The importance of high total body water/fat free mass ratio and serial changes in body composition for predicting hospital mortality in patients with severe pneumonia: a prospective cohort study.

PURPOSE: This study aimed to investigate the impact of body composition variables on hospital mortality compared to other predictive factors among patients with severe pneumonia. Additionally, we aimed to monitor the dynamic changes in body composition variables over the course on days 1, 3, and 8 after intensive care unit (ICU) admission for each patient. METHODS: We conducted a prospective study, enrolling patients with severe pneumonia admitted to the medical intensive care unit at Kaohsiung Chang Gung Memorial Hospital from February 2020 to April 2022. We collected clinical data from all patients and assessed their body composition at 1, 3, and 8 days post-ICU admission. On day 1, we analyzed clinical and body composition variables to predict in-hospital mortality. RESULTS: Multivariate analysis identified the Modified Nutrition Risk in the Critically Ill (mNUTRIC) score and the ratio of total body water to fat-free mass (TBW/FFM) as independent factors associated with in-hospital mortality in severe pneumonia patients. Receiver operating characteristic analysis determined that the TBW/FFM ratio was the most reliable predictive parameter of in-hospital mortality, with a cutoff value of 0.74. General linear regression with repeated measures analysis showed that hospital non-survivors displayed notable fluctuations in body water, fat, and muscle variables over the course of days 1, 3, and 8 after ICU admission. CONCLUSIONS: The mNUTRIC score and TBW/FFM ratio emerged as independent factors for predicting hospital mortality, with the TBW/FFM ratio demonstrating the highest reliability as a predictive parameter.

E-cadherin expression in the tumor microenvironment of advanced epidermal growth factor receptor-mutant lung adenocarcinoma and the association with prognosis.

BACKGROUND: The expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TILs), E-cadherin, and vimentin in lung cancer tumor microenvironment is known to impact patient survival or response to therapy. The expression of these biomarkers may also differ between primary lung tumors and brain metastatic tumors. In this study, we investigated the interaction between these biomarkers in lung tumors with or without concomitant brain metastasis and the interaction with paired brain metastatic tumors. METHODS: The study included 48 patients with stage IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. Sixteen of the forty-eight patients were diagnosed with brain metastasis, while the remaining thirty-two were not. All sixteen patients with brain metastasis had brain tumors. The expression of PD-L1, TILs (CD8+ T lymphocytes and FOXP3+ regulatory T lymphocytes), E-cadherin, and vimentin were evaluated using immunohistochemical (IHC) staining. RESULTS: Patients with brain metastasis exhibited a higher frequency of exon 19 deletion and uncommon EGFR mutations, a higher lung tumor vimentin score, worse progression-free survival (PFS), and overall survival (OS) than patients without brain metastasis. IHC staining showed no difference between paired lung and brain tumors. Patients with low PD-L1 expression had better PFS and OS. After multivariate analysis, higher body mass index, the presence of brain metastasis, bone metastasis, and uncommon EGFR mutations were correlated with worse PFS, while the presence of brain metastasis and high lung tumor E-cadherin score was associated with worse OS. CONCLUSIONS: In patients with stage IV EGFR-mutant lung adenocarcinoma, high E-cadherin expression in the lung tumor might be associated with worse OS. Vimentin expression in the lung tumor was positively related to the risk of brain metastasis.

Association of Hypernatremia with Immune Profiles and Clinical Outcomes in Adult Intensive Care Unit Patients with Sepsis.

