Chien Da Huang

The impact of delirium on the survival of mechanically ventilated patients

Objectives:To revalidate a means of assessing delirium in intensive care unit patients and to investigate the independent effect of delirium on the mortality of mechanically ventilated patients. Design:A prospective cohort study. Setting:A 37-bed medical intensive care unit of a tertiary care hospital. Patients:Subjects were 102 of 131 consecutive mechanically ventilated patients. Measurements:All the enrolled patients were assessed for delirium using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Mortality rate were compared between patients with or without delirium, and the predictors of death were investigated. Results:The two CAM-ICU assessors’ sensitivities in diagnosing delirium compared with reference standard were 91% and 95%, whereas their specificities were both 98%. They also demonstrated high interrater reliability with kappa statistics of 0.91. Delirium was present in 22 of 102 (22%) patients in the first 5 days. The delirious patients had higher intensive care unit mortality rate than nondelirious patients (63.6% vs. 32.5%, respectively), with a hazard ratio of 2.57 (95% confidence interval, 1.56–8.15). In multivariate analysis, delirium (odds ratio, 13.0; 95% confidence interval, 2.69–62.91), shock (odds ratio, 12.91; 95% confidence interval, 2.93–56.92), and illness severity (odds ratio, 9.61; 95% confidence interval, 2.24–41.18) were independent predictors of mortality. Conclusions:This study confirms previous work showing that delirium is an independent predictor for increased mortality among mechanically ventilated patients.

CD14+S100A9+ Monocytic Myeloid-derived Suppressor Cells and Their Clinical Relevance in Non–Small Cell Lung Cancer

RATIONALE Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T-cell immunity in tumor-bearing hosts. Their clinical relevance remains unclear. OBJECTIVES To identify subtypes of myeloid-derived suppressor cells in patients with non-small cell lung cancer (NSCLC) and their clinical relevance. METHODS CD11b(+)CD14(-) and CD11b(+)CD14(+) cells, determined and phenotyped by fluorescence-activated cell sorter analysis, in the peripheral blood mononuclear cells (PBMCs) of treatment-naive patients with advanced NSCLC were correlated with clinical data. T-cell activation in response to CD3/CD28 costimulation was determined by carboxy-fluorescein diacetate succinimidyl ester (CFSE) staining and ELISA analysis of IFN-γ. The percentage of CD11b(+)CD14(+)S100A9(+) cells in PBMCs was correlated with and tested as a predictor for treatment response in a cohort of patients prospectively receiving first-line cisplatin-based chemotherapy. MEASUREMENTS AND MAIN RESULTS Patients with NSCLC had a significantly higher ratio of CD11b(+)CD14(+) cells than healthy subjects, which was correlated with poor performance status and poor response to chemotherapy. The depletion of these cells in the PBMC reversed the suppression of CD8(+) and CD4(+) T cells. Isolated CD11b(+)CD14(+) cells suppressed CD8(+) T-cell proliferation and IFN-γ production, and the former effect was attenuated by the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine hydrochloride, arginase inhibitor N-hydroxy-nor-l-arginine (nor-NOHA), and blocking antibodies for IL-4Rα(+) and IL-10. CD11b(+)CD14(+) cells were monocyte-like, expressing CD33(+), CD15(-/low), IL-4Rα(+), and S100A9(+) and producing iNOS, arginase, and several cytokines. The ratio of S100A9(+) cells positively correlated with the suppressive ability of the CD11b(+)CD14(+) cells, was associated with poor response to chemotherapy, and predicted shorter progression-free survival. CONCLUSIONS CD14(+)S100A9(+) inflammatory monocytes in patients with NSCLC are a distinct subset of MDSCs, which suppress T cells by arginase, iNOS, and the IL-13/IL-4Rα axis. The amount of these inflammatory monocytes is associated with poor response to chemotherapy. Clinical trial registered with www.clinicaltrials.gov (NCT 01204307).

Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis.

