We previously reported that microvesicles (MVs) released by human mesenchymal stem cells (MSC) were as effective as the cells themselves in both
lipopolysaccharide and live bacteria-induced acute ...lung injury (ALI) mice models. However, it remained unclear whether the biological effect of MSC MV can be applied to human ALI.
In the current study, we tested the therapeutic effects of MSC MVs in a well-established ex vivo perfused human model of bacterial pneumonia. Using human donor lungs not used for transplantation, we instilled
bacteria intrabronchially and, 1 hour later, administered MSC MVs into the perfusate as therapy.
After 6 hours, instillation of
bacteria caused influx of inflammatory cells, which resulted in significant inflammation, lung protein permeability and pulmonary oedema formation. Administration of MSC MV significantly increased alveolar fluid clearance and reduced protein permeability and numerically lowered the bacterial load in the injured alveolus. The beneficial effect on bacterial killing was more pronounced with pretreatment of MSCs with a Toll-like receptor 3 agonist, polyinosinic:polycytidylic acid (Poly (I:C)), prior to the isolation of MVs. Isolated human alveolar macrophages had increased antimicrobial activity with MSC MV treatment in vitro as well. Although oxygenation and lung compliance levels were similar between injury and treatment groups, administration of MSC MVs numerically decreased median pulmonary artery pressure at 6 hours.
In summary, MSC MVs increased alveolar fluid clearance and reduced lung protein permeability, and pretreatment with Poly (I:C) enhanced the antimicrobial activity of MVs in an ex vivo perfused human lung with severe bacteria pneumonia.
Purpose
Previous studies assessing impact of acute respiratory distress syndrome (ARDS) on mortality have shown conflicting results. We sought to assess the independent association of ARDS with ...in-hospital mortality among intensive care unit (ICU) patients with sepsis.
Methods
We studied two prospective sepsis cohorts drawn from the Early Assessment of Renal and Lung Injury (EARLI;
n
= 474) and Validating Acute Lung Injury markers for Diagnosis (VALID;
n
= 337) cohorts. ARDS was defined by Berlin criteria. We used logistic regression to compare in-hospital mortality in patients with and without ARDS, controlling for baseline severity of illness. We also estimated attributable mortality, adjusted for illness severity by stratification.
Results
ARDS occurred in 195 EARLI patients (41%) and 99 VALID patients (29%). ARDS was independently associated with risk of hospital death in multivariate analysis, even after controlling for severity of illness, as measured by APACHE II (odds ratio OR 1.65 (95% confidence interval CI 1.02, 2.67),
p
= 0.04 in EARLI; OR 2.12 (CI 1.16, 3.92),
p
= 0.02 in VALID). Patients with severe ARDS (
P
/
F
< 100) primarily drove this relationship. The attributable mortality of ARDS was 27% (CI 14%, 37%) in EARLI and 37% (CI 10%, 51%) in VALID. ARDS was independently associated with ICU mortality, hospital length of stay (LOS), ICU LOS, and ventilator-free days.
Conclusions
Development of ARDS among ICU patients with sepsis confers increased risk of ICU and in-hospital mortality in addition to other important outcomes. Clinical trials targeting patients with severe ARDS will be best poised to detect measurable differences in these outcomes.
Using latent class analysis (LCA), two subphenotypes of acute respiratory distress syndrome (ARDS) have consistently been identified in five randomised controlled trials (RCTs), with distinct ...biological characteristics, divergent outcomes and differential treatment responses to randomised interventions. Their existence in unselected populations of ARDS remains unknown. We sought to identify subphenotypes in observational cohorts of ARDS using LCA.
LCA was independently applied to patients with ARDS from two prospective observational cohorts of patients admitted to the intensive care unit, derived from the Validating Acute Lung Injury markers for Diagnosis (VALID) (n=624) and Early Assessment of Renal and Lung Injury (EARLI) (n=335) studies. Clinical and biological data were used as class-defining variables. To test for concordance with prior ARDS subphenotypes, the performance metrics of parsimonious classifier models (interleukin 8, bicarbonate, protein C and vasopressor-use), previously developed in RCTs, were evaluated in EARLI and VALID with LCA-derived subphenotypes as the gold-standard.
