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Background: The main cause of death in pulmonary embolism (PE) is right-heart failure due to acute pressure overload. In this sense, extracorporeal membrane oxygenation (ECMO) might be useful in maintaining hemodynamic stability and improving organ perfusion. Some previous studies have reported ECMO as a bridge to reperfusion therapy of PE. However, little is known about the patients that benefit from ECMO.Methods: Patients who underwent ECMO due to pulmonary thromboembolism at a single university-affiliated hospital between January 2010 and December 2018 were retrospectively reviewed.Results: During the study period, nine patients received ECMO in high-risk PE. The median age of the patients was 60 years (range, 22–76 years), and six (66.7%) were male. All nine patients had cardiac arrests, of which three occurred outside the hospital. All the patients received mechanical support with veno-arterial ECMO, and the median ECMO duration was 1.1 days (range, 0.2–14.0 days). ECMO with anticoagulation alone was performed in six (66.7%), and ECMO with reperfusion therapy was done in three (33.3%). The 30-day mortality rate was 77.8%. The median time taken from the first cardiac arrest to initiation of ECMO was 31 minutes (range, 30–32 minutes) in survivors (n=2) and 65 minutes (range, 33–482 minutes) in non-survivors (n=7).Conclusion: High-risk PE with cardiac arrest has a high mortality rate despite aggressive management with ECMO and reperfusion therapy. Early decision to start ECMO and its rapid initiation might help save those with cardiac arrest in high-risk PE.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease (ILD) with variable and heterogeneous clinical course. The GAP (gender, age, and physiology) model had been used to predict mortality in patients with IPF, but does not contain exercise capacity. Therefore, our aim in this study was to develop new prognostic scoring system in the Korea IPF Cohort (KICO) registry.Materials and methodsThis is a retrospective study of Korean patients with IPF in KICO registry from June 2016 to August 2021. We developed new scoring system (the GAP6) based on the GAP model adding nadir saturation of percutaneous oxygen (SpO2) during six-minute walk test (6MWT) in the KICO registry and compared the efficacy of the GAP and the GAP6 model.ResultsAmong 2,412 patients in KICO registry, 966 patients were enrolled. The GAP6 model showed significant prognostic value for mortality between each stage [HR Stage II vs. Stage I = 2.89 (95% CI = 2.38–3.51), HR Stage III vs. Stage II = 2.68 (95% CI = 1.60–4.51)]. In comparison the model performance with area under curve (AUC) using receiver operating characteristic (ROC) curve analysis, the GAP6 model showed a significant improvement for predicting mortality than the GAP model (AUC the GAP vs. the GAP6, 0.646 vs. 0.671, p ConclusionThe GAP6 model adding nadir SpO2 during 6WMT for an indicator of functional capacity improves prediction ability with C-index and AUC. Additional multinational study is needed to confirm these finding and validate the applicability and accuracy of this risk assessment system.

BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are tolerable drugs used for patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). Serious adverse reactions are uncommon compared with cytotoxic drugs. CASE SUMMARY A 52-year-old man presented with general weakness and cytopenia. He had been taking erlotinib for 11 mo to treat NSCLC. The pathological diagnosis from the right upper lobe mass was adenocarcinoma with an EGFR mutation in exon 21 (L858R). He had previously received paclitaxel/carboplatin, gemcitabin/ vinorelbine chemotherapy, stereotactic radiosurgery for brain metastasis, and whole-brain radiotherapy as treatment for NSCLC. We diagnosed the patient with acute myeloid leukemia (AML). During the induction and consolidation chemotherapy for AML, the erlotinib was discontinued. When complete remission of the AML was achieved, since the lung masses were increased, pemetrexed/ cisplatin for the NSCLC was initiated. After two cycles of chemotherapy, the cytopenia was prolonged. AML relapse occurred with the same karyotype. CONCLUSION Therapy-related acute myeloid neoplasm (t-MN) is a rare but fatal late complication. Although a patient may be taking EGFR-TKIs, the possibility of t-MN should be considered. Further studies are needed to determine whether EGFR-TKI usage is a predisposing factor for t-MN.

Aim The efficacy and safety of pirfenidone have been previously demonstrated in patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF). However, the effect of pirfenidone in patients with advanced IPF remains unclear. Here, we investigated the effects of pirfenidone against advanced IPF in a real-world setting. Methods A prospective nationwide post-marketing study was conducted on 258 patients from 10 Korean institutions. Patients with a predicted forced vital capacity (FVC) less than 50% or a diffusing capacity of the lung for carbon monoxide (DLco) less than 35% at baseline were classified as the advanced IPF group. Results Of 219 patients included in the analysis, the majority were male (76.3%); the mean age was 67.3 years, and the advanced group accounted for 17.8% of the patients. The median treatment duration was 298 days. Among the subjects, 86.3% experienced adverse events (AEs), of which a decreased appetite (32.4%) and a photosensitivity reaction (13.7%) were the most frequent. The incidence of AEs was similar between the advanced and non-advanced groups (92.3% vs. 85.0%, respectively; p = 0.229). Although the overall discontinuation rate was higher in the advanced group than in the non-advanced group (74.4% vs. 50.0%, respectively; p = 0.006), the percentages of the patients who discontinued treatment as a result of AEs were similar in both groups (20.5% vs. 23.3%, respectively; p = 0.704). In all patients, the rates of decline in the predicted FVC and DLco over 48 weeks were − 4.3 ± 1.3% and − 4.4 ± 1.7%, respectively. There was no between-group difference in the rate of lung function decline. Conclusions Pirfenidone used for the treatment of patients with IPF in a real-world setting was well tolerated, with an acceptable safety profile and a consistent therapeutic effect, regardless of the disease severity. Trial Registration ClinicalTrials.gov NCT03761082; the trial was retrospectively registered on December 3, 2018. Electronic supplementary material The online version of this article (10.1007/s12325-020-01328-8) contains supplementary material, which is available to authorized users.