Objective:To determine serum concentrations of thrombomodulin, the marker of endothelial injury, in patients with sepsis-induced disseminated intravascular coagulation and multiple organ dysfunction syndrome and to investigate the independent association between this marker and the development of disseminated intravascular coagulation, multiple organ dysfunction syndrome, and mortality. Design:A prospective cohort study. Setting:A 37-bed intensive care unit of a tertiary care hospital. Patients:One hundred consecutive patients with sepsis. Interventions:Serum thrombomodulin concentrations and the development of disseminated intravascular coagulation and multiple organ dysfunction syndrome were determined in patients on days 1 and 3 of sepsis. These data were used to determine an association between day 1 thrombomodulin concentrations and development of disseminated intravascular coagulation, multiple organ dysfunction syndrome, and mortality during intensive care unit stay. These connections were determined by the Cox proportional hazards model and plotting of receiver operating characteristic curves. Measurements and Main Results:Day 1 serum concentrations of thrombomodulin were higher in patients with disseminated intravascular coagulation (11.1 ± 1.0 vs. 5.3 ± 0.5 ng/mL; p < .0001) or multiple organ dysfunction syndrome (10.3 ± 0.7 vs. 4.3 ± 0.4 ng/mL; p < .0001) than those without, respectively. In patients with resolved disseminated intravascular coagulation (4.9 ± 0.5 vs. 8.9 ± 0.9 ng/mL, day 3 vs. day 1, p = .005) or multiple organ dysfunction syndrome (6.3 ± 1.4 vs. 12.0 ± 1.6 ng/mL, day 3 vs. day 1, p < .0001) on day 3 of sepsis, day 3 levels of thrombomodulin were down from day 1. Thrombomodulin concentration independently predicted the development of disseminated intravascular coagulation (hazard ratio 1.13, p < .0001), multiple organ dysfunction syndrome (hazard ratio 1.12, p < .0001), and mortality (hazard ratio 1.19, p < .0001) during intensive care unit stay. The area under the receiver operating characteristic curve showed that day 1 serum thrombomodulin levels had good discriminative power in predicting the development of disseminated intravascular coagulation (0.811), multiple organ dysfunction syndrome (0.896), and mortality (0.803) during intensive care unit stay. Conclusions:Endothelial cell injury is critical in the progression from disseminated intravascular coagulation to multiple organ dysfunction syndrome and subsequent mortality in septic patients. Serum concentrations of thrombomodulin may be used in monitoring disseminated intravascular coagulation and multiple organ dysfunction syndrome in these patients.

The Endothelin A Receptor Mediates Fibrocyte Differentiation in Chronic Obstructive Asthma The Involvement of Connective Tissue Growth Factor

RATIONALE Fibrocytes possess increased differentiability into α-smooth muscle actin (α-SMA)(+) myofibroblasts in chronic obstructive asthma (COA) and contribute to pulmonary fibrosis. Endothelin-1 (ET-1) induces matrix-associated gene expression through the ETA receptor (ETAR) and promotes fibroblast differentiation. However, the mechanism of fibrocyte differentiation remains unclear. OBJECTIVES To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA. METHODS Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or α-SMA were identified by flow cytometry. MEASUREMENTS AND MAIN RESULTS We showed the accumulation of fibrocytes in bronchial walls and overexpression of CTGF in fibrocytes from patients with COA. After being cultured, CTGF was increased in fibrocytes from patients with COA, but not from those of normal participants or patients with asthma without obstruction. Serum levels of ET-1 and the expression of the ETAR in fibrocytes were significantly higher in patients with COA compared with normal participants and patients with asthma without obstruction. Treatment with the ETAR antagonist (BQ123), but not ETBR antagonist (BQ788), reduced the expression of CTGF and α-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated α-SMA expression induced by ET-1 in fibrocytes from normal participants. CONCLUSIONS Our findings demonstrate for the first time that the ETAR pathway is vital for CTGF expression, which results in fibrocyte differentiation in COA, and suggests that an ETAR antagonist may be a potential antifibrotic agent in preventing the development of fibrosis in patients with COA.

Reduced nuclear factor-κB repressing factor: a link toward systemic inflammation in COPD

Chronic systemic inflammation is implicated in the systemic manifestations and, probably, the excess mortality risk of chronic obstructive pulmonary disease (COPD). The role of nuclear factor (NF)-&kgr;B repressing factor (NRF), a DNA-binding, protein-inhibiting NF-&kgr;B response gene, in human diseases has not been explored. We hypothesised that the NRF-negative regulatory mechanism is impaired in COPD peripheral blood mononuclear cells (PBMCs) leading to excessive interleukin (IL)-8/CXCL8 production. NRF expression, NF-&kgr;B activation, IL-8/CXCL8 release and intracellular oxidative stress were assessed in PBMCs of normal subjects and stable COPD patients. Primary PBMCs with NRF overexpression, NRF knockdown and exposure to H2O2 were used to elucidate the mechanisms. Stable COPD patients, especially those with severe COPD, showed decreased NRF expression, enhanced NF-&kgr;B activation and increased IL-8/CXCL8 release in PBMCs compared with normal subjects. This was associated with reduced NRF and increased RNA polymerase II occupancy at the IL-8/CXCL8 promoter. NRF knockdown enhanced IL-8/CXCL8 production in normal PBMCs, whilst NRF overexpression attenuated IL-8/CXCL8 production. Intracellular oxidative stress was increased in COPD PBMCs. H2O2-decreased NRF expression and -enhanced IL-8/CXCL8 production was augmented in COPD PBMCs. NRF expression is reduced in PBMCs of stable COPD patients, probably through oxidative stress, leading to increased production of IL-8/CXCL8 and potentially chronic systemic inflammation.