A 2-class model best fit the population in VALID (p=0.0010) and in EARLI (p<0.0001). Class 2 comprised 27% and 37% of the populations in VALID and EARLI, respectively. Consistent with the previously described 'hyperinflammatory' subphenotype, Class 2 was characterised by higher proinflammatory biomarkers, acidosis and increased shock and worse clinical outcomes. The similarities between these and prior RCT-derived subphenotypes were further substantiated by the performance of the parsimonious classifier models in both cohorts (area under the curves 0.92-0.94). The hyperinflammatory subphenotype was associated with increased prevalence of chronic liver disease and neutropenia and reduced incidence of chronic obstructive pulmonary disease. Measurement of novel biomarkers showed significantly higher levels of matrix metalloproteinase-8 and markers of endothelial injury in the hyperinflammatory subphenotype, whereas, matrix metalloproteinase-9 was significantly lower.
Previously described subphenotypes are generalisable to unselected populations of non-trauma ARDS.
The age of onset of type 2 diabetes is decreasing. Because non-Chinese patients with early-onset type 2 diabetes (defined here as diagnosis at <40 years) have increased risk of vascular ...complications, we investigated effects of early-onset versus late-onset type 2 diabetes on risk of non-fatal cardiovascular diseases in China.
We did a cross-sectional survey using data from the China National HbA1c Surveillance System (CNHSS), including 222,773 Chinese patients with type 2 diabetes in 630 hospitals from 106 cities in 30 provinces of China in 2012. We documented demographic information and clinical profiles. Non-fatal cardiovascular disease was defined as non-fatal coronary heart disease or non-fatal stroke. Prevalence of non-fatal cardiovascular diseases was standardised to the Chinese population in 2011. We did logistic regression analysis to obtain odds ratios (ORs) for the risk of cardiovascular disease in patients with early-onset versus late-onset type 2 diabetes. Because the CNHSS did not contain patients on diet or lifestyle treatment alone, and did not capture information on smoking or lipid or antihypertensive treatment, we validated our findings in another dataset from a cross-sectional, multicentre observational study (the 3B study) of outpatients with type 2 diabetes to confirm that exclusion of patients with diet treatment only and non-adjustment for lipid-lowering and antihypertensive drugs did not introduce major biases in the main analysis.
Of 222,773 patients recruited from April 1, 2012, to June 30, 2012, 24,316 (11%) had non-fatal cardiovascular disease. Patients with early-onset diabetes had a higher age-adjusted prevalence of non-fatal cardiovascular disease than did patients with late-onset diabetes (11·1% vs 4·9%; p<0·0001). After adjustment for age and sex, patients with early-onset type 2 diabetes had higher risk of non-fatal cardiovascular disease than did those with late-onset type 2 diabetes (OR 1·91, 95% CI 1·81-2·02). Adjustment for duration of diabetes greatly attenuated the effect size for risk of non-fatal cardiovascular disease (1·13, 1·06-1·20). Results of the validation study showed that exclusion of patients with diet only and non-adjustment for lipid-lowering and antihypertensive drugs resulted in marginal changes in ORs for risk of non-fatal cardiovascular disease in patients with early-onset versus late-onset type 2 diabetes. Early-onset type 2 diabetes remained associated with increased risk of cardiovascular disease, attributable to longer duration of diabetes.
Chinese patients with early-onset type 2 diabetes are at increased risk of non-fatal cardiovascular disease, mostly attributable to longer duration of diabetes.
Novo Nordisk China (for the China National HbA1c Surveillance System CNHSS) and Merck Sharp & Dohme China (for the 3B study).
The potential therapeutic value of cell-based therapy with mesenchymal stem cells (MSC) has been reported in mouse models of polymicrobial peritoneal sepsis. However, the mechanisms responsible for ...the beneficial effects of MSC have not been well defined. Therefore, we tested the therapeutic effect of intravenous bone marrow-derived human MSC in peritoneal sepsis induced by gram-negative bacteria. At 48 h, survival was significantly increased in mice treated with intravenous MSC compared with control mice treated with intravenous fibroblasts (3T3) or intravenous PBS. There were no significant differences in the levels of TNF-α, macrophage inflammatory protein 2, or IL-10 in the plasma. However, there was a marked reduction in the number of bacterial colony-forming units of Pseudomonas aeruginosa in the blood of MSC-treated mice compared with the 3T3 and PBS control groups. In addition, phagocytic activity was increased in blood monocytes isolated from mice treated with MSC compared with the 3T3 and PBS groups. Furthermore, levels of C5a anaphylotoxin were elevated in the blood of mice treated with MSC, a finding that was associated with upregulation of the phagocytosis receptor CD11b on monocytes. The phagocytic activity of neutrophils was not different among the groups. There was also an increase in alternately activated monocytes/macrophages (CD163- and CD206-positive) in the spleen of the MSC-treated mice compared with the two controls. Thus intravenous MSC increased survival from gram-negative peritoneal sepsis, in part by a monocyte-dependent increase in bacterial phagocytosis.