Coronavirus disease 2019 (COVID-19) has become a major health burden worldwide, with over 450 million confirmed cases and 6 million deaths. Although the acute phase of COVID-19 management has been established, there is still a long way to go to evaluate the long-term clinical course or manage complications due to the relatively short outbreak of the virus. Pulmonary fibrosis is one of the most common respiratory complications associated with COVID-19. Scarring throughout the lungs after viral or bacterial pulmonary infection have been commonly observed, but the prevalence of post– COVID-19 pulmonary fibrosis is rapidly increasing. However, there is limited information available about post–COVID-19 pulmonary fibrosis, and there is also a lack of consensus on what condition should be defined as post–COVID-19 pulmonary fibrosis. During a relatively short follow-up period of approximately 1 year, lesions considered related to pulmonary fibrosis often showed gradual improvement; therefore, it is questionable at what time point fibrosis should be evaluated. In this review, we investigated the epidemiology, risk factors, pathogenesis, and management of post–COVID-19 pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia, which presents with a progressive worsening dyspnea, and thus a poor outcome. The members of the Korean Academy of Tuberculosis and Respiratory Diseases as well as the participating members of the Korea Interstitial Lung Disease Study Group drafted this clinical practice guideline for IPF management. This guideline includes a wide range of topics, including the epidemiology, pathogenesis, risk factors, clinical features, diagnosis, treatment, prognosis, and acute exacerbation of IPF in Korea. Additionally, we suggested the PICO for the use of pirfenidone and nintendanib and for lung transplantation for the treatment of patients with IPF through a systemic literature review using experts' help in conducting a meta-analysis. We recommend this guideline to physicians, other health care professionals, and government personnel in Korea, to facilitate the treatment of patients with IPF.

Rationale: In recent decades, diagnosis and treatment recommendations for idiopathic pulmonary fibrosis (IPF) have changed. In Korea, the average life expectancy has increased, unmet healthcare nee...

Background: Excessive alveolar epithelial cell(AEC) death by repeated injury play a role in the pathogenesis of lung fibrosis. Recently reports show defective lipid metabolism in AEC contributes to development or progression of lung fibrosis and normal lipid metabolism relies on proper mitochondrial function. Fatty acid synthase(FASN) is key enzyme catalyzes the conversion of acetyl-CoA and malonyl-CoA to saturated fatty acids. Objectives: We investigated whether regulation of FASN expression in AECs modulate severity of lung fibrosis and to find its possible mechanism. Methods: We generated FASN knock-down, overexpression stable cell lines and human FASN transgenic (TG) mice, with conditionally induced alveolar epithelium to overexpress FASN. Cell proliferation and apoptosis assay were performed treated with bleomycin(BLM). Lung fibrosis was established by BLM inhaled FASN TG mice. Measurement and Results: We found that FASN protein was mainly expressed at AECs in controls but significantly reduced in IPF lung. Knockdown of FASN significantly increased but overexpression of FASN attenuate apoptotic cell death. FASN overexpression reduces BLM-induced loss of mitochondrial membrane potential and downregulate mitochondrial ROS production. FASN TG mice dramatically attenuated BLM-induced lung inflammation and fibrosis. Conclusions: These findings suggest that defective FASN production may associated with IPF pathogenesis and augmentation of FASN in the lung may have therapeutic potential in preventing lung fibrosis. This study was supported by National research foundation of Korea grant 2019R1A2C1006351.

Asthma exacerbation is induced by the interaction of genes and environmental factors such as cigarette smoke. NLRP4 counteracts the activity of the inflammasome, which is responsible for asthma exacerbation. In this study, we analyzed the association of single-nucleotide polymorphisms of NLRP4 with the annual rate of exacerbation and evaluated the additive effect of smoking in 1454 asthmatics. Asthmatics possessing the minor allele of rs1696718G A had more frequent exacerbation episodes than those homozygous for the common allele (0.59 vs. 0.36/year) and the association was present only in current and ex-smokers. There was a significant interaction between the amount smoked and rs16986718 genotypes (p = 0.014) and a positive correlation between the number of annual exacerbation episodes and amount smoked only in rs16986718G A AA homozygotes. The prevalence of frequent exacerbators (≥2 exacerbation episodes/year) was 2.5 times higher in rs16986718G A minor allele homozygotes than in common allele homozygotes (12.0% vs. 5.9%). Furthermore, the prevalence was 6 times higher in rs16986718G A minor allele homozygotes who were current and ex-smokers than in nonsmokers (25.6% vs. 4.1%). The minor allele of rs16986718G A in NLRP4 may be a genetic marker that predicts asthma exacerbation in adult asthmatics who smoke.

Objectives Multidisciplinary discussions (MDDs) have emphasized improve medical services and outcomes. We used a multidisciplinary approach to explore whether patient emotional satisfaction and confidence affected treatment outcomes in rheumatic disease (RD)-related interstitial lung disease (ILD). Methods From December 2015 to April 2017, we evaluated 23 patients with RD and ILD and 21 with idiopathic pulmonary fibrosis (IPF). Patients with RD and ILD were managed with MDDs. Patients with IPF received standardized medical care by the same pulmonologist. All patients completed brief multiple-choice questionnaires exploring their perceptions of their illnesses and their attitudes toward medical treatment, and completed the Patient Health Questionnaire-2. Results The MDD patients could more easily identify disease symptoms regardless of age stratification (under 65 age: P = 0.020, 65 years or older: P = 0.003). Among the 65 years or older group, it shows higher levels of illness perception in terms of disease timeline in the MDD group (P = 0.035). Also, the MDD group reported higher levels of satisfaction in terms of the explanations they received and their involvement in discussion, and greater satisfaction with medical staff. However, the groups did not differ significantly between treatment outcomes such as changes in forced vital capacity, the diffusion capacity of carbon monoxide, or changes in high-resolution computed tomography. Conclusions MDDs afforded satisfactory management compared with standardized medical care. The MDD group felt better attention fromand satisfaction with medical staff, and had greater identification in their treatment. Further research engaging in MDDs with a comparable control group is required.

