Association of Late Radiographic Assessment of Lung Edema Score with Clinical Outcome in Patients with Influenza-Associated Acute Respiratory Distress Syndrome.

Background: Influenza virus infection leads to acute pulmonary injury and acute respiratory distress syndrome (ARDS). The Radiographic Assessment of Lung Edema (RALE) score has been proposed as a reliable tool for the evaluation of the opacity of chest X-rays (CXRs). This study aimed to examine the RALE scores and outcomes in patients with influenza-associated ARDS. Methods: Patients who were newly diagnosed with influenza-associated ARDS from December 2015 to March 2016 were enrolled. Two independent reviewers scored the CXRs obtained on the day of ICU admission and on days 2 and 7 after intensive care unit (ICU) admission. Results: During the study, 47 patients had influenza-associated ARDS. Five died within 7 days of ICU admission. Of the remaining 42, non-survivors (N = 12) had higher Sequential Organ Failure Assessment scores (SOFA) at ICU admission and higher day 7 RALE scores than survivors (N = 30). The day 7 RALE score independently related to late in-hospital mortality (aOR = 1.121, 95% CI: 1.014-1.240, p = 0.025). Conclusions: The RALE score for the evaluation of opacity on CXRs is a highly reproducible tool. Moreover, RALE score on day 7 was an independent predictor of late in-hospital mortality in patients with influenza-associated ARDS.

NLRP3 Inflammasome Activates Endothelial-to-Mesenchymal Transition via Focal Adhesion Kinase Pathway in Bleomycin-Induced Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis has poor clinical outcomes despite antifibrotic treatment. The nucleotide-binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) inflammasome and endothelial-to-mesenchymal transition (EndoMT) were shown to be involved in the pathogenesis of pulmonary fibrosis. However, the detailed mechanism is unknown. Our study aimed to investigate the role of the NLRP3 inflammasome in the regulation of EndoMT in pulmonary fibrosis. The inhibition of the NLRP3 inflammasome via a caspase-1 inhibitor, Ac-YVAD-cmk (YVAD), was intraperitoneally administered to male C57BL/6 mice (8-12 weeks old) one hour before bleomycin intratracheal injection (1.5 U/kg). Immunohistochemical staining, Masson's trichrome staining, enzyme-linked immunosorbent assay, immunofluorescence, and Western blotting were used to assess the activity of the NLRP3 inflammasome and EndoMT in lung samples from mice. Human pulmonary microvascular endothelial cells (HPMECs) were used as a model of EndoMT in vitro with YVAD and bleomycin stimulation. We observed the activation of the NLRP3 inflammasome and EndoMT (decreased vascular endothelial cadherin with increased alpha-smooth muscle actin and vimentin) in the lung samples after bleomycin. However, inhibition of the NLRP3 inflammasome significantly reduces EndoMT via inhibiting focal adhesion kinase (FAK). In vitro studies also confirmed these findings. In conclusion, NLRP3 inflammasome inhibition could reduce lung inflammation and fibrosis via the regulation of EndoMT by the FAK pathway.

DUSP8 induces TGF-ß-stimulated IL-9 transcription and Th9-mediated allergic inflammation by promoting nuclear export of Pur-α.

Dual-specificity phosphatase 8 (DUSP8) is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T cell-specific Dusp8 conditional KO (T-Dusp8 cKO) mice, mass spectrometry analysis, ChIP-Seq, and immune analysis, we found that DUSP8 interacted with Pur-α, stimulated interleukin-9 (IL-9) gene expression, and promoted Th9 differentiation. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-α upon TGF-ß signaling, leading to the nuclear export of Pur-α and subsequent IL-9 transcriptional activation. Furthermore, Il-9 mRNA levels were induced in Pur-α-deficient T cells. In addition, T-Dusp8-cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in the allergic asthma model. Reduction of Il-9 mRNA levels in T cells and allergic responses of T-Dusp8-cKO mice was reversed by Pur-α knockout. Remarkably, DUSP8 protein levels and the DUSP8-Pur-α interaction were indeed increased in the cytoplasm of T cells from people with asthma and patients with atopic dermatitis. Collectively, DUSP8 induces TGF-ß-stimulated IL-9 transcription and Th9-induced allergic responses by inhibiting the nuclear translocation of the transcriptional repressor Pur-α. DUSP8 may be a T-cell biomarker and therapeutic target for asthma and atopic dermatitis.