Abstract Background Individually, diabetes mellitus, hypertension, and dyslipidemia have been shown to increase the risk of cardiovascular disease. While traditional management of Type 2 diabetes has ...focused mainly on glycemic control, robust evidence supports the integration of hypertension and dyslipidemia management to reduce the risk of cardiovascular disease. The primary objective of this study was to assess the level of control of blood glucose, blood pressure, and blood lipids (3Bs) among patients with type 2 diabetes. An additional objective was to investigate the impact of hospital type, physician specialty, treatment pattern, and patient profile on clinical outcomes. Methods This was a cross-sectional, multicenter observational study. A nationally representative sample of outpatients with established type 2 diabetes were enrolled at hospitals representative of geographic regions, tiers, and physician specialties in China. Main clinical measurements were the levels of glycosylated hemoglobin (HbA1c), blood pressure, and total serum cholesterol in reference to target goals. Results A total of 25,817 adults with type 2 diabetes (mean age 62.6 years, 47% male) were enrolled at 104 hospitals. Seventy-two percent reported comorbid hypertension, dyslipidemia, or both. Patients with concurrent type 2 diabetes, hypertension, and dyslipidemia were 6 times more likely to report a prior history of cardiovascular disease compared with those with type 2 diabetes alone. The mean HbA1c level was 7.6%. While 47.7%, 28.4%, and 36.1% of patients achieved the individual target goals for control of blood glucose (HbA1c <7%), blood pressure (systolic blood pressure <130 mm Hg, diastolic blood pressure <80 mm Hg), and blood lipids (total cholesterol <4.5 mmol/L), respectively, only 5.6% achieved all 3 target goals. Lower body mass index (<24 kg/m2 ), no active smoking or drinking, higher education, and diabetes duration <5 years were independent predictors of better cardiovascular disease risk control. Conclusion Achieving adequate control of risk factors for cardiovascular disease in patients with type 2 diabetes remains a clinical challenge. Interventions to achieve control of 3Bs coupled with modification of additional cardiovascular disease predictors are crucial for optimization of clinical outcomes in patients with type 2 diabetes.
BACKGROUNDWhether airspace biomarkers add value to plasma biomarkers in studying acute respiratory distress syndrome (ARDS) is not well understood. Mesenchymal stromal cells (MSCs) are an ...investigational therapy for ARDS, and airspace biomarkers may provide mechanistic evidence for MSCs' impact in patients with ARDS.METHODSWe carried out a nested cohort study within a phase 2a safety trial of treatment with allogeneic MSCs for moderate-to-severe ARDS. Nonbronchoscopic bronchoalveolar lavage and plasma samples were collected 48 hours after study drug infusion. Airspace and plasma biomarker concentrations were compared between the MSC (n = 17) and placebo (n = 10) treatment arms, and correlation between the two compartments was tested. Airspace biomarkers were also tested for associations with clinical and radiographic outcomes.RESULTSCompared with placebo, MSC treatment significantly reduced airspace total protein, angiopoietin-2 (Ang-2), IL-6, and soluble TNF receptor-1 concentrations. Plasma biomarkers did not differ between groups. Each 10-fold increase in airspace Ang-2 was independently associated with 6.7 fewer days alive and free of mechanical ventilation (95% CI, -12.3 to -1.0, P = 0.023), and each 10-fold increase in airspace receptor for advanced glycation end-products (RAGE) was independently associated with a 6.6-point increase in day 3 radiographic assessment of lung edema score (95% CI, 2.4 to 10.8, P = 0.004).CONCLUSIONMSCs reduced biological evidence of lung injury in patients with ARDS. Biomarkers from the airspaces provide additional value for studying pathogenesis, treatment effects, and outcomes in ARDS.TRIAL REGISTRATIONClinicalTrials.gov NCT02097641.FUNDINGNational Heart, Lung, and Blood Institute.
