Clinical outcomes of difficult-to-wean patients with ventilator dependency at intensive care unit discharge.

BACKGROUND: Ventilator-dependent patients in the intensive care unit (ICU) who are difficult to wean from invasive mechanical ventilation (IMV) have been increasing in number. However, data on the clinical outcomes of difficult-to-wean patients are lacking. We aimed to evaluate clinical outcomes in patients discharged from the ICU with tracheostomy and ventilator dependency. METHODS: We retrospectively investigated clinical course and survival in patients requiring home mechanical ventilation (HMV) with a tracheostomy and difficulty weaning from IMV during medical ICU admission from September 2013 through August 2016 at Severance Hospital, Yonsei University, Seoul, Korea. RESULTS: Of 84 difficult-to-wean patients who were started on HMV in the medical ICU, 72 survived, were discharged from the ICU, and were included in this analysis. HMV was initiated after a median of 23 days of IMV, and the successful weaning rate was 46% (n=33). In-hospital mortality rate was significantly lower in the successfully weaned group than the unsuccessfully weaned group (0% vs. 23.1%, respectively; P=0.010). Weaning rates were similar according to primary diagnosis, but high body mass index (BMI), low Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score at ICU admission, and absence of neuromuscular disease were associated with weaning success. After a median follow-up of 4.6 months (range, 1-27 months) for survivors, 3-month (n=64) and 6-month (n=59) survival rates were 82.5% and 72.2%, respectively. Survival rates were higher in the successfully weaned group than the unsuccessfully weaned group at 3 months (96.4% vs. 69.0%; P=0.017) and 6 months (84.0% vs. 62.1%; P=0.136) following ICU discharge. CONCLUSIONS: In summary, 46% of patients who started HMV were successfully weaned from the ventilator in general wards. High BMI, low APACHE II score, and absence of neuromuscular disease were factors associated with weaning success.

Prognostic impact of the ratio of the main pulmonary artery to that of the aorta on chest computed tomography in patients with idiopathic pulmonary fibrosis.

BACKGROUND: In many clinical disorders, there is a relationship between the ratio of the diameter of the main pulmonary artery (mPA) to that of the aorta (Ao) on chest computed tomography (CT). The aim of this study was to determine if the mPA/Ao ratio at diagnosis is associated with the clinical characteristics and outcomes in patients with idiopathic pulmonary fibrosis (IPF). METHODS: We retrospectively reviewed the diameters of the pulmonary artery and aorta on chest CT, clinical characteristics, and results of other examinations in 303 patients at the time of initial diagnosis of IPF at our tertiary care center between 2011 and 2015. The primary outcomes were death and lung transplantation. The patients were followed up until June 2017. RESULTS: One hundred and eight patients (35.6%) died and 58 (19.1%) underwent lung transplantation during follow-up. The mean mPA and Ao diameters were 28.3 mm and 34.0 mm, respectively, and the mean mPA/Ao ratio was 0.84. Thirty-one patients (10.2%) had an mPA/Ao ratio > 1.0 and 182 (60.1%) had an mPA/Ao ratio > 0.8. Patients with an mPA/Ao ratio > 0.8 had a lower DLco value than those with an mPA/Ao ratio ≤ 0.8. In Kaplan-Meier analysis, patients with an mPA/Ao ratio > 1.0 or > 0.8 had worse outcomes than those with an mPA/Ao ratio ≤ 1.0 and ≤ 0.8, respectively. CONCLUSIONS: A higher mPA/Ao ratio based on 1.0 and 0.8 is associated with unfavorable prognosis in patients with IPF.

Risk factors and clinical characteristics of Pneumocystis jirovecii pneumonia in lung cancer.