The main e-cigarette component vegetable glycerin enhances neutrophil migration and fibrosis in endotoxin-induced lung injury via p38 MAPK activation.

We investigated the effects of vegetable glycerin (VG), a main e-cigarette constituent, on endotoxin-induced acute lung injury (ALI). Mice received intratracheal administration of 30% VG in phosphate buffered saline (PBS) vehicle or only PBS (control) for 4 days. On Day 5, mice received an intratracheal instillation of lipopolysaccharide (LPS) (LPS group and VG + LPS group) or PBS (VG group and control group). Lung histopathology, expression of chemokine receptors, and regulatory signaling were analyzed 24 h after the Day 5 treatment. VG significantly increased ALI-associated histopathological and fibrotic changes in both the VG group and LPS-induced ALI mice (VG + LPS group). Immunohistochemistry (IHC) and western blot analyses revealed that VG administration resulted in upregulation of neutrophil markers [lymphocyte antigen 6 complex locus G6D (Ly6G) and myeloperoxidase (MPO)] as well as upregulation of the expression of transforming growth factor-ß (TGF-ß), a central mediator of fibrogenesis, in the lungs of both VG and VG + LPS groups. VG enhanced the expression of adhesion molecules [very late antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1)] and increased activation of p38 mitogen-activated protein kinase (p38 MAPK) to prompt neutrophil recruitment in the lungs of mice with ALI. Intraperitoneal administration of a p38 inhibitor attenuated these histopathological changes significantly as well as VG-induced upregulation in expression of Ly6G, MPO, VLA-4, VCAM-1, TGF-ß, and collagen-1 in mice with ALI. In conclusion, VG enhances neutrophil chemotaxis and fibrosis and it amplifies the inflammatory response associated with LPS-induced ALI in the lungs via enhancement of p38 MAPK activity.

Nintedanib Inhibits Endothelial Mesenchymal Transition in Bleomycin-Induced Pulmonary Fibrosis via Focal Adhesion Kinase Activity Reduction.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD). Pulmonary fibroblasts play an important role in the development of IPF. Emerging evidence indicates that pulmonary endothelial cells could be the source of pulmonary fibroblasts through endothelial mesenchymal transition (EndoMT), which contributes to pulmonary fibrosis. EndoMT is a complex process in which endothelial cells lose their expression of endothelial markers and give rise to the characteristics of mesenchymal cells, including morphological fibroblast-like change and the expression of mesenchymal markers, which result in cardiac, renal, and dermal fibroses. Furthermore, EndoMT inhibition attenuates pulmonary fibrosis. Herein, we demonstrate that nintedanib, a tyrosine kinase receptor inhibitor, ameliorated murine bleomycin (BLM)-induced pulmonary fibrosis and suppressed the in vivo and in vitro models of EndoMT. We demonstrated that the activity of focal adhesion kinase (FAK), a key EndoMT regulator, increased in murine lung tissues and human pulmonary microvascular endothelial cells after BLM stimulation. Nintedanib treatment inhibited BLM-induced FAK activation and thus suppressed both in vivo and in vitro BLM-induced EndoMT. Importantly, we found that the VEGF/FAK signaling pathway was involved in nintedanib regulating EndoMT. These novel findings help us understand the mechanism and signaling pathway of EndoMT to further develop more efficacious drugs for IPF treatment.

Prognostic factors for advanced lung cancer patients with do-not-intubate order in intensive care unit: a retrospective study.