The clinical course of idiopathic pulmonary fibrosis (IPF) is difficult to predict, partly owing to its heterogeneity. Composite physiologic index (CPI) and gender-age-physiology (GAP) models are easy-to-use predictors of IPF progression. This study aimed to compare the predictive values of these two models. From 2003 to 2007, the Korean Interstitial Lung Disease (ILD) Study Group surveyed ILD patients using the 2002 ATS/ERS criteria. A total of 832 patients with IPF were enrolled in this study. CPI was calculated as follows: 91.0 − (0.65 × %DLCO) − [0.53 × %FVC + [0.34 × %FEV1. GAP stage was calculated based on gender (0–1 points), age (0–2 points), and two physiologic lung function parameters (0–5 points). The two models had similar significant predictive values for patients with IPF (p

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

S100A9 is an endogenous danger signal that promotes and exacerbates the neutrophilic inflammatory response. To investigate the role of S100A9 in neutrophilic asthma, S100A9 levels were measured in sputum from 101 steroid-naïve asthmatics using an ELISA kit and the levels were significantly correlated with percentages of neutrophils in sputum. Intranasal administration of recombinant S100A9 markedly increased neutrophil numbers at 8h and 24h later with concomitant elevation of IL-1β, IL-17, and IFN-γ levels. Treatment with an anti-S100A9 antibody restored the increased numbers of neutrophils and the increased airway resistance in OVA/CFA mice toward the levels of sham-treated mice. Concomitantly, the S100A9 and neutrophil elastase double positive cells were markedly reduced with attenuation of IL-1β, IL-17, and IFN-γ levels by the treatment with the anti-S100A9 antibody. Our data support a role of S100A9 to initiate and amplify the neutrophilic inflammation in asthma, possibly via inducing IL-1β, IL-17 and IFN-γ.

Interstitial lung disease (ILD) occurs in 15% of patients with collagen vascular disease (CVD), referred to as connective tissue disease (CTD). Despite advances in management strategies, ILD continues to be a significant cause of mortality in patients with CVD-associated ILD (CTD-ILD). There is a lack of randomized, clinical trials assessing pharmacological agents for CTD-ILD, except in cases of ILD-associated systemic sclerosis (SSc). This may be due to the lack of CTD cases available, the difficulty of histological confirmation of ILD, and the various types of CTD and ILD. As a result, evidence-based pharmacological treatment of CTD-ILD is not yet well established. CTD-ILD presents with varying degrees of histology, from inflammation to fibrosis, and a wide spectrum of clinical manifestations, from minimal symptoms to respiratory failure. This renders it difficult for clinicians to make decisions regarding treatment options, observational strategies, optimal timing for interventions, and the appropriateness of pharmacological agents for treatment. There is no specific treatment for reversing fibrosis-like idiopathic pulmonary fibrosis in a clinical setting. This review describes pharmacological interventions for SSc-ILD described in randomized control trials, and presents an overview of recent advances of CTD-ILD-dependent treatments based on the types of CTD.

Oral anticoagulant therapy is frequently and increasingly prescribed for patients at risk of arterial or venous thromboembolism (VTE). Although elective surgical or invasive procedures have necessitated temporary interruption of anticoagulants, managing these patients has been performed empirically and been poorly investigated. This study was designed to evaluate the adequacy of perioperative anticoagulation using enoxaparin. This was a retrospective, single-center study that evaluated the efficacy and safety of therapeutic-dose enoxaparin for bridging therapy in patients on long-term warfarin at Soonchunhyang University Hospital in Korea between August 2009 and July 2011. Warfarin was discontinued 5 days before surgery, and enoxaparin was administered twice daily by subcutaneous injection at a dose of 1 mg per kg from 3 days before the procedure to the last dose 24 hours before the procedure. Anticoagulation was restarted if proper hemostasis had been confirmed. There were 49 patients, of whom 25 (51%) were men, and the mean age was 63 years. Thirty-four (69%) received warfarin therapy for VTE, and 9 (18%) for atrial fibrillation. Twenty-nine patients (59%) underwent major surgery and 20 (41%) minor surgery. The mean postoperative duration of enoxaparin was 4 days. No patients had thromboembolic complications through 30 days after the procedure. The overall 30-day mortality rate was 0%. In conclusion, our findings demonstrate that bridging therapy with therapeutic-dose enoxaparin is feasible and associated with a low incidence of major bleeding and no thromboembolic complications. However, the optimal approach to managing patients perioperatively is uncertain and requires further evaluation., Graphical Abstract

Background: Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have been the standard first-line therapy in patients with metastatic non-small cell lung cancer (NSCLC). There have been no head to head comparisons among gefitinib, erlotinib, and afatinib for such patients, brain metastasis in EGFR-mutant NSCLC. The best EGFR-TKI for their treatment is not yet known. We aimed to assess the relative efficacy among gefitinib, erlotinib, and afatinib using network meta-analysis. Methods: A systematic literature review with electronic databases was conducted. We included patients with brain metastasis and EGFR positive NSCLC. End-points were objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events. Data were extracted from included studies. We regarded different standard chemotherapy regimens as “chemotherapy” for network comparisons. Results: Eight studies involving 446 patients with brain metastasis and EGFR positive NSCLC were enrolled in the meta-analysis. Rank probability showed that afatinib had potentially better PFS compared with gefitinib and erlotinib (HR (95% CI): 0.76 (0.06-6.82); 1.00 (0.04-26.10) and 2.20 (0.03-170.64) respectively). Gefitinib revealed better OS than erlotinib and afatinib (HR (95% CI): 0.42(0.10-1.70); 1.03 (0.01-76.98) and 1.14(0.14-9.01) respectively). The data of objective response rate and adverse events for analysis were not available. Conclusions: The published data for EGFR mutant NSCLC patients with brain metastasis were limited. Our study indicated potentially better outcomes of afatinib and gefitinib in this population.