Solid malignancies are associated with the development of Pneumocystis jirovecii pneumonia (PJP). This study aimed to evaluate the risk factors for PJP among patients with lung cancer. This retrospective case-control study compared patients who had lung cancer with PJP (n = 112) or without PJP (n = 336) matched according to age, sex, histopathology, and stage. PJP definition was based on (i) positive PCR or direct immunofluorescence results for pneumocystis, (ii) clinical symptoms and radiological abnormalities that were consistent with a pneumonic process, and (iii) received targeted PJP treatment. The development of PJP was associated with radiotherapy (RTx), concurrent chemoradiotherapy (CCRTx), lymphopenia, and prolonged high-dose steroid therapy (20 mg of prednisolone equivalent per day for ≥3 weeks). Multivariate analysis revealed independent associations with prolonged high-dose steroid therapy (odds ratio [OR]: 1.96, 95% confidence interval [CI]: 1.06-3.63; p = 0.032) and CCRTx (OR: 2.09, 95% CI: 1.27-3.43; p = 0.004). Steroid use was frequently related to RTx pneumonitis or esophagitis (29 patients, 43.3%). Prolonged high-dose steroid therapy and CCRTx were risk factors for PJP development among patients with lung cancer. As these patients had a poor prognosis, clinicians should consider PJP prophylaxis for high-risk patients with lung cancer.

The Effects of Retinoic Acid and MAPK Inhibitors on Phosphorylation of Smad2/3 Induced by Transforming Growth Factor ß1.

BACKGROUND: Transforming growth factor ß (TGF-ß), retinoic acid (RA), p38 mitogen-activated protein kinase (MAPK), and MEK signaling play critical roles in cell differentiation, proliferation, and apoptosis. We investigated the effect of RA and the role of these signaling molecules on the phosphorylation of Smad2/3 (p-Smad2/3) induced by TGF-ß1. METHODS: A549 epithelial cells and CCD-11Lu fibroblasts were incubated and stimulated with or without all-trans RA (ATRA) and TGF-ß1 and with MAPK or MEK inhibitors. The levels of p-Smad2/3 were analyzed by western blotting. For animal models, we studied three experimental mouse groups: control, bleomycin, and bleomycin+ATRA group. Changes in histopathology, lung injury score, and levels of TGF-ß1 and Smad3 were evaluated at 1 and 3 weeks. RESULTS: When A549 cells were pre-stimulated with TGF-ß1 prior to RA treatment, RA completely inhibited the p-Smad2/3. However, when A549 cells were pre-treated with RA prior to TGF-ß1 stimulation, RA did not completely suppress the p-Smad2/3. When A549 cells were pre-treated with MAPK inhibitor, TGF-ß1 failed to phosphorylate Smad2/3. In fibroblasts, p38 MAPK inhibitor suppressed TGF-ß1-induced p-Smad2. In a bleomycin-induced lung injury mouse model, RA decreased the expression of TGF-ß1 and Smad3 at 1 and 3 weeks. CONCLUSION: RA had inhibitory effects on the phosphorylation of Smad induced by TGF-ß1 in vitro, and RA also decreased the expression of TGF-ß1 at 1 and 3 weeks in vivo. Furthermore, pre-treatment with a MAPK inhibitor showed a preventative effect on TGF-ß1/Smad phosphorylation in epithelial cells. As a result, a combination of RA and MAPK inhibitors may suppress the TGF-ß1-induced lung injury and fibrosis.

Usefulness of the preoperative prognostic nutritional index score as a predictor of the outcomes of lung transplantation: A single-institution experience.

BACKGROUND & AIMS: There is increasing evidence that preoperative nutritional status is a predictor of disease severity and mortality after lung transplantation (LTX). This study aimed to evaluate preoperative nutritional assessment as a predictor of LTX outcomes. METHODS: We included 132 patients who underwent single or double LTX at Severance Hospital, Yonsei University, between October 2010 and April 2016. The Prognostic Nutritional Index (PNI) scores were calculated as follows: 10 × serum albumin value (g/dL) + 0.005 × peripheral lymphocyte count (/mm3). The optimal cut-off PNI score for the prediction of postoperative overall survival was set at 41.15 using receiver operating characteristics analysis. The efficacies of PNI and other clinical factors in predicting LTX outcomes were determined using univariate and multivariate Cox proportional hazard analyses. RESULTS: Patients with PNI <41.15 (PNI-low group) were older, had higher preoperative C-reactive protein levels, and had lower nutritional status scores than did those in the PNI-high group (PNI ≥ 41.15). Based on Kaplan-Meier analysis, the overall survival rate was significantly better in the PNI-high group (78.3%) than in the PNI-low group (28.6%) (P < 0.001). Age, sex, body mass index, use of preoperative mechanical ventilation, C-reactive protein level, neutrophil-to-lymphocyte ratio, and PNI score were independent prognostic factors. Survival was significantly higher in the PNI-high group (hazard ratio: 0.220; P < 0.001) than in the PNI-low group, and incidence of complications ≥ grade IV was higher in the PNI-low group than in the PNI-high group (P < 0.001). Multivariate regression analysis showed that preoperative PNI score was significantly associated with postoperative survival, even after adjusting for other confounding factors. CONCLUSIONS: Our findings suggest that PNI is a useful prognostic marker for the identification of high-risk lung transplant recipients. Preoperative nutritional assessment using PNI may provide useful information for reducing postoperative morbidity and mortality.