BACKGROUND: The survival of patients with lung cancer undergoing critical care has improved. An increasing number of patients with lung cancer have signed a predefined do-not-intubate (DNI) order before admission to the intensive care unit (ICU). These patients may still be transferred to the ICU and even receive non-invasive ventilation (NIV) support. However, there is still a lack of prognostic predictions in this cohort. Whether patients will benefit from ICU care remains unclear. METHODS: We retrospectively collected data from patients with advanced lung cancer who had signed a DNI order before ICU admission in a tertiary medical center between 2014 and 2016. The clinical characteristics and survival outcomes were discussed. RESULTS: A total of 140 patients (median age, 73 years; 62.1% were male) were included, had been diagnosed with stage III or IV non-small cell lung cancer (NSCLC) (AJCC 7th edition), and signed a DNI. Most patients received NIV during ICU stay. The median APACHE II score was 14 (standard error [SE], ± 0.66) and the mean PaO2/FiO2 ratio (P/F ratio) was 174.2 (SD, ± 104 mmHg). The APACHE II score was significantly lower in 28-day survivors (survivor: 12 (± 0.98) vs. non-survivor: 15 (± 0.83); p = 0.019). The P/F ratio of the survivors was higher than that of non-survivors (survivors: 209.6 ± 111.4 vs. non-survivors: 157.9 ± 96.7; p = 0.006). Patients with a P/F ratio ≥ 150 had better 28-day survival (p = 0.005). By combining P/F ratio ≥ 150 and APACHE II score < 16, those with high P/F ratios and low APACHE II scores during ICU admission had a notable 28-day survival compared with the rest (p < 0.001). These prognostic factors could also be applied to 90-day survival (p = 0.003). The prediction model was significant for those with driver mutations in 90-day survival (p = 0.021). CONCLUSIONS: P/F ratio ≥ 150 and APACHE II score < 16 were significant prognostic factors for critically ill patients with lung cancer and DNI. This prediction could be applied to 90-day survival in patients with driver mutations. These findings are informative for clinical practice and decision-making.

Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified, Randomized, Controlled Trial.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation represents a distinct phenotype that might respond to treatment with inhaled corticosteroids. Fractional exhaled nitric oxide (FENO) might predict eosinophilic inflammation and guide treatment option. We hypothesized that COPD patients with different baseline levels of FENO might have differentiated response to treatment with salmeterol/fluticasone (SFC) or tiotropium (TIO). METHODS: This open-label, randomized-controlled trial enrolled treatment-naïve COPD patients who were stratified into high- (≥23.5ppb) and low-FENO group, followed by 12-week treatment with SFC or TIO. A linear mixed model with repeated measures was applied to analyze the changes in FENO (primary outcome), COPD assessment test (CAT) score, FEV1, and parameters in induced sputum and blood after treatment. RESULTS: 134 patients were divided into 4 subgroups: low-FENO/SFC (n=30), low-FENO/TIO (n=29), high-FENO/SFC (n=37), and high-FENO/TIO (n=38). At baseline, FENO 23.5ppb clearly differentiated between eosinophilic and non-eosinophilic inflammation groups based on the eosinophils in induced sputum and blood. FENO significantly correlated with sputum and blood eosinophils at baseline. High-FENO/SFC (vs. high-FENO/TIO) subgroup had significant reduction in FENO and sputum inflammation profiles (including eosinophils, macrophages, matrix metalloproteinase-9, and interlukin-8) after treatment. These differences were not replicated between low-FENO/SFC and low-FENO/TIO subgroups. The improvement in CAT and FEV1 after treatment was indiscriminate between SFC and TIO in the low- and high-FENO groups. CONCLUSION: High baseline FENO can serve as an indicator of eosinophilic airway inflammation in COPD patients who may respond favorably to treatment with inhaled corticosteroids/long-acting ß2-agonists. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02546349.

Influencing factors for tracheostomy in patients with acute traumatic C3-C5 spinal cord injury and acute respiratory failure.

BACKGROUND: Patients with traumatic spinal cord injury (SCI) at C3-C5 have a wide range of tracheostomy rates (27%-75%), and the influencing factors for tracheostomy remain unclear. We conducted a retrospective case-control study to identify the influencing factors for tracheostomy in this subset of patient population. METHODS: A total of 101 acute traumatic C3-C5 SCI patients with acute respiratory failure requiring translaryngeal intubation and invasive mechanical ventilation (IMV) for more than 48 hours were identified and divided into the no tracheostomy (No-TCO, n = 59) and tracheostomy group (TCO, n = 42) groups. Clinical data were retrospectively reviewed and analyzed. RESULTS: Compared with the No-TCO patients, the TCO patients had a higher proportion of C3 level injury, lower Glasgow Coma Scale (GCS), and lower blood hemoglobin levels at admission. During the first weaning attempt, the TCO patients had lower levels of maximal inspiratory pressure, maximal expiratory pressure, and minute ventilation but had a higher level of rapid shallow breathing index (RSBI). The TCO patients had longer durations of IMV, ICU stay, and hospitalization compared with the No-TCO patients. Moreover, due to prolonged IMV, the TCO patients had a higher incidence of complications, including ventilator-associated pneumonia, bacteremia, urinary tract infection, and acute kidney injury compared with the No-TCO patients. Multivariate logistic regression analysis revealed that low GCS at admission and high initial RSBI were independent risk factors for tracheostomy. Importantly, a combination of these two influencing factors synergistically increased the odds ratio for tracheostomy. CONCLUSION: Low GCS at admission and high initial RSBI are two independent influencing factors that synergistically impact tracheostomy in our patients. These findings are helpful for making the decision of performing tracheostomy in this subset of patient population.