호흡곤란 및 흉통을 주소로 내원한 환자에서 심낭삼출이 첫 증상으로 발현된 일차성 쇼그렌증후군을 건조증상, 침샘조직검사, 그리고 심낭삼출액 분석을 포함하여 진단하고 성공적으로 치료하였기에 문헌고찰과 함께 증례보고하는 바이다.

Cryptogenic organizing pneumonia (COP) is an idiopathic interstitial pneumonia characterized by a subacute course and favorable prognosis with corticosteroids. However, some patients show resistance to steroids. Macrolides have been used with success in those patients showing resistance to steroids. A few reports showed treatment failure with macrolides in patients with COP who were resistant to steroids. In this report, we described two cases of COP who showed different responses to clarithromycin. One recovered completely, but the other gradually showed lung fibrosis with clarithromycin.

We developed a genetic marker set of single nucleotide polymorphisms (SNPs) by summing risk scores of 14 SNPs showing a significant association with aspirin-exacerbated respiratory disease (AERD) from our previous 660 W genome-wide association data. The summed scores were higher in the AERD than in the aspirin-tolerant asthma (ATA) group (P=8.58 × 10(-37)), and were correlated with the percent decrease in forced expiratory volume in 1 s after aspirin challenge (r(2)=0.150, P=5.84 × 10(-30)). The area under the curve of the scores for AERD in the receiver operating characteristic curve was 0.821. The best cutoff value of the summed risk scores was 1.01328 (P=1.38 × 10(-32)). The sensitivity and specificity of the best scores were 64.7% and 85.0%, respectively, with 42.1% positive and 93.4% negative predictive values. The summed risk score may be used as a genetic marker with good discriminative power for distinguishing AERD from ATA.

Rationale: Alveolar epithelial cell (AEC) injury leading to cell death is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF). Among regulated/programmed cell death, the excessive apoptosis of AECs has been widely implicated in IPF pathogenesis. Necroptosis is a type of regulated/programmed necrosis. A multiprotein complex composed of receptor-interacting protein kinase-1 and -3 (RIPK1/3) plays a key regulatory role in initiating necroptosis. Although necroptosis participates in disease pathogeneses through the release of damage-associated molecular patterns (DAMPs), its association with IPF progression remains elusive. In this study, we attempted to illuminate the involvement of RIPK3-regulated necroptosis in IPF pathogenesis. Method: IPF lung tissues were used to detect necroptosis, and the role of RIPK3 was determined using cell culturing models of AECs. Lung fibrosis models of bleomycin (BLM) treatment were also used. Measurement and main results: RIPK3 expression levels were increased in IPF lungs and both apoptosis and necroptosis were detected in AECs. Necrostatin-1 and RIPK3 knockdown experiments in AECs revealed the participation of necroptosis in BLM and hydrogen peroxide-induced cell death. BLM treatment induced RIPK3 expression in AECs and increased High Mobility Group Box 1 (HMGB1) and interleukin 1β (IL-1β) levels in mouse lungs. The efficient attenuation of BLM-induced lung inflammation and fibrosis was determined by necrostatin-1 and in RIPK3 knockout mice with a concomitant reduction in HMGB1 and IL-1β. Conclusions: These findings suggest that RIPK3-regulated necroptosis in AECs is involved in the mechanism of lung fibrosis development through the release of DAMPs.

BACKGROUND Ozone is well known as an important component of ambient air pollutants. Ozone can aggravate respiratory symptoms in patients with bronchial asthma, but, not in healthy person. We hypothesized asthma itself may show different response to ozone compared to nonasthma. OBJECTIVE This study was performed to evaluate the differences of response to ozone between normal and asthmatic mice model in terms of status of oxidant injury and antioxidant activity. METHODS Three parts per million of ozone was exposed to ovalbumin (OVA)-induced murine asthma model for 3 hours at 3, 7, 14, 21 days after completion of asthma model. Airway responsiveness to methacholine was measured after completion of asthma model. Bronchoalveolar lavage (BAL), protein extraction from lung for Western blot and immunohistochemistry of 4-hydroxy-2-nonenal (4-HNE), proliferating cell nuclear antigen (PCNA), NF-E2 related factor 2 (Nrf-2), and activity of glutathione were performed at before and each ozone exposure day. RESULTS Airway hyper-responsiveness and increased eosinophils in BAL fluid were observed in asthma model. In asthma model, the expression of 4-HNE already more increased at baseline (without ozone) compared to those in sham model. This increased expression is more enhanced at 3 days after ozone exposure. The expression of PCNA was significantly increased in OVA-model compared to those in sham model. The expression of Nrf-2 was observed at baseline, and 3 and 7 days after exposure ozone in asthma model, but not in sham model. The activity of glutathione increased significantly after exposure of ozone, but not in sham model. CONCLUSION Murine asthma model has enhanced oxygen toxicity and antioxidant activity response to ozone.

Objectives Asthma can be suppressed by inhaled corticosteroids (ICS). However, response to ICS shows marked inter-individual variability. This study is aimed to identify the genetic variants associated with the change in the percentage of forced expiratory volume in 1 second (%ΔFEV1) following ICS treatment. Methods A genome-wide association study was performed in a Korean asthmatic cohort. To further investigate these genetic associations, 11 additional single-nucleotide polymorphisms (SNPs) on the allantoicase (ALLC) gene were selected from the HapMap database and genotyped in the same asthmatic patients in the follow-up study. Results In a genome-wide study, we identified the lowest P-value in ALLC, but none of the SNPs met the genome-wide association criteria (P Conclusions Although the associated signals could not overcome the genome-wide multiple correction due to small sample size (n = 189), our results suggest that associated SNPs of ALLC might be genetic predictors of response to ICS, at least with respect to ΔFEV1 in Korean asthmatics.