Permissive fluid volume in adult patients undergoing extracorporeal membrane oxygenation treatment.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a cardiorespiratory support technique for patients with circulatory or pulmonary failure. Frequently, large-volume fluid resuscitation is needed to ensure sufficient extracorporeal blood flow in patients initiating ECMO. However, excessive overhydration is known to increase mortality in critically ill patients. Therefore, in order to define a tolerant volume range in patients undergoing ECMO treatment, the association between cumulative fluid balance (CFB) and outcome was evaluated in patients undergoing ECMO. METHODS: This retrospective multicenter cohort study was conducted with 723 patients who underwent ECMO in three tertiary care hospitals between 2005 and 2016. CFB was calculated as total fluid input minus total fluid output during the first 3 days from ECMO initiation. The patients were divided into groups that initiated ECMO owing to cardiovascular disease (CVD)-related or non-cardiovascular disease (non-CVD)-related causes. The primary endpoint was mortality within 90 days after ECMO commencement. RESULTS: Totals of 406 and 317 patients were included in the CVD and non-CVD groups, respectively. In the CVD group, the mean age was 58.4 ± 17.7 years, and 68.2% were male. The mean age was 55.7 ± 15.7 years, and 65.3% were male in the non-CVD group. The median CFB values were 64.7 and 53.5 ml/kg in the CVD and non-CVD groups, respectively. Multivariable analysis using Cox proportional hazards models revealed a significantly increased risk of 90-day mortality in patients with higher CFB values in both the CVD and non-CVD groups. However, the risks were elevated only in the two CFB quartile groups with the largest CFB amounts. Cubic spline models showed that mortality risk began to increase significantly when CFB was 82.3 ml/kg in the CVD group. In patients with respiratory diseases, the mortality risk increase was significant for those with CFB levels above 189.6 ml/kg. CONCLUSIONS: Mortality risk did not increase until a certain level of fluid overload was reached in patients undergoing ECMO. Adequate fluid resuscitation is critical to improving outcomes in these patients.

The C-Reactive Protein/Albumin Ratio as a Predictor of Mortality in Critically Ill Patients.

The C-reactive protein (CRP)/albumin ratio has recently emerged as a marker for poor prognosis or mortality across various patient groups. This study aimed to identify the association between CRP/albumin ratio and 28-day mortality and predict the accuracy of CRP/albumin ratio for 28-day mortality in medical intensive care unit (ICU) patients. This was a retrospective cohort study of 875 patients. We evaluated the prognostic value of CRP/albumin ratio to predict mortality at 28 days after ICU admission, using Cox proportional hazard model and Kaplan-Meier survival analysis. The 28-day mortality was 28.0%. In the univariate analysis, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (p < 0.001), CRP level (p = 0.045), albumin level (p < 0.001), and CRP/albumin ratio (p = 0.032) were related to 28-day mortality. The area under the receiver operating characteristic (ROC) curve (the area under the ROC curves (AUC)) of CRP/albumin ratio was higher than that of CRP for mortality (0.594 vs. 0.567, p < 0.001). The cut-off point for CRP/albumin ratio for mortality was 34.3. On Cox proportional-hazard regression analysis, APACHE II score (hazards ratio (HR) = 1.05, 95% confidence interval (CI) = 1.04⁻1.07, p < 0.001) and CRP/albumin ratio (HR = 1.68, 95% CI = 1.27⁻2.21, p < 0.001 for high CRP/albumin ratio) were independent predictors of 28-day mortality. Higher CRP/albumin ratio was associated with increased mortality in critically ill patients.

Factors Associated with Lung Function Recovery at the First Year after Lung Transplantation.