Both hypernatremia and an abnormal immune response may increase hospital mortality in patients with sepsis. This study examined the association of hypernatremia with abnormal immune response and mortality in 520 adult patients with sepsis in an intensive care unit (ICU). We compared the mortality and ex vivo lipopolysaccharide (LPS)-induced inflammatory response differences among patients with hyponatremia, eunatremia, and hypernatremia, as well as between patients with acquired hypernatremia on ICU day 3 and those with sustained eunatremia over first three ICU days. Compared with eunatremia or hyponatremia, hypernatremia led to higher 7 day, 14 day, 28 day, and hospital mortality rates (p = 0.030, 0.009, 0.010, and 0.033, respectively). Compared with sustained eunatremia, acquired hypernatremia led to higher 7, 14, and 28 day mortality rates (p = 0.019, 0.042, and 0.028, respectively). The acquired hypernatremia group nonsignificantly trended toward increased hospital mortality (p = 0.056). Day 1 granulocyte colony-stimulating factor (G-CSF) and tumor necrosis factor (TNF) α levels were relatively low in patients with hypernatremia (p = 0.020 and 0.010, respectively) but relatively high in patients with acquired hypernatremia (p = 0.049 and 0.009, respectively). Thus, in ICU-admitted septic patients, hypernatremia on admission and in ICU-acquired hypernatremia were both associated with higher mortality. The higher mortality in patients with hypernatremia on admission was possibly related to the downregulation of G-CSF and TNF-α secretion after endotoxin stimulation. Compared to sustained eunatremia, acquired hypernatremia showed immunoparalysis at first and then hyperinflammation on day 3.

The Survival of Septic Patients with Compensated Liver Cirrhosis Is Not Inferior to That of Septic Patients without Liver Cirrhosis: A Propensity Score Matching Analysis.

Background: We aimed to determine whether septic patients with liver cirrhosis (LC) had worse survival than septic patients without liver cirrhosis (WLC). We also investigated the survival of septic patients with compensated liver cirrhosis (CLC) and decompensated liver cirrhosis (DLC). Methods: This study enrolled 776 consecutive adult patients with sepsis admitted to the medical intensive care units of a tertiary referral hospital. Clinical factors and laboratory data were collected for analysis. Propensity scoring was also used for the control of selection bias. The variables included in the propensity model were age, sex, presence of diabetes mellitus, hypertension, cardiovascular accident, chronic kidney disease, malignancy, APCHE II (Acute Physiology and Chronic Health Evaluation) score, hemoglobin, and platelet data on the day when sepsis was confirmed. Seven-day, ICU, and hospital mortality were analyzed after correcting for these confounding factors. Results: Of the 776 septic patients, 64 (8.2%) septic patients presented with LC. Patients were divided into two groups­LC (n = 64) and WLC (n = 712)­which presented different rates of hospital mortality (LC: 62.5% vs. WLC: 41.0%, p = 0.001). We further separated septic patients with LC into two groups: patients with CLC (n = 24) and those with DLC (n = 40). After propensity score matching, the survival of septic patients with CLC (63.6%) was not inferior to patients WLC (54.5%) (p = 0.411). Patients with DLC had more hospital mortality, even after matching (p < 0.05). The Quick SOFA (qSOFA) score, SOFA score, and sub-SOFA score were also comparable between groups. SOFA scores were not significantly different between the CLC and WLC groups after matching. Poor SOFA scores were observed in the DLC group on days 3 and 7 after matching (p < 0.05). Conclusions: Septic patients with LC had higher mortality compared to patients WLC before matching. However, after propensity score matching, the survival of septic patients with CLC was non-inferior to patients WLC.

Dynamic monitoring of kidney injury status over 3 days in the intensive care unit as a sepsis phenotype associated with hospital mortality and hyperinflammation.

BACKGROUND: Sepsis-associated acute kidney injury (AKI) often worsens with the deterioration of a patient's condition. Therefore, we hypothesized that monitoring AKI dynamically from day 1 to day 3 was potential to predict hospital mortality. Specifically, we explored whether monitoring AKI dynamically in the intensive care unit (ICU) could be a sepsis phenotype predictive of mortality. A new classification was established based on the change in the AKI stage from admission day 1 and day 3. We compared the hospital mortality, cytokines, and immune response pattern between each group. METHODS: We retrospectively enrolled 523 patients with sepsis, and we calculated the AKI stages on day 1 and day 3 admission to ICUs. Among these 523 people, 388 of them were assigned to normal, improved, and deteriorated groups according to the changes in the AKI stages. 263 of which did not develop AKI on day 1 and day 3 (normal group). The AKI stage improved in 68 patients (improved group) and worsened in 57 (deteriorated group). We compared the mortality rates between the groups, and identified the relationship between the dynamic AKI status, immune response patterns, and cytokine levels. RESULTS: The hospital mortality rate in the deteriorated group was higher than that in the non-deteriorated group (combination of normal and improved group) (p = 0.004). Additionally, according to the Kaplan-Meier analysis, the non-deteriorated group had a distinct hospital survival curve (p = 0.004). Furthermore, both the overexpression of tumor necrosis factor-α and decreased monocyte expression of human leukocyte antigen-DR were present in the deteriorated group. CONCLUSIONS: The deteriorated group was associated with a higher hospital mortality rate, potentially resulting from an abnormal inflammatory response. Worsening AKI in the first 3 days of ICU admission may be a sepsis phenotype predictive of hospital mortality.