Consensus statement and recommendations on the treatment of COVID-19: 2021 update.

Many treatments including antiviral and non-antiviral drugs, and critical care are considered for the management of coronavirus disease 2019 (COVID-19). Practice recommendations need to be updated and graded according to the critical evaluation of rapidly emerging literature. In June 2020, Research Center for Epidemic Prevention-National Yang Ming Chiao Tung University formed a task group comprising infectious disease clinicians, pulmonologists, and intensivists with varied areas of expertise. The steering committee prioritized questions and outcomes. The keywords for the searches were COVID-19 and prone position, extracorporeal membrane oxygenation (ECMO), noninvasive positive pressure ventilation (NIPPV), remdesivir, lopinavir, hydroxychloroquine/chloroquine (HCQ/CQ), azithromycin, corticosteroid, tocilizumab, convalescent plasma therapy, and intravenous immunoglobin (IVIG). A systematic review of peer-reviewed literature was performed by the consensus panel. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used in assessing the certainty of evidence and making recommendations. The effects of COVID-19 treatments on mortality and clinical improvement were summarized in 11 tables, and GRADE was presented to define the strength and quality of evidence for recommendation. The consensus recommended that prone position implanted in COVID-19 patients with hypoxic respiratory failure (IIC), careful selection for the support of ECMO (IIB), NIPPV being feasible but a risk of staff contamination (IIC), remdesivir generally administered in mild-to-moderate COVID-19 patients (IA), the use of dexamethasone in critically ill COVID-19 patients (IA), and the use of tociliziumab in hospitalized severe/critical COVID-19 patient with elevated markers of systemic inflammation (IA). The consensus recommended against the use of lopinavir/ritonavir (IB), HCQ/CQ (IA), azithromycin (IA), convalescent plasma therapy (IA), and IVIG (IA). The inception of the consensus and task group has provided much-needed evidence of the efficacy and safety of various therapies for the management of COVID-19 patients, and make a description about the benefits and harms for most treatments.

Nintedanib Regulates GRK2 and CXCR2 to Reduce Neutrophil Recruitment in Endotoxin-Induced Lung Injury.

The role of nintedanib, a multiple tyrosine kinase inhibitor, in the treatment of sepsis-induced acute lung injury (ALI) remains unclear. Lipopolysaccharide (LPS), also known as endotoxin, has been used to induce ALI. The goal of this study was to assess the effect of nintedanib in attenuating the histopathological changes of LPS-induced ALI. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h and 10 min before intratracheal endotoxin instillation. Lung histopathological characteristics, adhesion molecule expression, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed after 24 h. We found that nintedanib significantly reduced histopathological changes and neutrophil recruitment in LPS-induced ALI. The number of neutrophils in bronchoalveolar lavage fluid (BALF) was reduced in nintedanib-treated relative to untreated mice with ALI. Nintedanib mediated the downregulation of the chemotactic response to LPS by reducing the expression of adhesion molecules and the phosphorylated p38:total p38 mitogen-activated protein kinase (MAPK) ratio in the lungs of mice with ALI. Nintedanib also reduced the expression of lymphocyte antigen 6 complex locus G6D (Ly6G) and very late antigen 4 (VLA-4) in BALF neutrophils and mediated the downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in mice with LPS-induced ALI. Nintedanib improved the histopathological changes of LPS-induced ALI by reducing neutrophil chemotaxis. These effects were mediated by the inhibition of adhesion molecules via the activation of GRK2 and the inhibition of p38 MAPK and CXCR2.