Melanocortin 3 Receptor (MC3R) is one of the families of seven-transmembrane G-protein-coupled receptors, and a recent study showed that MCR3 promoter polymorphism was significantly associated with the susceptibility of tuberculosis (TB) in South African population. We analyzed six MC3R polymorphisms to examine the genetic effects on the risk of pulmonary TB in Korean subjects by using TaqMan assays and case–control analyses. Using statistical analyses, one common promoter polymorphism (MC3R rs11575886 T > C) was found to be associated with an increased risk of pulmonary TB. The frequency of the C-bearing genotype of rs11575886 was higher in pulmonary TB patients than in normal controls (p = 0.03, OR = 1.46) although the significance was not retained after correction. In silico analysis for the difference of transcription binding factor (TF), motif between C and T allele demonstrated that the TF motif and its threshold scores of C allele were lower than those of T allele. The C allele of rs11575886 could be a risk allele for the pulmonary TB by affecting the binding of TF. Our findings suggest that polymorphisms in MC3R might be one of genetic factors for the risk of pulmonary TB development in Korean subjects.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea and worsening lung function due to remodeling of the lung, including epithelial mesenchymal transition. ADAM33 is a disintegrin and metalloprotease domain-containing protein, which may be related to lung fibrosis by exerting angiogenesis and remodeling of the lung. Thus, we evaluated the association of single-nucleotide polymorphisms (SNPs) of ADAM33 with the risk of IPF. A total of 237 patients with IPF and 183 healthy subjects participated in the present study. Nine polymorphisms were selected. Genotyping was performed by single-base extension. Polymorphisms and haplotypes were analyzed for associations with the risk of IPF using multiple logistic regression models controlling for age, gender, and smoking status as covariates. All SNPs were in Hardy-Weinberg equilibrium. The minor allele frequency (MAF) of rs628977G>A in intron 21 was significantly lower in subjects with surgical IPF than in normal controls in the recessive model [33.2 vs. 38.0 %, p = 0.02, OR = 0.40 (0.19–0.84)]. When the subjects with clinical IPF were included, the difference in MAF persisted with a p value of 0.03 [OR = 0.50 (0.27–0.94)]. ADAM33 rs628977G>A was marginally associated with a decreased risk of IPF in a recessive model.

The risk of dying from a pulmonary embolism (PE) is estimated to be about 30% if inotropic support is required and no cardiopulmonary arrest occurs. Fibrinolysis in massive PE is regarded as a life-saving intervention, unless there is a high risk of bleeding following the use of the fibrinolytic therapy. Rivaroxaban is an oral factor Xa inhibitor, however its anticoagulation effects before or after administration of fibrinolytics in massive PE are still unknown. Two patents were admitted: 61-year-old woman with repeated syncope, and a 73-year-old woman was admitted with dyspnea and poor oral intake. Systemic arterial hypotension with radiologic confirmation led to a diagnosis of massive PE in both patients. Rivaroxaban was administered before in one, and after firbrinolytic therapy in the other. One showed similar efficacy of rivaroxaban with currently used anticoagulants after successful fibrinolysis, and the other one without antecedent administration of the fibrinolytic agent showed unfavorable efficacy of rivaroxaban.

Warfarin is the main oral anticoagulant effective for the prevention of stroke in patients with atrial fibrillation, and for the prevention and treatment of venous thromboembolism. It has a narrow therapeutic window of effectiveness and safety, which may lead to underuse. Accordingly, dose adjustments are mandatory for its effective and safe treatment, which depends on the time spent in the therapeutic International Normalized Ratio (INR) range (TTR). Hence, TTR is a key determinant of outcomes for patients receiving anticoagulation with warfarin. It is well known that lower rates of TTR in warfarin patients leads to an increased risk of bleeding or thromboembolic complications. Many studies have reported on the accuracy and precision of point-of-care (POC) devices when used by patients for INR monitoring on warfarin anticoagulation, as well as their good correlations with conventional plasma INR measurements within therapeutic ranges. Previous studies have indicated that a patient self-testing model may be superior to usual care or an anticoagulation clinic model in the quality of INR control. Recently, there has been increasing demand for high-quality warfarin management in Korea. Nevertheless, no domestic data have been reported on warfarin anticoagulation management using a patient self-testing (PST) model. Here, we describe our experiences with warfarin management using a PST model where the warfarin dose was adjusted by the anticoagulation clinic staff on the basis of a validated algorithm with the INR values self-tested by patients at home using capillary blood on the POC device CoaguChek-XS (Roche Diagnostics, Mannheim, Germany).