Body Mass Index, Weight Loss, and Mortality Risk in Advanced-Stage Non-Small Cell Lung Cancer Patients: A Focus on EGFR Mutation.

Body mass index (BMI) influences the prognosis of patients with non-small cell lung cancer (NSCLC), including both early-stage and late-stage NSCLC patients that are undergoing chemotherapies. However, earlier research on the relationship between BMI and survival in patients taking epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) yielded contradictory results. These publications either had a limited number of patients or were getting TKIs in various lines of therapy, which might explain why the outcomes were contradictory. As a result, we undertook retrospective study to examine the effect of BMI on survival outcomes in patients with advanced EGFR mutant NSCLC receiving first-line EGFR-TKIs. We also compared the findings to those with wild-type EGFR. Between November 2010 and March 2014, 513 patients with advanced NSCLC were enrolled in the study. According to the adjusted BMI cut-off point for Asia, 35 out of 513 (6.8%) patients were underweight (BMI < 18.5 kg/m2), whereas 197 (38.4%) were overweight (BMI > 24 kg/m2). Overweight patients with wild-type EGFR exhibited longer progression-free survival (4.6 vs. 2.1 months, p = 0.003) and overall survival (OS) (8.9 vs. 4.3 months, p = 0.003) than underweight patients. Overweight patients with EGFR mutations had a longer OS than normal-weight patients (23.0 vs. 20.2 months, p = 0.025). Bodyweight reduction was related to a shorter OS in both the mutant EGFR patients (17.1 vs. 30.5 months, p < 0.001) and the wild-type EGFR patients (7.8 vs. 18.7 months, p < 0.001). In conclusion, advanced stages NSCLC patients with a lower BMI and early weight loss had a worse outcome that was independent of EGFR mutation status.

Application of Peak Glucose Range and Diabetes Status in Mortality Risk Stratification in Critically Ill Patients with Sepsis.

The effects of diabetes and glucose on the outcomes of patients with sepsis are somewhat conflicting. This retrospective study enrolled 1214 consecutive patients with sepsis, including a subpopulation of 148 patients with immune profiles. The septic patients were stratified according to their Diabetes mellitus (DM) status or peak glucose level (three-group tool; P1: ≤140 mg/dL, P2: 141-220 mg/dL, P3: >220 mg/dL) on day 1. Although the DM group had a lower hazard ratio (HR) for 90-day mortality compared to non-DM patients, the adjusted HRs were insignificant. The modified sequential organ failure assessment-glucose (mSOFA-g) score can predict 90-day survival in patients with and without diabetes (ß = 1.098, p < 0.001; ß = 1.202, p < 0.001). The goodness of fit of the mSOFA-g score was 5% higher than the SOFA score of the subgroup without diabetes. The SOFA score and human leukocyte antigen-D-related (HLA-DR) expression were comparable between the groups. The P3 group had lower HLA-DR expression on days 1 and 3 and a higher 90-day mortality. The three-group tool was useful for predicting 90-day mortality in patients with separate Kaplan-Meier survival curves and mortality HRs in the construction and validation cohorts. The peak glucose level, instead of diabetes status, can be used as an easy adjunctive tool for mortality risk stratification in critically ill septic patients.