Induced Pluripotent Stem Cell-Derived Conditioned Medium Promotes Endogenous Leukemia Inhibitory Factor to Attenuate Endotoxin-Induced Acute Lung Injury.

The conditioned medium of induced pluripotent stem cells (iPSC-CM) can attenuate neutrophil recruitment and endothelial leakage of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Therefore, we investigated the mechanisms by which iPSC-CM regulate the interaction between neutrophils and the endothelium in ALI. Murine iPSCs (miPSCs) were delivered intravenously to male C57BL/6 mice (8-12 weeks old) 4 h after intratracheal LPS injection. A miPSC-derived conditioned medium (miPSC-CM) was delivered intravenously to mice after intratracheal LPS injection. DMSO-induced HL-60 cells (D-HL-60, neutrophil-like cells) and human umbilical vein endothelial cells (HUVECs) were used as in vitro models to assess the interaction of neutrophils and endothelial cells. miPSC-CM diminished the histopathological changes in the lungs and the neutrophil count in bronchoalveolar lavage fluids of ALI mice. miPSC-CM attenuated the expression of adhesion molecules in the lungs of ALI mice. Human iPSC conditioned medium (hiPSC-CM) reduced the expression of adhesion molecules in a HUVEC and D-HL-60 co-culture after LPS stimulation, which decreased the transendothelial migration (TEM) of D-HL-60. A human angiogenesis factors protein array revealed that leukemia inhibitory factor (LIF) was not detected in the absence of D-HL-60 and hiPSC-CM groups. hiPSC-CM significantly promoted the production of endogenous LIF in in vitro models. Administration of an anti-LIF antibody not only reversed the effect of iPSC-CM in ALI mice, but also blocked the effect of iPSC-CM on neutrophils TEM in in vitro models. However, a controlled IgG had no such effect. Our study demonstrated that iPSC-CM promoted endogenous LIF to inhibit neutrophils TEM and attenuate the severity of sepsis-induced ALI.

Angiopoietin-2 outperforms other endothelial biomarkers associated with severe acute kidney injury in patients with severe sepsis and respiratory failure.

BACKGROUND: Endothelial dysfunction and injury is a major pathophysiologic feature of sepsis. Sepsis is also the most frequent cause of acute kidney injury (AKI) in critically ill patients. Though most studies of AKI in sepsis have focused on tubular epithelial injury, the role of endothelial dysfunction and injury is less well studied. The goal of this study was first to investigate whether endothelial dysfunction and injury biomarkers were associated with severe AKI in sepsis patients. The second goal was to determine the best performing biomarker for severe AKI and whether this biomarker was associated with severe AKI across different etiologies of sepsis and clinical outcomes. METHODS: We studied adults with severe sepsis and acute respiratory failure (ARF) enrolled in the prospective observational Validating Acute Lung Injury markers for Diagnosis (VALID) study. Plasma endothelial dysfunction and injury biomarkers, including angiopoietin-2, soluble vascular endothelial cadherin (sVE-cadherin), endocan and syndecan-1, were measured at study enrollment. Primary analysis focused on the association between endothelial biomarker levels with severe AKI (defined as Kidney Disease: Improving Global Outcomes [KDIGO] AKI stage 2 or 3), other organ dysfunctions (defined by Brussels organ failure scores), and comparison of pulmonary versus non-pulmonary sepsis. RESULTS: Among 228 sepsis patients enrolled, 141 developed severe AKI. Plasma levels of angiopoietin-2, endocan, sVE-cadherin, and syndecan-1 were significantly higher in sepsis patients with severe AKI compared to those without severe AKI. Among four endothelial biomarkers, only angiopoietin-2 was independently associated with severe AKI (odds ratio 6.07 per log increase, 95% CI 2.34-15.78, p < 0.001). Plasma angiopoietin-2 levels by quartile were significantly higher in sepsis patients with hepatic, coagulation, and circulatory failure. Plasma angiopoietin-2 levels were also significantly higher in patients with non-pulmonary sepsis compared to subjects with pulmonary sepsis. CONCLUSION: Among four biomarkers of endothelial dysfunction and injury, angiopoietin-2 had the most robust independent association with development of severe AKI in patients with severe sepsis and ARF. Plasma angiopoietin-2 levels were also associated with other organ dysfunctions, non-pulmonary sepsis, and death. These findings highlight the importance of early endothelial dysfunction and injury in the pathogenesis of sepsis-induced AKI.

Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis.

Neutrophils are involved in the alveolitis of idiopathic pulmonary fibrosis (IPF). However, their pathogenic mechanisms are still poorly understood. Nintedanib has antifibrotic and anti-inflammatory activity in IPF. This study aimed to investigate the regulatory mechanism of nintedanib on neutrophil chemotaxis in bleomycin (BLM)-induced pulmonary fibrosis. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h after a bleomycin intratracheal injection (1.5 U/kg). Lung histopathological findings, the expression of cytokines, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed. The effect of nintedanib was also investigated in a mouse model with adoptive neutrophil transfer in vivo. Nintedanib significantly decreased the histopathological changes and neutrophil recruitment in BLM-induced pulmonary fibrosis. Nintedanib mediated a downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and very late antigen 4 (VLA-4) expression, as well as an upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in BLM-induced pulmonary fibrosis. Nintedanib also decreased the activation of endothelial cells by the decreased expression of vascular cell adhesion molecule 1 (VCAM-1). The effect of nintedanib on regulating neutrophil chemotaxis was also confirmed by a mouse model with adoptive neutrophil transfer in vivo. In conclusion, nintedanib reduces neutrophil chemotaxis and endothelial cell activation to regulate the severity of BLM-induced pulmonary fibrosis. These effects are associated with an enhancement of GRK2 activity and a reduction in CXCR2 and VLA-4 expression on neutrophils and a decrease in VCAM-1 expression on endothelial cells.

Comparisons of clinical features and outcomes between Elizabethkingia meningoseptica and other glucose non-fermenting Gram-negative bacilli bacteremia in adult ICU patients.

BACKGROUND: Clinical information of Elizabethkingia meningoseptica (EM) bacteremia in intensive care unit (ICU) patients is limited and the impact on outcomes uncertain. The aim of this study was to investigate the clinical features and impact of EM bacteremia compared to other glucose non-fermenting Gram-negative bacilli (GNF-GNB) bacteremia in ICU patients. METHODS: This retrospective cohort study enrolled 70 patients who developed GNF-GNB bacteremia after ICU admission, including 19 cases of EM bacteremia (19/70, 27.1%). The main outcome measure was in-hospital mortality. RESULTS: The patients with EM bacteremia had a lower rate of appropriate antibiotic therapy (15.8% vs. 62.7%, p < 0.001) and a longer time to appropriate antibiotic therapy (76.8 ± 46.4 vs. 35.1 ± 38.7 h, p < 0.001), but with a less severity in acute physiology and chronic health evaluation (APACHE) II score and shock status (p < 0.05) at the onset of bacteremia, compared to those with non-EM bacteremia. The in-hospital mortality between those with EM bacteremia and non-EM bacteremia was similar (63.2% vs. 51.0%, p = 0.363). However, primary bacteremia was more frequently noted in EM compared with non-EM group (57.9% vs. 25.5%, p = 0.011), and odds ratio 4.294 (95% confidence interval 1.292-14.277, p = 0.017) in multivariate regression analysis. CONCLUSION: Among the patients with GNF-GNB bacteremia, the numbers of the cases with primary bacteremia and inappropriate therapy were significantly more in EM group than those in non-EM group.

Antibody blockade of Dectin-2 suppresses house dust mite-induced Th2 cytokine production in dendritic cell- and monocyte-depleted peripheral blood mononuclear cell co-cultures from asthma patients.