PURPOSE: Post-operative pulmonary function is an important prognostic factor for lung transplantation. The purpose of this study was to identify factors affecting recovery of forced expiratory volume in 1 second (FEV1) at the first year after lung transplantation. MATERIALS AND METHODS: We retrospectively reviewed the medical records of lung transplantation patients between October 2012 and June 2016. Patients who survived for longer than one year and who underwent pulmonary function test at the first year of lung transplantation were enrolled. Patients were divided into two groups according to whether they recovered to a normal range of FEV1 (FEV1 ≥80% of predicted value vs. <80%). We compared the two groups and analyzed factors associated with lung function recovery. RESULTS: Fifty-eight patients were enrolled in this study: 28 patients (48%) recovered to a FEV1 ≥80% of the predicted value, whereas 30 patients (52%) did not. Younger recipients [odds ratio (OR), 0.92; 95% confidence interval (CI), 0.87-0.98; p=0.010], longer duration of mechanical ventilator use after surgery (OR, 1.14; 95% CI, 1.03-1.26; p=0.015), and high-grade primary graft dysfunction (OR, 8.08; 95% CI, 1.67-39.18; p=0.009) were identified as independent risk factors associated with a lack of full recovery of lung function at 1 year after lung transplantation. CONCLUSION: Immediate postoperative status may be associated with recovery of lung function after lung transplantation.

Pneumocystis jirovecii pneumonia (PCP) PCR-negative conversion predicts prognosis of HIV-negative patients with PCP and acute respiratory failure.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is often fatal in human immunodeficiency (HIV)-negative patients and typically presents with respiratory insufficiency. Predicting treatment failure is challenging. This study aimed to identify prognostic factors and examine PCP polymerase chain reaction (PCR)-negative conversion in non-HIV PCP patients with respiratory failure. METHOD: We retrospectively enrolled 81 non-HIV patients diagnosed with and treated for PCP with respiratory failure in the intensive care unit at a tertiary hospital over a 3-year period. PCP was diagnosed via nested PCR-mediated detection of Pneumocystis jirovecii in induced sputum samples, endotracheal aspirates, and bronchoalveolar lavage fluids. PCP PCR was performed weekly to check for negative conversion. RESULTS: The overall survival rate was 35.8%. Seventy-four patients (91.3%) required mechanical ventilation, and 6 (7.4%) required high-flow nasal oxygen treatment. The PCP PCR-negative conversion rate was 70.5% (survivors, 97%; non-survivors, 63.5%); the median time to conversion was 10 (7.0-14.0) days. On univariate analysis, the APACHE II score (p < 0.001), renal failure requiring renal replacement therapy (p = 0.04), PCP PCR-negative conversion (p = 0.003), and the PaO2/FiO2 ratio (first 24 hours) (p < 0.001) significantly correlated with mortality. On multivariate analysis, PCP PCR-negative conversion (hazard ratio, 0.433; 95% confidence interval, 0.203-0.928; p = 0.031) and the PaO2/FiO2 ratio (first 24 hours) (hazard ratio, 0.988; 95% confidence interval, 0.983-0.993; p < 0.001) independently predicted prognosis. CONCLUSIONS: Determination of PCP PCR-negative conversion and PaO2/FiO2 ratios may help physicians predict treatment failure and mortality in non-HIV PCP patients with respiratory failure.

Relationship between depression and lung function in the general population in Korea: a retrospective cross-sectional study.

Background: Lung function and depression are closely related to many chronic lung diseases. However, few studies have evaluated this association in the general population. In this study, we evaluated the relationship between lung function and depression in the general population in Korea. Participants and methods: Data from the Ansung-Ansan cohort, a community-based cohort in Korea, were used to analyze the relationships between depression and lung function parameters. A total of 3,321 men and women aged 40-69 years were enrolled. Spirometry data included the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio. Depression was defined as a score of ≥16 by the Beck Depression Inventory (BDI). A propensity score analysis was conducted with the aim of reducing the bias of the retrospective study. Results: The overall prevalence of depression in the study population was 13.1% (434/3,321 participants). Depression was significantly more prevalent in women than in men (P<0.001) and in never smokers than in ever smokers (P<0.001). The group with depression was older (P<0.001) and had a lower average body mass index (BMI) (P=0.015) than the group without depression. The FEV1 (P<0.001), FVC (P<0.001), and FEV1/FVC ratio (P=0.022) were significantly lower in the group with depression than in the group without depression. After adjusting for age, sex, BMI, and smoking status, the mean FEV1 was lower in the group with a high BDI score than in the group with a low BDI score (P=0.044). Using multiple linear regression analysis and adjusting for covariates, no statistically significant relationship between lung function and the BDI score was found. However, the BDI score and FEV1 were inversely related in subjects older than 50 years (P=0.023). Conclusion: Depression is associated with decreased lung function in the general population, especially in adults older than 50 years.