Application of a 72 h National Early Warning Score and Incorporation with Sequential Organ Failure Assessment for Predicting Sepsis Outcomes and Risk Stratification in an Intensive Care Unit: A Derivation and Validation Cohort Study.

We investigated the best timing for using the National Early Warning Score 2 (NEWS2) for predicting sepsis outcomes and whether combining the NEWS2 and the Sequential Organ Failure Assessment (SOFA) was applicable for mortality risk stratification in intensive care unit (ICU) patients with severe sepsis. All adult patients who met the Third International Consensus Definitions for Sepsis and Septic Shock criteria between August 2013 and January 2017 with complete clinical parameters and laboratory data were enrolled as a derivation cohort. The primary outcomes were the 7-, 14-, 21-, and 28-day mortalities. Furthermore, another group of patients under the same setting between January 2020 and March 2020 were also enrolled as a validation cohort. In the derivation cohort, we included 699 consecutive adult patients. The 72 h NEWS2 had good discrimination for predicting 7-, 14-, 21-, and 28-day mortalities (AUC: 0.780, 0.724, 0.700, and 0.667, respectively) and was not inferior to the SOFA (AUC: 0.740, 0.680, 0.684, and 0.677, respectively). With the new combined NESO tool, the hazard ratio was 1.854 (1.203-2.950) for the intermediate-risk group and 6.810 (3.927-11.811) for the high-risk group relative to the low-risk group. This finding was confirmed in the validation cohort using a separated survival curve for 28-day mortality. The 72 h NEWS2 alone was non-inferior to the admission SOFA or day 3 SOFA for predicting sepsis outcomes. The NESO tool was found to be useful for 7-, 14-, 21-, and 28-day mortality risk stratification in patients with severe sepsis.

Impact of Body Mass Index on the Survival of Patients with Sepsis with Different Modified NUTRIC Scores.

Nutritional status affects the survival of patients with sepsis. This retrospective study analyzed the impact of body mass index (BMI) and modified nutrition risk in critically ill (mNUTRIC) scores on survival of these patients. Data of 1291 patients with sepsis admitted to the intensive care unit (ICU) were extracted. The outcomes were mortality, duration of stay, ICU stay, and survival curve for 90-day mortality. Logistic regression analysis was performed to examine the risk factors for mortality. Cytokine and biomarker levels were analyzed in 165 patients. The 90-day survival of underweight patients with low mNUTRIC scores was significantly better than that of normal-weight patients with low mNUTRIC scores (70.8% vs. 58.3%, respectively; p = 0.048). Regression model analysis revealed that underweight patients with low mNUTRIC scores had a lower risk of mortality (odds ratio = 0.557; p = 0.082). Moreover, normal-weight patients with low mNUTRIC scores had the lowest human leukocyte antigen DR (HLA-DR) level on days 1 (underweight vs. normal weight vs. overweight: 94.3 vs. 82.1 vs. 94.3, respectively; p = 0.007) and 3 (91.8 vs. 91.0 vs. 93.2, respectively; p = 0.047). Thus, being underweight may not always be harmful if patients have optimal clinical nutritional status. Additionally, HLA-DR levels were the lowest in patients with low survival.

Risk factors and associated outcomes of ventilator-associated events developed in 28 days among sepsis patients admitted to intensive care unit.

We hypothesized that Ventilator-Associated Event (VAE) within 28 days upon admission to medical intensive care units (ICUs) can be a predictor for poor outcomes in sepsis patients. We aimed to determine the risk factors and associated outcomes of VAE. A total of 453 consecutive mechanically ventilated (MV) sepsis patients were enrolled. Of them, 136 patients had immune profile study. Early VAE (< 7-day MV, n = 33) was associated with a higher mortality (90 days: 81.8% vs. 23.0% [non-VAE], P < 0.01), while late VAE (developed between 7 and 28 days, n = 85) was associated with longer MV day (43.8 days vs. 23.3 days [non-VAE], P < 0.05). The 90-day Kaplan-Meier survival curves showed three lines that separate the groups (non-VAE, early VAE, and late VAE). Cox regression models with time-varying coefficient covariates (adjusted for the number of days from intubation to VAE development) confirmed that VAE which occurred within 28 days upon admission to the medical ICUs can be associated with higher 90-day mortality. The risk factors for VAE development include impaired immune response (lower human leukocyte antigen D-related expression, higher interleukin-10 expression) and sepsis progression with elevated SOFA score (especially in coagulation sub-score).