BACKGROUND: Dectin-2, which is a C-type lectin, interacts with the house dust mite (HDM) Dermatophagoides pteronyssinus allergen. This study aimed to investigate whether Dectin-2 blockade by antagonistic monoclonal antibodies (MoAbs) attenuates HDM-induced allergic responses. METHODS: Two anti-Dectin-2 MoAbs were generated and validated for specific binding to Dectin-2 Fc fusion protein (Dectin-2.Fc) and inhibition of Dectin-2.Fc/HDM interaction. Patients with asthma exhibiting high titers of anti-D. pteronyssinus IgE were enrolled. Peripheral blood mononuclear cells with depleted CD14+ monocytes were obtained from these patients and co-cultured with autologous monocyte-derived conventional dendritic cells in the presence of D. pteronyssinus or its group 2 allergens (Der p 2). Interleukin (IL)-5 and IL-13 levels in the culture supernatants were determined using ELISA in the presence or absence of anti-Dectin-2 MoAbs. RESULTS: Two MoAbs, 6A4G7 and 17A1D10, showed specific binding to recombinant Dectin-2.Fc and inhibited HDM binding to Dectin-2.Fc. Both anti-Dectin-2 MoAbs inhibited IL-5 and IL-13 production in co-cultures with Der p 2 stimulation in a dose-dependent manner. 6A4G7 and 17A1D10 (3 µg/mL) significantly inhibited Der p 2-induced (3 µg/mL) IL-5 production by 69.7 and 86.4% and IL-13 production by 84.0 and 81.4%, respectively. Moreover, this inhibitory effect of the two MoAbs remained significant in the presence of D. pteronyssinus. CONCLUSIONS: Anti-Dectin-2 MoAbs significantly inhibited HDM-induced allergic responses in vitro and therefore have the potential to become therapeutic agents in mite-induced allergic diseases.

Haptoglobin-2 variant increases susceptibility to acute respiratory distress syndrome during sepsis.

Acute respiratory distress syndrome (ARDS) is an inflammatory lung disorder that frequently complicates critical illness and commonly occurs in sepsis. Although numerous clinical and environmental risk factors exist, not all patients with risk factors develop ARDS, raising the possibility of genetic underpinnings for ARDS susceptibility. We have previously reported that circulating cell-free hemoglobin (CFH) is elevated during sepsis, and higher levels predict worse outcomes. Excess CFH is rapidly scavenged by haptoglobin (Hp). A common HP genetic variant, HP2, is unique to humans and is common in many populations worldwide. HP2 haptoglobin has reduced ability to inhibit CFH-mediated inflammation and oxidative stress compared with the alternative HP1. We hypothesized that HP2 increases ARDS susceptibility during sepsis when plasma CFH levels are elevated. In a murine model of sepsis with elevated CFH, transgenic mice homozygous for Hp2 had increased lung inflammation, pulmonary vascular permeability, lung apoptosis, and mortality compared with wild-type mice. We then tested the clinical relevance of our findings in 496 septic critically ill adults, finding that HP2 increased ARDS susceptibility after controlling for clinical risk factors and plasma CFH. These observations identify HP2 as a potentially novel genetic ARDS risk factor during sepsis and may have important implications in the study and treatment of ARDS.

Post-intensive care unit respiratory failure in older patients liberated from intensive care unit and ventilator: The predictive value of the National Early Warning Score on intensive care unit discharge.

AIM: The older adult population is continuously growing worldwide and there is increasing use of medical recourse in older patients, especially for those requiring intensive care unit (ICU) care and mechanical ventilation (MV). The present study aimed to investigate the burden and predictors of post-ICU respiratory failure in older ICU patients weaned from MV. METHODS: In the present retrospective study, older ICU patients aged ≥60 years, who were successfully weaned from MV and discharged to the general ward from the ICU of Taipei Veterans General Hospital, Taipei, Taiwan, in 2011, were included. Biomarkers on ICU discharge, as well as the National Early Warning Score (NEWS) were recorded and calculated. The outcome measure was post-ICU respiratory failure before day 14 (PIRF-14) requiring reinstitution of MV. Logistical regression was used to assess the predictors for PIRF-14. RESULTS: Of 272 patients included, 23 (8.5%) developed PIRF-14. The post-ICU in-hospital mortality rates were 47.8% and 6.8% in patients with and without PIRF-14 (adjusted OR 12.597, 95% CI 4.368-36.331). In a multivariate analysis, the levels of NEWS and hemoglobin on ICU discharge were independent predictors for PIRF-14 (adjusted OR 1.273, 95% CI 1.076-1.507 and 0.645, 95% CI 0.474-0.879). In particular, patients with a NEWS of ≥10 and subsequent PIRF-14 had a 15-fold increased risk of mortality as compared with those without both factors (adjusted OR 15.418, 95% CI 4.344-54.720). CONCLUSIONS: PIRF-14 is associated with high mortality in older ICU patients, and NEWS is a significant predictor for PIRF-14, which could be used to early identify patients at risk of post-ICU respiratory failure in the specific population. Geriatr Gerontol Int 2019; 19: 317-322.