Comparison of short-term outcomes for connective tissue disease-related interstitial lung disease and idiopathic pulmonary fibrosis after lung transplantation.

BACKGROUND: Pulmonary involvement is common in connective tissue disease (CTD), and respiratory failure is a major cause of morbidity and mortality in CTD-related interstitial lung disease (CTD-ILD). Lung transplantation is thus important for these patients. However, survival, outcomes, and management of these patients after transplantation have been debated. The aim of this study was to evaluate the outcomes for CTD-ILD compared to those for idiopathic pulmonary fibrosis (IPF) after lung transplantation. METHODS: We performed a single-centre retrospective study of 62 patients with CTD-ILD or IPF who underwent lung transplantation at a tertiary hospital in South Korea between October 2012 and October 2016. RESULTS: Patients with CTD-ILD (n=15) were younger (46 vs. 60 years, P=0.001) and were less likely to be male (33.3% vs. 76.6%, P=0.004) than were patients with IPF (n=47). The 1-year cumulative survival rate was 80.0% for CTD-ILD and 59.6% for IPF (log-rank P=0.394). There was no difference in the cumulative survival rate (log-rank P=0.613) of age- and sex-matched patients with CTD-ILD (n=15) and IPF (n=15). The incidence of primary graft dysfunction was similar (P=0.154), and 2 (18.2%) patients developed possible CTD flare. CONCLUSIONS: Patients with CTD-ILD and those with IPF who underwent lung transplantation had similar survival rates.

Prognostic value of pre-transplant mean pulmonary arterial pressure in lung transplant recipients: a single-institution experience.

BACKGROUND: Currently, lung transplantation (LTX) is considered to be a curative treatment option in patients with end-stage lung disease. Although pulmonary hypertension (PH), confirmed by cardiac catheterization, is a prognostic factor in patients undergoing LTX, the prognostic value of PH in Asian lung transplant recipients remains uncertain. In this study, we aimed to determine whether PH before LTX may serve as a prognostic factor for survival in Asian patients. METHODS: The medical records of 50 patients [male, 27; female, 23; mean age, 51.0 (41.0-60.0) years], who received preoperative right heart catheterization (RHC) and echocardiography before single or double LTX at Severance Hospital between January 2010 and December 2014, were reviewed. The relationship between 1-year survival after LTX and PH [mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest] was evaluated. RESULTS: The mean right ventricular systolic pressure and mPAP were 48.5 (22.8) and 30.0 (24.0-40.0) mmHg. Of the 50 patients, 17 (34.0%) died within a year after LTX. The 1-year survival rate among patients with mPAP ≥25 mmHg (58.8%) was lower than the survival rate among patients with mPAP <25 mmHg (87.5%). Pre-transplantation mPAP of ≥25 mmHg was associated with post-transplantation survival [hazard ratio (HR), 4.832; 95% confidence interval (CI), 1.080-21.608, P=0.039]. The presence of preoperative PH was also associated with an increased risk of postoperative complications. CONCLUSIONS: Confirmation of PH via preoperative cardiac catheterization was associated with the prognosis of the patient after LTX. Clinicians should consider the necessity for early transplantation surgery before the mPAP reaches ≥25 mmHg.

Prevalence of pre-transplant anti-HLA antibodies and their impact on outcomes in lung transplant recipients.