Impact of corticosteroid treatment on clinical outcomes of influenza-associated ARDS: a nationwide multicenter study.

BACKGROUND: Corticosteroid treatment has been widely used in the treatment of septic shock, influenza, and ARDS, although some previous studies discourage its use in severe influenza patients. This multicenter retrospective cohort study conducted in the intensive care units (ICUs) of eight medical centers across Taiwan aims to determine the real-world status of corticosteroid treatment in patients with influenza-associated acute respiratory distress syndrome (ARDS) and its impact on clinical outcomes. Between October 2015 and March 2016, consecutive ICU patients with virology-proven influenza infections who fulfilled ARDS and received invasive mechanical ventilation were enrolled. The impact of early corticosteroid treatment (≥ 200 mg hydrocortisone equivalent dose within 3 days after ICU admission, determined by a sensitivity analysis) on hospital mortality (the primary outcome) was assessed by multivariable logistic regression analysis, and further confirmed in a propensity score-matched cohort. RESULTS: Among the 241 patients with influenza-associated ARDS, 85 (35.3%) patients receiving early corticosteroid treatment had similar baseline characteristics, but a significantly higher hospital mortality rate than those without early corticosteroid treatment [43.5% (37/85) vs. 19.2% (30/156), p < 0.001]. Early corticosteroid treatment was independently associated with increased hospital mortality in overall patients [adjusted odds ratio (95% CI) = 5.02 (2.39-10.54), p < 0.001] and in all subgroups. Earlier treatment and higher dosing were associated with higher hospital mortality. Early corticosteroid treatment was associated with a significantly increased odds of subsequent bacteremia [adjusted odds ratio (95% CI) = 2.37 (1.01-5.56)]. The analyses using a propensity score-matched cohort showed consistent results. CONCLUSIONS: Early corticosteroid treatment was associated with a significantly increased hospital mortality in adult patients with influenza-associated ARDS. Earlier treatment and higher dosing were associated with higher hospital mortality. Clinicians should be cautious while using corticosteroid treatment in this patient group.

Incorporation of dynamic segmented neutrophil-to-monocyte ratio with leukocyte count for sepsis risk stratification.

The association between sepsis and segmented neutrophil-to-monocyte (SeMo) ratio is unclear. We postulated that an increase in dynamic SeMo ratio measurement can be applied in risk stratification. This retrospective study included 727 consecutive sepsis patients in medical intensive care units (ICUs), including a subpopulation of 153 patients. According to the leukocyte (white blood cell, WBC) count on day 3 (normal range, between 4,000/µL and 12,000/µL) and delta SeMo (value of SeMo ratio on day 3 minus value of SeMo ratio on day 1; normal delta SeMo, <7), patients were grouped into 3 (delta SeMo & WBC tool). The survival lines separated significantly with hazard ratios of 1.854 (1.342-2.560) for the delta SeMo or WBC abnormal group and 2.860 (1.849-4.439) for the delta SeMo and WBC abnormal group compared to the delta SeMo and WBC normal group. Delta SeMo & WBC tool and delta sequential organ failure assessment (SOFA) tool performed better than the other tools (delta SeMo, delta WBC, day 3 WBC, and day 1 WBC). Severity in delta SeMo & WBC tool and delta SeMo tool reflected the immune dysfunction score, cytokine expression, and human leukocyte antigen D-related monocyte expression on day 1 and day 3. There was correspondence between delta SOFA and delta WBC and between delta SeMo and delta cytokine expression. Incorporation of dynamic SeMo ratio with WBC count provides risk stratification for sepsis patients admitted in the ICU.

Effect of do-not-resuscitate orders on patients with sepsis in the medical intensive care unit: a retrospective, observational and propensity score-matched study in a tertiary referral hospital in Taiwan.