Diagnostic value of endobronchial ultrasonography for pulmonary tuberculosis

OBJECTIVES We sought to compare the diagnostic yields of acid-fast bacilli smears and Mycobacterium tuberculosis cultures in terms of bronchoalveolar lavage fluid and histologic examination of transbronchial lung biopsy specimens for pulmonary tuberculosis by using bronchoscopy with versus without endobronchial ultrasonography in patients with negative acid-fast bacilli smears or no sputum production. METHODS From June 2005 to July 2006, a total of 451 patients were given diagnoses of and treated for pulmonary tuberculosis in a university-affiliated hospital. Among them, 121 patients who received bronchoscopy because of sputum-negative conditions were recruited. Of these, 73 patients received bronchoscopy with endobronchial ultrasonography, and 48 patients received conventional bronchoscopy. RESULTS Patients who received bronchoscopy with endobronchial ultrasonography had higher diagnostic yields of acid-fast bacilli smears (31.5% vs 12.5%, P = .018) in bronchoalveolar lavage fluid, M tuberculosis in bronchoalveolar lavage fluid (67.1% vs 47.9%, P = .024), and pathologic reports of tuberculosis in transbronchial lung biopsy specimens (32.9% vs 4.2%, P < .0001) than patients who received conventional bronchoscopy. With the aid of endobronchial ultrasonography, the overall diagnostic yield for tuberculosis by using bronchoscopic procedures (smears and cultures of bronchoalveolar lavage fluid and transbronchial lung biopsy specimens) was higher (80.8%) than for those who did not undergo endobronchial ultrasonography (58.3%, P = .035). CONCLUSIONS The addition of endobronchial ultrasonography to diagnostic bronchoscopy increased the sensitivity for proving the presence of tuberculosis in a population of patients with negative acid-fast bacilli smears or no sputum production.

Ventilator-induced injury augments interleukin-1beta production and neutrophil sequestration in lipopolysaccharide-treated lungs.

ABSTRACT Mechanical ventilators are commonly used to support critically ill patients; however, inappropriate ventilator settings might initiate or augment lung injury. To determine whether a large tidal volume (Vt) augments inflammatory responses and neutrophil sequestration in the lungs of rats receiving intratracheal lipopolysaccharides (LPS). Rats received intratracheal instillation of LPS (0.5 mg/kg) followed by 4 h of mechanical ventilation (MV) at 60 strokes per min with a Vt of 10 mL/kg as control MV, or 30 strokes per min with a Vt of 20 mL/kg of body weight as high-volume MV (HMV). In addition, monoclonal antibodies against rat intercellular adhesion molecule 1 (ICAM-1) or immunoglobulin G (50 mg/kg) were administered 30 min before LPS instillation and MV. Our study demonstrates that HMV enhances pulmonary permeability and induces neutrophil recruitment into the alveolar space and pulmonary edema. Intratracheal instillation of LPS caused marked lung injury, neutrophil recruitment, and production of cytokines and chemokines. Combining LPS instillation and HMV synergistically upregulated interleukin 1&bgr; (IL-1&bgr;) production and neutrophil sequestration in lung tissues. The ICAM-1 expression in lung tissues was responsible for the synergistic effects of neutrophil sequestration. Synergistic upregulation of IL-1&bgr; production and neutrophil sequestration was attenuated by blocking ICAM-1 by neutralizing antibody pretreatment. High Vt MV in LPS-injured lung causes synergistic production of IL-1&bgr; and sequestration of neutrophil via ICAM-1-dependent effects.

