect on the Asthma Control Questionnaire (ACQ) scores, and as-needed ICS/LABA and as-needed SABA or LABA had lower ranks in p-rankogram than did the regular use of low-dose ICS. As-needed ICS with LABA or SABA was more effective than a similar dose of regular ICS for preventing exacerbation in mild-to-moderate asthma. As-needed ICS showed some weakness in improving lung function and controlling asthma symptoms.

Distinct properties of adipose stem cell subpopulations determine fat depot-specific characteristics.

In mammals, white adipose tissues are largely divided into visceral epididymal adipose tissue (EAT) and subcutaneous inguinal adipose tissue (IAT) with distinct metabolic properties. Although emerging evidence suggests that subpopulations of adipose stem cells (ASCs) would be important to explain fat depot differences, ASCs of two fat depots have not been comparatively investigated. Here, we characterized heterogeneous ASCs and examined the effects of intrinsic and tissue micro-environmental factors on distinct ASC features. We demonstrated that ASC subpopulations in EAT and IAT exhibited different molecular features with three adipogenic stages. ASC transplantation experiments revealed that intrinsic ASC features primarily determined their adipogenic potential. Upon obesogenic stimuli, EAT-specific SDC1+ ASCs promoted fibrotic remodeling, whereas IAT-specific CXCL14+ ASCs suppressed macrophage infiltration. Moreover, IAT-specific BST2high ASCs exhibited a high potential to become beige adipocytes. Collectively, our data broaden the understanding of ASCs with new insights into the origin of white fat depot differences.

The Impact of Air Pollutants and Meteorological Factors on Chronic Obstructive Pulmonary Disease Exacerbations: A Nationwide Study.

Rationale: Chronic obstructive lung disease (COPD) is a chronic progressive disease. Although smoking is the most important risk factor, 30% of patients with COPD are never-smokers, and environmental agents are also influential. The effects of air pollutants and meteorological factors on COPD exacerbations have not been studied extensively. Objectives: We aimed to investigate the air pollutants and meteorological factors that impact the incidence of COPD exacerbations. Methods: We obtained clinical data of COPD exacerbation cases from The National Health Insurance Service and merged it with 24-hour average values of air pollutants and meteorological factors from national databases. Patients who reside in eight metropolitan cities, where observatory stations are densely located, were selected for analysis. Results: In 1,404,505 patients with COPD between 2013 and 2018, 15,282 COPD exacerbations leading to hospitalization or emergency room visits were identified. Among the various air pollutants and meteorological factors, particulate matter ⩽2.5 µm in aerodynamic diameter (PM2.5), particulate matter ⩽10 µm in aerodynamic diameter (PM10), NO2, SO2, CO, O3, average temperature, and diurnal temperature range (DTR) were associated with COPD exacerbations. Generalized additive mode model analysis with cubic splines showed an inverted U-shaped relationship with PM2.5, PM10, CO, NO2, SO2, O3, DTR, and humidity, whereas it displayed a U-shaped pattern with the average temperature. Distinct patterns were found from 2015-2016 to 2017-2018. Conclusions: PM2.5, PM10, CO, NO2, O3, SO2, average temperature, humidity, and DTR affected the incidence of COPD exacerbations in various patterns, up to 10 lag days.