In ARDS, elevated pulmonary dead-space fraction (V
/V
) is a particularly strong indicator of mortality risk. Whether the magnitude of V
/V
is modified by the underlying etiology of ARDS and whether ...this influences the strength of its association with mortality remains unknown. We sought to elucidate the impact of ARDS etiology on V
/V
and also to determine whether ARDS severity, as classified by the Berlin definition, has correspondence with changes in V
/V
.
This single-center, retrospective, observational study (2010-2016) measured V
/V
in 685 subjects with ARDS as part of clinical management with lung-protective ventilation. Volumetric capnography was used to measure V
/V
with 99% of measurements occurring within 48 h of ARDS onset. Demographic information as well as illness severity scores and pulmonary mechanics data also were collected. Multivariate logistic regression modeling was done to assess the strength of association between V
/V
and mortality.
V
/V
was elevated across etiologies, with aspiration and pneumonia having significantly higher V
/V
than non-pulmonary sepsis or trauma. Differences in the magnitude of V
/V
across etiologies did not necessarily correspond with mortality between etiologies. However, within each etiology grouping, V
/V
was significantly elevated in non-survivors versus survivors. The same results were found in both moderate and severe (but not mild) ARDS using the Berlin definition. In the final adjusted model, the strongest mortality risk was V
/V
, wherein the risk of death increased by 22% for every 0.05 increase in V
/V
.
V
/V
magnitude varies by ARDS etiology, as does mortality. Only in mild ARDS does V
/V
fail to distinguish non-survivors from survivors. Nonetheless, V
/V
has the strongest association with mortality risk in those with ARDS.
Although lung transplantation aims to improve health-related quality of life (HRQL), existing instruments fail to include health domains considered important in this population.
We aimed to develop a ...comprehensive lung transplant-specific instrument to address this shortcoming.
We developed a pool of 126 candidate items addressing domains previously identified as important by lung transplant recipients. Through cognitive interviews conducted in 43 transplant recipients, items deemed irrelevant or redundant were dropped. The 84 remaining items were field tested in lung transplant recipients. Exploratory and confirmatory factor analyses were used to evaluate the factor structure, and scales were evaluated for internal consistency and construct validity.
The 84-item preliminary survey was administered to 201 lung transplant recipients with a mean age of 57.9 (±12.7) years; 46% were female. After factor analyses and internal consistency evaluation, we retained 60 items comprising the Lung Transplant Quality of Life (LT-QOL) Survey. The LT-QOL contains 10 scales that measure symptoms, health perceptions, functioning, and well-being. The confirmatory factor analysis model had good approximate fit (comparative fit index = 0.990; standardized root-mean-square residual = 0.062). Cronbach αs for the 10 scales ranged from 0.75 to 0.95. Interscale correlations were consistent with hypothesized relationships. Subjects with severe chronic lung allograft dysfunction (n = 13) reported significantly worse HRQL than subjects without chronic lung allograft dysfunction (n = 168) on 6 of the 10 LT-QOL scales.
The LT-QOL is a new, multidimensional instrument that characterizes and quantifies HRQL in lung transplant recipients.
Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. ...Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes.
We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted at two sites, one tertiary care center and one urban safety net hospital. RIARDS was defined according to previous studies as improvement of hypoxemia defined as (i) PaO
:FiO
> 300 or (ii) SpO2: FiO
> 315 on the day following diagnosis of ARDS (day 2) or (iii) unassisted breathing by day 2 and for the next 48 h (defined as absence of endotracheal intubation on day 2 through day 4). Plasma biomarkers were measured on samples collected on the day of study enrollment, and ARDS phenotypes were allocated as previously described.
RIARDS accounted for 21% of all ARDS participants. Patients with RIARDS had better clinical outcomes compared to those with persistent ARDS, with lower hospital mortality (13% vs. 57%; p value < 0.001) and more ICU-free days (median 24 vs. 0; p value < 0.001). Plasma levels of interleukin-6, interleukin-8, and plasminogen activator inhibitor-1 were significantly lower among patients with RIARDS. The hypoinflammatory phenotype of ARDS was more common among patients with RIARDS (78% vs. 51% in persistent ARDS; p value = 0.001).
This study identifies a high prevalence of RIARDS in a multicenter observational cohort and confirms the more benign clinical course of these patients. We report the novel finding that RIARDS is characterized by lower concentrations of plasma biomarkers of inflammation compared to persistent ARDS, and that hypoinflammatory ARDS is more prevalent among patients with RIARDS. Identification and exclusion of RIARDS could potentially improve prognostic and predictive enrichment in clinical trials.
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