BACKGROUND: Previous studies have suggested that antibodies against human leukocyte antigen (HLA) are associated with worse outcomes in lung transplantation. However, little is known about the factors associated with outcomes following lung transplantation in Asia. Accordingly, we investigated the prevalence of anti-HLA antibodies in recipients before transplantation and assessed their impact on outcomes in Korea. METHODS: A single-center retrospective study was conducted. The study included 76 patients who received a lung transplant at a tertiary hospital in South Korea between January 2010 and March 2015. RESULTS: Nine patients (11.8%) had class I and/or class II panel-reactive antibodies greater than 50%. Twelve patients (15.8%) had anti-HLA antibodies with a low mean fluorescence intensity (MFI, 1000-3000), 7 (9.2%) with a moderate MFI (3000-5000), and 12 (15.8%) with a high MFI (> 5000). Ten patients (13.2%) had suspected donor-specific antibodies (DSA), and 60% (6/10) of these patients had antibodies with a high MFI. In an analysis of outcomes, high-grade (≥2) primary graft dysfunction (PGD) was more frequent in patients with anti-HLA antibodies with moderate-to-high MFI values than in patients with low MFI values (39.4% vs. 14.0%, p = 0.011). Of 20 patients who survived longer than 2 years and evaluated for pBOS after transplant, potential bronchiolitis obliterans syndrome (pBOS) or BOS was more frequent in patients with anti-HLA antibodies with moderate-to-high MFI than in patients with low MFI, although this difference was not statistically significant (50.0% vs. 14.3%, p = 0.131). CONCLUSIONS: The prevalence of anti-HLA antibodies with high MFI was not high in Korea. However, the MFI was relatively high in patients with DSA. Anti-HLA antibodies with moderate-to-high MFI values were related to high-grade PGD. Therefore, recipients with high MFI before lung transplantation should be considered for desensitization and close monitoring.

Usefulness of Bronchoscopic Rebiopsy of Non-Small Cell Lung Cancer with Acquired Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor.

Background: Approximately 50% of non-small cell lung cancer (NSCLC) patients with acquired resistance to EGFR-TKI harbor the EGFR mutation T790M. The recent development and wide use of third-generation EGFR-TKIs targeting T790M-mutant NSCLCs have increased the importance of rebiopsy after EGFR-TKI failure. We aimed to investigate the advantages of flexible bronchoscopy as a rebiopsy method and the prevalence of and factors affecting the T790M mutation after EGFR-TKI failure. Methods: We investigated 139 patients who had undergone bronchoscopic rebiopsy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) between Sep 2014 and Jul 2016. Results: Among the 139 patients, bronchoscopic rebiopsy yielded successful pathological diagnoses in 102 (73.4%). Among them, 41 patients with EGFR-mutant lung adenocarcinoma and EGFR-TKI progression were selected for an investigation of T790M mutation prevalence at rebiopsy. The initial EGFR mutations were exon 19 del (56.1%), L858R or L861Q (34.1%), and others (9.8%). The most common rebiopsy method was transbronchial lung biopsy (41.5%), followed by EBUS-TBNA (26.8%) and endobronchial biopsy (19.5%). The median interval to T790M emergence was the longest among cases with exon 19 deletion (14.1 months), followed by exon 21 L858R or L861Q (11.3 months) and other rare EGFR mutations (2.9 months). The T790M mutation was identified in 18 (43.9%) patients, and exon 19 del was the most significant factor affecting T790M mutation development (hazard ratio: 6.875, P = 0.014). Conclusions: Bronchoscopy was more useful than other rebiopsy approaches. The T790M emergence rate was highest in cases with exon 19 deletion, likely as a consequence of long-term EGFR-TKI exposure.

Inhibition of insulin-like growth factor receptor-1 reduces necroptosis-related markers and attenuates LPS-induced lung injury in mice.

Insulin-like growth factor-1 (IGF-1) levels are known to increase in the bronchoalveolar lavage fluid (BALF) of patients with acute respiratory distress syndrome. Herein, we investigated the role of IGF-1 in lipopolysaccharide (LPS)-induced lung injury. In LPS-treated cells, expressions of receptor-interacting protein 3 (RIP3) and phosphorylated mixed lineage kinase domain-like protein (MLKL) were decreased in IGF-1 receptor small interfering RNA (siRNA)-treated cells compared to control cells. The levels of pro-inflammatory cytokines including interleukin (IL)-1ß, IL-6, IL-10, tumour necrosis factor-α, and macrophage inflammatory protein 2/C-X-C motif chemokine ligand 2 in the supernatant were significantly reduced in IGF-1 receptor siRNA-treated cells compared to control cells. In LPS-induced murine lung injury model, total cell counts, polymorphonuclear leukocytes counts, and pro-inflammatory cytokine levels in the BALF were significantly lower and histologically detected lung injury was less common in the group treated with IGF-1 receptor monoclonal antibody compared to the non-treated group. On western blotting, RIP3 and phosphorylated MLKL expressions were relatively decreased in the IGF-1 receptor monoclonal antibody group compared to the non-treated group. IGF-1 may be associated with RIP3-mediated necroptosis in vitro, while blocking of the IGF-1 pathway may reduce LPS-induced lung injuries in vivo.