OBJECTIVE: The aim of this study was to determine whether do-not-resuscitate (DNR) orders affect outcomes in patients with sepsis admitted to intensive care unit (ICU). DESIGN: This is a retrospective observational study. PARTICIPANTS: We enrolled 796 consecutive adult intensive care patients at Kaohsiung Chang Gung Memorial Hospital, a 2700-bed tertiary teaching hospital in southern Taiwan. A total of 717 patients were included. MAIN MEASURES: Clinical factors such as age, gender and other clinical factors possibly related to DNR orders and hospital mortality were recorded. KEY RESULTS: There were 455 patients in the group without DNR orders and 262 patients in the group with DNR orders. Within the DNR group, patients were further grouped into early (orders signed on intensive care day 1, n=126) and late (signed after day 1, n=136). Patients in the DNR group were older and more likely to have malignancy than the group without DNR orders. Mortality at days 7, 14 and 28, as well as intensive care and hospital mortality, were all worse in these patients even after propensity-score matching. There were higher Charlson Comorbidity Index in the emergency room, but better outcomes in those with early-DNR orders compared with late-DNR orders. CONCLUSIONS: DNR orders may predict worse outcomes for patients with sepsis admitted to medical ICUs. The survival rate in the early-DNR order group was not inferior to the late-DNR order group.

Application of dynamic pulse pressure and vasopressor tools for predicting outcomes in patients with sepsis in intensive care units.

PURPOSE: We aimed to determine whether the combination of dynamic pulse pressure and vasopressor (DPV) use is applicable for mortality risk stratification in patients with severe sepsis. We proposed the use of the DPV tool and compared it with traditional sepsis severity indices. MATERIALS AND METHODS: All adult patients who met the sepsis criteria of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) between August 2013 and January 2017 were eligible for the study. Patients who expired within 3 days of admission to the intensive care unit (ICU) were excluded. The primary outcomes were 7-day and 28-day mortality. RESULTS: The study participants included 757 consecutive adult patients. A subpopulation of 155 patients underwent immune profiling assays on days 1, 3, and 7 of ICU admission. The DPV tool had a better performance for predicting 7-day mortality (area under curve, AUC: 0.70), followed by the Sequential Organ Failure Assessment (SOFA) (AUC: 0.64), the plus pulse pressure (AUC: 0.64). For predicting 28-day mortality, the DPV tool was not inferior to the SOFA (AUC: 0.61), DPV tool (AUC: 0.59). CONCLUSIONS: The DPV tool can be applied for 7-day and 28-day mortality risk prediction in patients with sepsis.

Mortality and vertebral fracture risk associated with long-term oral steroid use in patients with chronic obstructive pulmonary disease: A systemic review and meta-analysis.

Short-term oral steroid use may improve lung function and respiratory symptoms in patients with stable chronic obstructive pulmonary disease (COPD). However, long-term oral steroid (LTOS) use is not recommended owing to its potential adverse effects. Our study aimed to investigate whether chronic use of oral steroids for more than 4 months would increase mortality and vertebral fracture risk in patients with stable COPD. A systemic search of the PubMed database was conducted, and meta-analysis was performed using Review Manager 5.3. Five studies with a total of 1795 patients showed there was an increased risk of mortality in patients using LTOS (relative risk, 1.63; 95% confidence interval (CI), 1.19-2.23; p < 0.0001; I2 = 86%). In addition, four studies with a total of 17,764 patients showed there was an increased risk of vertebral fracture in patients using LTOS (odds ratio, 2.31; 95% CI, 1.52-3.50; p = 0.03; I2 = 65%). Our meta-analysis showed LTOS was associated with increased mortality and vertebral fracture risk in patients with COPD, and this risk may be due to the adverse effects of LTOS and progression COPD.

Insufficient Nutrition and Mortality Risk in Septic Patients Admitted to ICU with a Focus on Immune Dysfunction.