Increased phenotypic differentiation and reduced corticosteroid sensitivity of fibrocytes in severe asthma

BACKGROUND Patients with severe asthma are less responsive to corticosteroid therapy and show increased airway remodeling. The mesenchymal progenitors, fibrocytes, may be involved in the remodeling of asthmatic airways. We propose that fibrocytes in severe asthma are different from those in nonsevere asthma. OBJECTIVES To examine the survival, myofibroblastic differentiation, and C-C chemokine receptor 7 (CCR7) expression in blood fibrocytes from patients with severe and nonsevere asthma and study the effect of corticosteroids on fibrocyte function. METHODS The nonadherent non-T-cell fraction of blood mononuclear cells was isolated from healthy subjects and patients with nonsevere and severe asthma. Total and differentiating fibrocytes were identified by their expression of CD45, collagen I, and α-smooth muscle actin using flow cytometry. The expression of CCR7 and of the glucocorticoid receptor was measured by using flow cytometry. RESULTS Increased numbers of circulating fibrocytes, with greater myofibroblastic differentiation potential, were observed in patients with severe asthma. Dexamethasone induced apoptosis, leading to reduction in the number of cultured fibrocytes and total nonadherent non-T cells from healthy subjects and patients with nonsevere asthma but not from patients with severe asthma. Dexamethasone reduced CCR7 expression in fibrocytes from patients with nonsevere asthma but not from patients with severe asthma. Glucocorticoid receptor expression was attenuated in fibrocytes from patients with severe asthma. CONCLUSIONS Patients with severe asthma have elevated numbers of circulating fibrocytes that show enhanced myofibroblastic differentiation and that are less responsive to the effects of corticosteroids.

Eosinophils from asthmatics release IL-5 in an autocrine fashion to prevent apoptosis through upregulation of Bcl-2 expression

Interleukin (IL)-5 plays an important role in maintaining the survival of eosinophils via the specific α-subunit of its receptor. Apoptosis, a form of programmed cell death, is thought to represent a mechanism that promotes the resolution of eosinophilic inflammation in asthma. The aim of our present study is to investigate whether IL-5 acts in an autocrine fashion on eosinophil apoptosis in asthmatics. Immunoreactivities of intracellular IL-5 and IL-5 receptor α-subunit (Rα) were detected uniquely on the eosinophils. The magnitude of IL-5 and IL-5 Rα expression on eosinophils was significantly higher in asthmatics than that of normal subjects (p < 0.05) determined by flow cytometry. Apoptosis of eosinophils was measured by the propidium iodide staining method and DNA ladder. The percent of apoptotic eosinophils from asthmatics was significantly increased by coincubation with anti-hIL-5 Rα Ab (0.1, 0.5, and 2.5 µg/mL) for 1, 2, or 16 hours than was those of corresponding controls (p < 0.05, n = 8). However, there was no significant effect of anti-hIL-5 Rα Ab on eosinophil apoptosis in normal subjects. Furthermore, the expression of B-cell lymphoma-2 (Bcl-2) proteins was significantly inhibited by the anti-hIL-5 Rα Ab or antisense IL-5 oligonucleotides in asthmatics (p < 0.05, n = 8), but there was no significant change in eosinophils from normal subjects. This study demonstrates that eosinophils from asthmatics release IL-5 in an autocrine fashion to act on their own IL-5 receptors in prevention of apoptosis through the upregulation of Bcl-2 expression.

Clinical characteristics and treatment outcomes of patients with low- and high-concentration isoniazid-monoresistant tuberculosis.

Background Isoniazid (INH) resistance is now the most common type of tuberculosis (TB) infection resistance worldwide. The aim of this study was to evaluate the clinical characteristics and treatment outcomes of patients with low- and high-concentration INH-monoresistant TB. Methods One hundred and thirty-four patients with culture-confirmed INH-monoresistant TB during 2006 January to 2007 December were retrospectively enrolled. INH resistance was classified as either low-concentration or high-concentration resistance according to the critical concentrations of 0.2 µg/mL or 1 µg/mL of INH, respectively. The patients’ clinical outcomes, treatment regimens, and treatment duration were analyzed. Results The treatment success rates between low- and high-concentration INH-resistant TB were similar (81.8% vs. 86.7%). The treatment regimens and treatment duration were similar between both groups. Only a minor percentage of the patients in both groups received 6-month treatment regimens (low vs. high concentration resistance, 9.1% vs. 13.3%; respectively, p = 0.447) The most common reason for treatment duration longer than 6 months was pyrazinamide given for less than 6 months, followed by a delay in clinical response to treatment. Multivariable analysis showed that prior tuberculosis treatment (Odds ratio, 2.82, 95% C.I., 1.02–7.77, p = 0.045) was the only independent risk factor for unsuccessful treatment outcome. Conclusion Different levels of INH resistance did not affect the treatment outcomes of patients with INH-monoresistant tuberculosis. Prolonged Rifampin-containing regimens may achieve those good outcomes in patients with low- and high-concentration INH-monoresistant TB.