Vascular endothelial cadherin shedding is more severe in sepsis patients with severe acute kidney injury.

BACKGROUND: Vascular endothelial cadherin (VE-cadherin) is a membrane protein that is the major component of adherens junctions between endothelial cells. It is crucial for regulating vascular integrity, endothelial permeability, and angiogenesis. During inflammatory processes, VE-cadherin is shed into circulation (sVE-cadherin). Plasma sVE-cadherin is elevated in sepsis, malignancy, autoimmune diseases, and coronary atherosclerosis. However, the relationship between specific organ failures, especially severe acute kidney injury (AKI) defined by requirement for renal replacement therapy (AKI-RRT), and plasma sVE-cadherin levels in severe sepsis has not been well studied. METHODS: The present study is a prospective study of critically ill adults with sepsis and acute respiratory failure (age ≥ 18 years) enrolled in the Validating Acute Lung Injury markers for Diagnosis (VALID) study. Plasma sVE-cadherin was measured at study enrollment. Primary analysis focused on the association between sVE-cadherin levels and the development of AKI, AKI-RRT, other organ dysfunction as defined by Brussels organ failure scores, pulmonary versus non-pulmonary sepsis, acute respiratory distress syndrome (ARDS), and in-hospital mortality. RESULTS: Of 228 severe sepsis patients included, 80 (35%) developed AKI-RRT. Plasma sVE-cadherin levels at enrollment were significantly higher in patients with AKI-RRT compared with patients without AKI-RRT (p = 0.003). Plasma sVE-cadherin levels by quartile were significantly higher in severe sepsis patients with acute kidney injury stage 3 (p = 0.044) as defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Patients with greater than 2 organ failures had higher plasma sVE-cadherin levels than patients with 2 or fewer organ failures (p < 0.001). In a multivariable analysis, plasma sVE-cadherin was independently associated with AKI-RRT (odds ratio 6.44 per log increase in plasma sVE-cadherin, 95% CI 1.126-36.847, p = 0.036). Plasma sVE-cadherin levels were significantly higher in patients with non-pulmonary sepsis compared to pulmonary sepsis (p < 0.001). CONCLUSION: Shedding of sVE-cadherin is associated with severe acute kidney injury and with more severe organ dysfunction in patients with sepsis, suggesting that breakdown of endothelial adherens junctions may contribute to the pathogenesis of organ dysfunction in sepsis. Further studies of sVE-cadherin as a biomarker of disease severity in clinical sepsis are needed to better elucidate the role of VE-cadherin shedding in sepsis-induced severe organ dysfunction.

Prognostic factors of noninvasive mechanical ventilation in lung cancer patients with acute respiratory failure.

INTRODUCTION: Few studies have reported outcomes of lung cancer patients with acute respiratory failure (RF) using noninvasive positive pressure ventilation (NIPPV). The aim of this study was to investigate the prognostic factors in these patients. MATERIALS AND METHODS: This retrospective observational study included all hospitalized lung cancer patients who received NIPPV for acute RF. It was conducted at a tertiary medical center in Taiwan from 2005 to 2010. The primary outcome was all cause mortality at 28 days after the initiation of NIPPV. Secondary outcomes included all-cause in-hospital mortality, weaning from NIPPV, intubation rate, tracheostomy rate, duration of NIPPV, hospital stay and intensive care unit stay. RESULTS: The all-cause mortality rate at day 28 of the enrolled 58 patients was 39.66%. The 90-day and 1-year mortality rates were 63.79% and 86.21%, respectively. NIPPV as the first line therapy for RF had higher 28-day mortality rate than it used for post-extubation RF (57.6% versus 16.0%, p<0.05). Independent predictors of mortality at 28 days were progressive disease or newly diagnosed lung cancer (OR 14.02 95% CI 1.03-191.59, p = 0.048), combined with other organ failure (OR 18.07 95% CI 1.87-172.7, p = 0.012), and NIPPV as the first line therapy for RF (OR 35.37 95% CI 3.30-378.68, p = 0.003). CONCLUSION: Lung cancer patients using NIPPV with progressive or newly diagnosed cancer disease, combined with other organ failure, or NIPPV as the first line therapy for respiratory failure have a poor outcome.