Changes in cytokine responses to TB antigens ESAT-6, CFP-10 and TB 7.7 and inflammatory markers in peripheral blood during therapy.

Multiple cytokines and inflammatory markers control TB infection. We aimed to investigate the changes in multiple cytokines and inflammatory markers in active TB patients following anti-TB drug therapy. Twenty-nine patients with active TB were recruited prospectively between December 2010 and July 2017. Blood samples were collected before (T0), after 2 months (T2), and at the end of anti-TB treatment (Tend). We measured the levels of Interferon (IFN)-γ, interleukin (IL)-2, IL-12, IL-10, IL-13 and tumor necrosis factor (TNF)-α in supernatants collected from the QuantiFERON-TB Gold In-Tube assay (QFT-GIT), as well as the WBC, neutrophil, platelet count and neutrophil to lymphocyte ratio (NLR) in whole blood. Compared with baseline levels, WBC, neutrophil, and platelet counts were significantly lower following treatment. In addition, the NLR after treatment significantly decreased compared with baseline, whereas the IL-2/IFN-γ ratio increased after treatment. In conclusion, the levels of IL-2/IFN-γ ratios in the supernatant and the NLR might be useful biomarkers to evaluate the effectiveness of drug therapy in active TB patients.

Feasibility of Immediate in-Intensive Care Unit Pulmonary Rehabilitation after Lung Transplantation: A Single Center Experience.

BACKGROUND: Physical function may influence perioperative outcomes of lung transplantation. We investigated the feasibility of a pulmonary rehabilitation program initiated in the immediate postoperative period at an intensive care unit (ICU) for patients who underwent lung transplantation. METHODS: We retrospectively evaluated 22 patients who received pulmonary rehabilitation initiated in the ICU within 2 weeks after lung transplantation at our institution from March 2015 to February 2016. Levels of physical function were graded at the start of pulmonary rehabilitation and then weekly throughout rehabilitation according to criteria from our institutional pulmonary rehabilitation program: grade 1, bedside (G1); grade 2, dangling (G2); grade 3, standing (G3); and grade IV, gait (G4). RESULTS: The median age of patients was 53 years (range, 25 to 73 years). Fourteen patients (64%) were males. The initial level of physical function was G1 in nine patients, G2 in seven patients, G3 in four patients, and G4 in two patients. Patients started pulmonary rehabilitation at a median of 7.5 days (range, 1 to 29 days) after lung transplantation. We did not observe any rehabilitation-related complications during follow-up. The final level of physical function was G1 in six patients, G3 in two patients, and G4 in 14 patients. Fourteen of the 22 patients were able to walk with or without assistance, and 13 of them maintained G4 until discharge; the eight remaining patients never achieved G4. CONCLUSIONS: Our results suggest the feasibility of early pulmonary rehabilitation initiated in the ICU within a few days after lung transplantation.

Erythropoietin-Producing Hepatoma Receptor Tyrosine Kinase A2 Modulation Associates with Protective Effect of Prone Position in Ventilator-induced Lung Injury.