Immune dysfunction is seen both in sepsis patients and in those with malnutrition. This study aimed to determine whether insufficient nutrition and immune dysfunction have a synergistic effect on mortality in critically ill septic patients. We conducted a prospective observational study from adult sepsis patients admitted to intensive care units (ICUs) between August 2013 and June 2016. Baseline characteristics including age, gender, body mass index, NUTRIC, Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were recorded. Immune dysfunction, defined by human leukocyte antigen DR (HLA-DR) expression, was tested at days 1, 3, and 7 of ICU admission. The study included 151 patients with sepsis who were admitted to the ICU. The 28-day survivors had higher day 7 caloric intakes (89% vs 73%, p = 0.042) and higher day 1-HLA-DR expression (88.4 vs. 79.1, p = 0.045). The cut-off points of day 7 caloric intake and day 1-HLA-DR determined by operating characteristic curves were 65.1% and 87.2%, respectively. Immune dysfunction was defined as patients with day 1-HLA-DR < 87.2%. Insufficient nutrition had no influence on survival outcomes in patients with immune dysfunction. However, patients with insufficient nutrition had poor prognosis when they were immune competent. Insufficient nutrition and immune dysfunction did not have a synergistic effect on mortality in critically ill septic patients.

Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and is primarily characterized by an uncontrolled systemic inflammatory response. In the present study, we developed an effective adjunct therapy mediated by a novel mechanism, to attenuate overt inflammation. LPS-treated macrophages were adopted as an in vitro model of endotoxin-induced inflammation during sepsis. Experiments were carried out using primary mouse peritoneal macrophages and the murine macrophage cell line RAW264.7, to elucidate the mechanisms by which HDAC2 modulates endotoxin-induced inflammation. RESULTS: Results revealed that PAI-1, TNF, and MIP-2 expression were inhibited by theophylline, an HDAC2 enhancer, in a RAW macrophage cell line, following LPS-induced inflammation. Thus, HDAC2 plays an important role in immune defense by regulating the expression of inflammatory genes via the c-Jun/PAI-1 pathway. During LPS-induced inflammation, overexpression of HDAC2 was found to inhibit PAI-1, TNF, and MIP-2 expression. Following LPS stimulation, HDAC2 knockdown increased nuclear translocation and DNA binding of c-Jun to the PAI-1 gene promoter, thereby activating PAI-1 gene transcription. Furthermore, inhibition of PAI-1 by TM5275 alone or in combination with theophylline notably suppressed TNF and MIP-2 expression. CONCLUSION: HDAC2 can attenuate lipopolysaccharide-induced inflammation by regulating c-Jun and PAI-1 expression in macrophages.

Development and validation of immune dysfunction score to predict 28-day mortality of sepsis patients.

BACKGROUND: Sepsis-induced immune dysfunction ranging from cytokines storm to immunoparalysis impacts outcomes. Monitoring immune dysfunction enables better risk stratification and mortality prediction and is mandatory before widely application of immunoadjuvant therapies. We aimed to develop and validate a scoring system according to patients' immune dysfunction status for 28-day mortality prediction. METHODS: A prospective observational study from a cohort of adult sepsis patients admitted to ICU between August 2013 and June 2016 at Kaohsiung Chang Gung Memorial Hospital in Taiwan. We evaluated immune dysfunction status through measurement of baseline plasma Cytokine levels, Monocyte human leukocyte-DR expression by flow cytometry, and stimulated immune response using post LPS stimulated cytokine elevation ratio. An immune dysfunction score was created for 28-day mortality prediction and was validated. RESULTS: A total of 151 patients were enrolled. Data of the first consecutive 106 septic patients comprised the training cohort, and of other 45 patients comprised the validation cohort. Among the 106 patients, 21 died and 85 were still alive on day 28 after ICU admission. (mortality rate, 19.8%). Independent predictive factors revealed via multivariate logistic regression analysis included segmented neutrophil-to-monocyte ratio, granulocyte-colony stimulating factor, interleukin-10, and monocyte human leukocyte antigen-antigen D-related levels, all of which were selected to construct the score, which predicted 28-day mortality with area under the curve of 0.853 and 0.789 in the training and validation cohorts, respectively. CONCLUSIONS: The immune dysfunction scoring system developed here included plasma granulocyte-colony stimulating factor level, interleukin-10 level, serum segmented neutrophil-to-monocyte ratio, and monocyte human leukocyte antigen-antigen D-related expression appears valid and reproducible for predicting 28-day mortality.