Exacerbation of COPD is a major risk factor for bad prognosis of COPD. A few plasma proteins have been discovered to associate with hospital admission due to exacerbation up to date. We tried to find new plasma biomarkers to predict the exacerbation of COPD.We examined the plasma of normal control (n = 8) and COPD stable (n = 8) and exacerbation (n = 8) using 2-Dimentional Electrophoresis. The differentially expressed protein spots were identified by MALDI-TOF. ELISA were performed for quantitative measurement of RARα in plasma from normal control (n = 37) and COPD (n = 35).17 proteins were differentially expressed in plasma between stable and exacerbation state in the subjects with COPD. Identification using MALDI-TOF showed that retinoic acid receptor alpha, ninein, isoform CRA_a, alpha-1 antitrypsin, fibrinogen gamma, tyrosyl-DNA phosphodiesterase 2, and T cell receptor delta chain were increased in exacerbation of COPD, while fibrin beta, Crystal Structure Of An Autoimmune Complex Between A Human Igm RF* And Igg1 Fc, transferrin, serpin peptidase inhibitor member 6, complement factor B preproprotein, Chain B, Crig Bound To C3c, and WD repeat-containing protein 1 isoform 1 were decreased. Quantitative measurement showed that RARα plasma levels significantly increased in exacerbation state compared to stable state of COPD (n = 14). In the plasma of stable state, the COPD subjects (n = 14) having more than 0.4 time/yr of admission had very high levels of RAR alpha protein and those (n = 11) having less than 0.4 times/yr of admission had the intermediate levels compared to those having no exacerbation (n = 10). ROC analysis of RAR alpha levels to frequency of admission showed an area under the curve of 0.844. A cut-off of 0.154 ng/ml of RAR alpha predicted hospital admission with a sensitivity of 71.4% and a specificity of 92.8%.The proteomic analysis of plasma indicates that alteration of several proteins may be associated with admission of COPD. Among them, plasma RAR alpha level may predict hospital admission with a sensitivity of 71.4% and a specificity of 92.8%.

Aspirin-exacerbated respiratory disease (AERD) is characterized by the development of airway obstruction in asthmatic individuals following the ingestion of aspirin or other nonsteroidal anti-inflammatory drugs. TAPBP (TAP-binding protein, tapasin) is upregulated by eicosanoids, which act as potent inflammatory molecules in aspirin-related reactions. Thus, functional alterations in the TAPBP gene may contribute toward AERD.We examined the relationship between the single nucleotide polymorphisms on the TAPBP gene and AERD.A group of asthmatic patients (n=1252) underwent the oral aspirin challenge. Oral aspirin challenge reactions were categorized into two groups as follows: 15% or greater decreases in forced expiratory volume in 1 s or naso-ocular and skin reactions (AERD), or 15% or less decreases in forced expiratory volume in 1 s without naso-ocular and skin reactions (aspirin-tolerant asthma). Five single nucleotide polymorphisms of the TAPBP gene were genotyped.Logistic regression analysis showed that the minor allele frequencies of TAPBP rs2071888 CG (Thr260Arg) on exon 4 (P0.05), which was in absolute linkage disequilibrium with rs1059288 TC on 3'UTR, were significantly higher in the AERD group than in the aspirin-tolerant asthma group, and the P values remained significant after multiple comparisons (Pcorr=0.006, odds ratio: 1.37, 95% confidence interval: 1.11-1.69, additive model; Pcorr=0.009, odds ratio: 1.52, 95% confidence interval: 1.14-2.03, dominant model). Alpha-helical wheel plotting showed that 260Arg had greater hydrophilic helical property than 260Thr.TAPBP polymorphisms may play a role in the development of AERD.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea and worsening lung function. ACE is increased in the bronchoalveolar lavage fluid from patients with IPF, suggesting the role of ACE in the pathogenesis of IPF. We evaluated the role of single-nucleotide polymorphisms (SNPs) in the development risk of IPF. Two-hundred twenty patients with IPF and 456 healthy subjects were included in this study. Eleven polymorphisms were selected among those reported previously. Genotype was performed by single base extension. Although absolute LD (|D′| = 1 and r 2 = 1) was not present, 11 SNPs showed tight LDs. The logistic analysis of the all of 11 SNPs on the ACE genes between patients with IPF and healthy subjects were found to be related with the risk of IPF in recessive type. However, in patients with IPF diagnosed by surgical lung biopsy, only two SNP of −5538T>C and +21288_insdel SNPs were related with the risk of IPF in co-dominant type, and there were no SNPs related with the risk of IPF in dominant type. In patients with IPF diagnosed by clinical criteria or surgical lung biopsy, four SNPs on promoter (−5538T>C, −5508A>C, −3927T>C, −115T>C), one on intron (+15276A>G), one on exon (+21181G>A), and one in three prime region (+21288_insdel) were related with the risk of IPF. This study showed a newly discovered SNP of ACE associated with the risk of development of IPF. ACE −5538T>C and −5508A>C significantly associated with risk of IPF in Korea.

Aim To investigate the association of single nucleotide polymorphisms (SNP) on IL17RA gene with Aspirin Exacerbated Respiratory Disease (AERD) and the functional effect of these variants on expression of IL17RA gene products. Material & methods 15 SNPs of IL17RA gene were analyzed in 825 normal controls and 143 subjects with AERD and 411 with aspirin-tolerant asthma (ATA) and functionally characterized using measurement of protein and m-RNA expression. Result Minor alleles frequencies of the three SNPs ( −1075 A > G, −947 A > G, −50 C > T) and one haplotype ( BL1_ht1 ) were significantly lower in AERD compared to those in ATA ( p corr = 0.002–0.03). IL17RA protein expression and mRNA amount in CD14 + peripheral blood monocytes and mononuclear cells were significantly increased in subjects carrying the common alleles homozygote compared with those carrying the minor alleles. Conclusions The minor alleles of the three SNPs may decrease the risk of AERD via attenuation of IL17RA gene expression.