The erythropoietin-producing hepatoma (Eph) receptor tyrosine kinase A2 (EphA2) and its ligand, ephrinA1, play a pivotal role in inflammation and tissue injury by modulating the epithelial and endothelial barrier integrity. Therefore, EphA2 receptor may be a potential therapeutic target for modulating ventilator-induced lung injury (VILI). To support this hypothesis, here, we analyzed EphA2/ephrinA1 signaling in the process of VILI and determined the role of EphA2/ephrinA1 signaling in the protective mechanism of prone positioning in a VILI model. Wild-type mice were ventilated with high (24 ml/kg; positive end-expiratory pressure, 0 cm; 5 h) tidal volume in a supine or prone position. Anti-EphA2 receptor antibody or IgG was administered to the supine position group. Injury was assessed by analyzing the BAL fluid, lung injury scoring, and transmission electron microscopy. Lung lysates were evaluated using cytokine/chemokine ELISA and Western blotting of EphA2, ephrinA1, PI3Kγ, Akt, NF-κB, and P70S6 kinase. EphA2/ephrinA1 expression was higher in the supine high tidal volume group than in the control group, but it did not increase upon prone positioning or anti-EphA2 receptor antibody treatment. EphA2 antagonism reduced the extent of VILI and downregulated the expression of PI3Kγ, Akt, NF-κB, and P70S6 kinase. These findings demonstrate that EphA2/ephrinA1 signaling is involved in the molecular mechanism of VILI and that modulation of EphA2/ehprinA1 signaling by prone position or EphA2 antagonism may be associated with the lung-protective effect. Our data provide evidence for EphA2/ehprinA1 as a promising therapeutic target for modulating VILI.

Risk Factor Analysis for Intraoperative Extracorporeal Membrane Oxygenation Weaning Failure After Lung Transplantation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been widely used for hemodynamic support during lung transplantation (LTx). We evaluated the risk factors associated with failure of weaning from ECMO in the operating room during LTx. METHODS: We retrospectively reviewed 74 consecutive patients who had undergone LTx from March 2013 to February 2016. Patients who underwent single LTx, multiorgan transplantation, and LTx for pulmonary hypertension were excluded. All operations were performed under ECMO support. Clinical data of donor, recipient, and intraoperative parameters were reviewed. RESULTS: Younger donors (40 ± 11 versus 45 ± 10 years, p = 0.047), donors with shorter mechanical ventilation (125 ± 74 versus 160 ± 80 minutes, p = 0.066) and donors with higher Pao2 at 100% oxygen (455 ± 87 mm Hg versus 399 ± 88 mm Hg, p = 0.008) were significantly different in the ECMO weaning group than in the weaning failure group. Of the recipients, the number of patients who had preoperative ECMO support were significantly fewer in the successful weaning group than in the weaning failure group (11.9% versus 34.4%, p = 0.061). The operation time was significantly shorter in the weaning group than in the weaning failure group (392 ± 66 versus 435 ± 82 minutes, p = 0.014). In multivariate logistic regression analysis, the independent risk factors for ECMO weaning were donor age (odds ratio 1.101, 95% confidence interval: 1.030 to 1.177, p = 0.005), donor Pao2 (odds ratio 0.992, 95% confidence interval: 0.984 to 0.999, p = 0.034), and operation time (odds ratio 1.010, 95% confidence interval: 1.000 to 1.019, p = 0.043). CONCLUSIONS: Our results showed that younger donor age, high Pao2, and shorter operation time were factors related to successful ECMO weaning in the operating room after LTx.

Clinical implications of the plasma EphA2 receptor level in critically ill patients with septic shock.

The Eph/ephrin receptor ligand system is known to play a role in inflammation induced by infection, injury, and inflammatory diseases. The present study aimed to evaluate plasma EphA2 receptor levels in critically ill patients with sepsis. This study was a prospective cohort study evaluating samples and clinical data from the medical intensive care unit (MICU) of a 2000-bed university tertiary referral hospital in South Korea. Positive correlations of the plasma EphA2 receptor level with the acute physiology and chronic health evaluation (APACHE) II score and the sequential organ failure assessment (SOFA) score were observed. The area under the curve (AUC) for the plasma EphA2 receptor level on a receiver operating characteristic curve was 0.690 (95% confidence interval [CI], 0.608-0.764); the AUCs for the APACHE II score and SOFA scores were 0.659 (95% CI, 0.576-0.736) and 0.745 (95% CI, 0.666-0.814), respectively. A Cox proportional hazard model identified an association between an increased plasma EphA2 receptor level (>51.5 pg mL-1) and increased risk of 28-day mortality in the MICU (hazard ratio = 3.22, 95% CI, 1.709-6.049). An increased plasma EphA2 receptor level was associated with sepsis severity and 28-day mortality among sepsis patients.