Immune profiles and clinical outcomes between sepsis patients with or without active cancer requiring admission to intensive care units.

BACKGROUND: Immunoparalysis was observed in both patients with cancer and sepsis. In cancer patients, Cytotoxic T lymphocyte antigen-4 and programmed cell death protein 1/programmed death-ligand 1 axis are two key components of immunoparalysis. Several emerging therapies against these two axes gained significant clinical benefit. In severe sepsis patients, immunoparalysis was known as compensatory anti-inflammatory response syndrome and this has been suggested as an important cause of death in patients with sepsis. It would be interesting to see if immune status was different in severe sepsis patients with or without active cancer. The aim of this study was to assess the differences in immune profiles, and clinical outcomes between severe sepsis patients with or without cancer admitted to ICU. METHODS: A combined retrospective and prospective observational study from a cohort of adult sepsis patients admitted to three medical ICUs at Kaohsiung Chang Gung Memorial Hospital in Taiwan between August 2013 and June 2016. RESULTS: Of the 2744 patients admitted to the ICU, 532 patients with sepsis were included. Patients were divided into those with or without active cancer according to their medical history. Of the 532 patients, 95 (17.9%) patients had active cancer, and 437 (82.1%) patients had no active cancer history. Patients with active cancer were younger (p = 0.001) and were less likely to have diabetes mellitus (p < 0.001), hypertension (p < 0.001), coronary artery disease (p = 0.004), chronic obstructive pulmonary disease (p = 0.002) or stroke (p = 0.002) compared to patients without active cancer. Patients with active cancer also exhibited higher baseline lactate levels (p = 0.038), and higher baseline plasma interleukin (IL)-10 levels (p = 0.040), higher trend of granulocyte colony-stimulating factor (G-CSF) (p = 0.004) compared to patients without active cancer. The 14-day, 28-day and 90-day mortality rates were higher for patients with active cancer than those without active cancer (P < 0.001 for all intervals). CONCLUSIONS: Among patients admitted to the ICU with sepsis, those with underling active cancer had higher baseline levels of plasma IL-10, higher trend of G-CSF and higher mortality rate than those without active cancer.

The impact of de novo liver metastasis on clinical outcome in patients with advanced non-small-cell lung cancer.

Liver metastasis has been found to affect outcome in prostate cancer and colorectal cancer, but its role in lung cancer is unclear. The current study aimed to evaluate the impact of de novo liver metastasis (DLM) on stage IV non-small cell lung cancer (NSCLC) outcomes and to examine whether tyrosine kinase inhibitors (TKI) reverse poor prognosis in patients with DLM and epidermal growth factor receptor (EGFR)-mutant NSCLC. Among 1392 newly diagnosed NSCLC patients, 490 patients with stage IV disease treated between November 2010 and March 2014 at Kaohsiung Chang Gung Memorial Hospital were included. Patients were divided into two groups according to DLM status. There were 75 patients in the DLM group and 415 patients in the non-DLM group. The DLM group included more patients with bone metastasis, fewer patients with a lymphocyte-to-monocyte ratio (LMR) > 3.1, and fewer patients with pleural metastasis. In the DLM group, Eastern Cooperative Oncology Group performance status 3-4 and LMR ≦3.1 were associated with poor outcome. In patients without DLM, overall survival (OS) was longer in patients with EGFR-mutant NSCLC than in those without (20.2 vs. 7.3 months, p < 0.001). Among DLM patients, OS was similar between the EGFR-mutant and wild-type EGFR tumor subgroups (11.9 vs. 7.7 months, p = 0.155). We found that DLM was a significant poor prognostic factor in the EGFR-mutant patients treated with EGFR-TKIs, whereas DLM did not affect the prognosis of EGFR-wild-type patients.