Background Innate T helper type 2 (Th2) immune responses mediated by interleukin (IL)-33, thymic stromal lymphopoietin (TSLP), and IL-25 have been shown to play an important role in pulmonary fibrosis of animal models; however, their clinical implications remain poorly understood. Methods TSLP, IL-25, and IL-33 concentrations were measured in bronchoalveolar lavage fluids obtained from normal controls (NCs; n = 40) and from patients with idiopathic pulmonary fibrosis (IPF; n = 100), non-specific interstitial pneumonia (NSIP; n = 22), hypersensitivity pneumonitis (HP; n = 20), and sarcoidosis (n = 19). Results The TSLP and IL-33 levels were significantly higher in patients with IPF relative to the NCs (p = 0.01 and p = 0.0001, respectively), NSIP (p = 4.95E − 7 and p = 0.0002, respectively), HP (p = 0.00003 and p = 0.000005, respectively), and sarcoidosis groups (p = 0.003 and p = 0.0001, respectively). However, the IL-25 levels were not significantly different between NC and IPF group (p = 0.432). Receiver operating characteristic curves of the TSLP and IL-33 levels revealed clear differences between the IPF and NC groups (AUC = 0.655 and 0.706, respectively), as well as between the IPF and the other lung disease groups (AUC = 0.786 and 0.781, respectively). Cut-off values of 3.52 pg/μg TSLP and 3.77 pg/μg IL-33 were shown to differentiate between the IPF and NC groups with 99.2 and 94.3% accuracy. Cut-off values of 4.66 pg/μg TSLP and 2.52 pg/μg IL-33 possessed 99.4 and 93.2% accuracy for differentiating among the IPF and other interstitial lung disease groups. Conclusions Innate immune responses may be associated with the development of IPF. Furthermore, the IL-33 and TSLP levels in BAL fluids may be useful for differentiating IPF from other chronic interstitial lung diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12890-017-0380-z) contains supplementary material, which is available to authorized users.

Purpose Asthma is a heterogeneous disease characterized by various types of airway inflammation and obstruction. Therefore, it is classified into several subphenotypes, such as early-onset atopic, obese non-eosinophilic, benign, and eosinophilic asthma, using cluster analysis. A number of asthmatics frequently experience exacerbation over a long-term follow-up period, but the exacerbation-prone subphenotype has rarely been evaluated by cluster analysis. This prompted us to identify clusters reflecting asthma exacerbation. Methods A uniform cluster analysis method was applied to 259 adult asthmatics who were regularly followed-up for over 1 year using 12 variables, selected on the basis of their contribution to asthma phenotypes. After clustering, clinical profiles and exacerbation rates during follow-up were compared among the clusters. Results Four subphenotypes were identified: cluster 1 was comprised of patients with early-onset atopic asthma with preserved lung function, cluster 2 late-onset non-atopic asthma with impaired lung function, cluster 3 early-onset atopic asthma with severely impaired lung function, and cluster 4 late-onset non-atopic asthma with well-preserved lung function. The patients in clusters 2 and 3 were identified as exacerbation-prone asthmatics, showing a higher risk of asthma exacerbation. Conclusions Two different phenotypes of exacerbation-prone asthma were identified among Korean asthmatics using cluster analysis; both were characterized by impaired lung function, but the age at asthma onset and atopic status were different between the two.

Supplementary data. (DOC 379 kb)

Background Idiopathic pulmonary fibrosis (IPF) is characterized by the complex interaction of cells involved in chronic inflammation and fibrosis. Global gene expression of a homogenous cell population will identify novel candidate genes. Methods Gene expression of fibroblasts derived from lung tissues (8 IPF and 4 controls) was profiled, and ontology and functional pathway were analyzed in the genes exhibiting >2 absolute fold changes with p-values 10-fold change. Among them, 13 were novel in relation with IPF. CCL8 expression was 22.8-fold higher in IPF fibroblasts. The levels of CCL8 mRNA and protein were 3 and 9-fold higher in 14 IPF fibroblasts than those in 10 control fibroblasts by real-time PCR and ELISA (p = 0.022 and p = 0.026, respectively). The CCL8 concentrations in BAL fluid was significantly higher in 86 patients with IPF than those in 41 controls, and other interstitial lung diseases including non-specific interstitial pneumonia (n = 22), hypersensitivity pneumonitis (n = 20) and sarcoidosis (n = 19) (p 28.61 pg/mL showed shorter survival compared to those with lower levels (p = 0.012). CCL8 was expressed by α-SMA-positive cells in the interstitium of IPF. Conclusions Transcriptome analysis identified several novel IPF-related genes. Among them, CCL8 is a candidate molecule for the differential diagnosis and prediction of survival. Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0493-6) contains supplementary material, which is available to authorized users.

Supplemental data. (DOC 102Â kb)

The aim of the present study was to develop a diagnostic set of single-nucleotide polymorphisms (SNPs) for discriminating aspirin-exacerbated respiratory disease (AERD) from aspirin-tolerant asthma (ATA) using the genome-wide association study (GWAS) data; the GWAS data were filtered according to p-values and odds ratios (ORs) using PLINK software, and the 10 candidate SNPs most closely associated with AERD were selected, based on 100 AERD and 100 ATA subjects. Using multiple logistic regression and receiver-operating characteristic (ROC) curve analysis, eight SNPs were chosen as the best model for distinguishing between AERD and ATA. The relative risk for AERD in each subject was calculated based on the relative risk of each of the eight SNPs. Ten of the original 109,365 SNPs highly associated (filtered with p0.001 and ORs) with the risk for AERD were selected. A combination model of the eight SNPs among the 10 SNPs showed the highest area under the ROC curve of 0.9. The overall relative risk for AERD based on the eight SNPs was significantly different between the AERD and ATA groups (p=2.802E-21), and the sensitivity and specificity were 78% and 88%, respectively. The candidate set of eight SNPs may be useful in predicting the risk for AERD.

Aspirin-exacerbated respiratory disease (AERD) is a respiratory disease characterized by acute bronchial responses upon the administration of non-steroidal anti‑inflammatory drugs (NSAIDs) and the immune response by mast cells is regarded as one of the noteworthy causes of AERD pathogenesis. The complement cascade is regarded as a key mechanism for clearing pathogens from the host. CD55 is one of the proteins involved in self-recognition, a central component of the complement system and autoimmunity. To investigate the associations between CD55 single nucleotide polymorphisms (SNPs) and the risk of AERD, we carried out logistic analyses with three genetic models and further regression analysis was performed with the fall rate of forced expiratory volume in 1 sec (FEV1) by aspirin provocation. However, our results demonstrate that no CD55 polymorphisms are associated with the risk of AERD and the fall rate of FEV1 (P>0.05). Therefore, our results suggest that CD55 polymorphisms are not genetic markers of aspirin‑induced bronchospasm, including FEV1, in the population studied. Although the genetic role of CD55 has been found to be integral to human immunity, our results indicate that genetic variations of CD55 do not influence the risk of AERD and the fall rate of FEV1 in the population studied.

BACKGROUND: The functional role of the human diffuse panbronchiolitis critical region 1 (DPCR1) gene, located in the major histocompatibility complex class I, has not been widely investigated. However, this gene is a well known genetic marker for diffuse panbronchiolitis, a disease affecting human respiratory bronchioles. In this study we explored the association between polymorphisms in DPCR1 and aspirin-exacerbated respiratory disease (AERD), an asthma phenotype. METHODS: Genotyping of 6 polymorphisms was carried out in a total of 189 Korean asthmatic patients stratified into 93 AERD cases and 96 aspirin tolerant asthma controls. Subjects who exhibited significant decrease of FEV1 by aspirin provocation were identified as AERD subjects. Logistic and regression analyses were performed to investigate the association between DPCR1 polymorphisms and the risk of AERD as well as FEV1 decline. RESULTS: Initial analysis revealed significant association of rs2517449 with AERD, with a P value of .03 via a recessive model; however, the association signal disappeared after multiple testing corrections. In addition, rs2517449 and rs2240804 also showed association signals with decline of FEV1 after aspirin provocation (P = .007 and .03, respectively, in a recessive model). After testing for multiple comparisons, only the association signal from rs2517449 was retained (Pcorr = .04), while other polymorphisms showed no associations with the risk of AERD and FEV1 decline. CONCLUSIONS: Our results show that polymorphisms in DPCR1 are not associated with the risk of AERD.

Summary Aspirin-exacerbated respiratory disease (AERD) is prevalent in about 10% of asthma patients and is characterized by a severe decline in forced expiratory volume in 1-s (FEV1), an important phenotype for total lung capacity, upon ingestion of aspirin. The general transcription factor IIH subunit 4 (GTF2H4) is positioned at 6p21.33, a part of the major histocompatibility complex (MHC) class II region that contains a number of genes that play an important role in the immune system. In addition, genetic variants in another general transcription factor IIH gene have revealed significant association with lung disease. To investigate whether GTF2H4 genetic variants could be a causative factor for AERD development and FEV1 decline by aspirin provocation, five common single-nucleotide polymorphisms (SNPs) were genotyped in 93 patients with AERD and 96 aspirin-tolerant asthma (ATA) controls. As a result, when adjusted for age, gender, smoking status and atopy as covariates, the rs1264307 variant and two haplotypes showed nominal signals in the association with AERD (P = 0.02–0.04), but the significances disappeared after corrections for multiple testing (corrected P > 0.05). In further multiple regression analysis, no genetic variants of GTF2H4 showed significant associations with FEV1 decline by aspirin provocation in asthmatics (P > 0.05). Despite the need for replications in larger cohorts, our preliminary findings suggest that GTF2H4 variants may not be associated with susceptibility to AERD and obstructive symptoms in asthmatics.

Purpose The human WD repeat-containing protein 46 (WDR46; also known as C6orf11), located at the disease-relevant centromere side of the class II major histocompatibility complex region, is hypothesized to be associated with risk of aspirin-exacerbated respiratory disease (AERD) as well as a decline in forced expiratory volume in the first second (FEV1), an important diagnostic marker of asthma. Methods To investigate the association between WDR46 and AERD, five single-nucleotide polymorphisms (SNPs) were genotyped in 93 AERD cases and 96 aspirin-tolerant asthma controls of Korean ethnicity. Three major haplotypes were inferred from pairwise comparison of the SNPs, and one was included in the association analysis. Differences in the frequency distribution of WDR46 SNPs and haplotype were analyzed using logistic and regression models via various modes of genetic inheritance. Results Depending on the genetic model, the logistic and regression analyses revealed significant associations between rs463260, rs446735, rs455567, rs469064, and WDR46_ht2 and the risk of AERD (P=0.007-0.04, Pcorr=0.01-0.04) and FEV1 decline after aspirin provocation (P=0.006-0.03, Pcorr=0.01-0.03). Furthermore, functional analysis in silico showed that the G>A allele of rs463260 located in the 5' untranslated region potentially matched a nucleotide sequence within an upstream open reading frame of WDR46. Conclusions These findings show for the first time that WDR46 is an important genetic marker of aspirin-induced airway inflammation and may be useful for formulating new disease-management strategies.

Background and objective: One of the clinical manifestations of refractory asthma (RA) in a certain group of patients is persistent airway obstruction (PAO), despite treatment with high doses of inhaled and/or systemic corticosteroids. Airway neutrophilic inflammation is frequently observed in RA; however, the relationship between neutrophilic inflammation and PAO has not been evaluated in this group of patients. The aim of this study was to compare the clinical parameters and patterns of inflammatory cells between patients with or without PAO due to RA, and to identify the factors associated with PAO. Methods: Seventy-seven patients with RA were recruited from a cohort of 2298 asthmatic patients. Sputum differential cell counts were performed at initial presentation. Clinical and physiological parameters were compared between patients with (n = 19) or without PAO (n = 58). Results: The group with PAO had a longer duration of asthma and a higher frequency of near-fatal asthma than the non-PAO group, although higher doses of inhaled corticosteroids were used in the PAO group (P = 0.037). Neutrophilic inflammation was predominant in the group with PAO, whereas eosinophilic inflammation was predominant in the non-PAO group (P = 0.003). When both groups were stratified according to smoking status, the non-smoking PAO group had the longest duration of asthma, with early onset of asthma (P