Purpose
Angiopoietin 2 (Ang2) and soluble receptor for advanced glycation end products (sRAGE) are markers of endothelial and pulmonary epithelial damage with prognostic implications in adult acute ...respiratory distress syndrome (ARDS), but unclear significance in pediatric ARDS (PARDS).
Methods
This was a prospective, observational study in children with PARDS (2012 Berlin and 2015 PALICC definitions) at the Children’s Hospital of Philadelphia. Plasma was collected within 48 h of PARDS onset and biomarkers quantified by enzyme-linked immunosorbent assay.
Results
In 82 children with PARDS (12 deaths, 15 %), Ang2 and sRAGE were higher in non-survivors than survivors (
p
< 0.01 for both). Mortality was highest in patients with Ang2 and sRAGE levels both above median values. Ang2 and sRAGE correlated with the number of non-pulmonary organ failures (both
p
< 0.001). Ang2 was higher in indirect lung injury and in immunocompromised children. In stratified analysis, both Ang2 and sRAGE were associated with mortality only in direct lung injury and in immunocompetent children, with no association evident in indirect lung injury or in immunocompromised children.
Conclusions
Ang2 and sRAGE in early PARDS were higher in non-survivors than survivors and strongly correlated with number of non-pulmonary organ failures. When stratified by type of lung injury, Ang2 and sRAGE were associated with mortality only in direct lung injury. Similarly, when stratified by immunocompromised status, Ang2 and sRAGE were associated with mortality only in immunocompetent children. The utility of these biomarkers for prognostication and risk stratification requires investigation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
ABSTRACTBackgroundAcute respiratory distress syndrome (ARDS) is a serious complication of sepsis, and sepsis-associated ARDS is associated with significant morbidity and mortality. To date, no study ...has directly examined the epidemiology of ARDS in severe sepsis from the earliest presentation to the health care system, the emergency department (ED). MethodsThis was a single-center retrospective, observational cohort study of 778 adults with severe sepsis presenting to the ED. The primary outcome was the development of ARDS requiring mechanical ventilation during the first 5 hospital days. Acute respiratory distress syndrome was defined using the Berlin definition. We used multivariable logistic regression to identify risk factors associated independently with ARDS development. ResultsThe incidence of ARDS was 6.2% (48/778 patients) in the entire cohort. Acute respiratory distress syndrome development varied across the continuum of care0.9% of patients fulfilled criteria for ARDS in the ED, 1.4% admitted to the ward developed ARDS, and 8.9% admitted to the intensive care unit developed ARDS. Acute respiratory distress syndrome developed a median of 1 day after admission and was associated with a 4-fold higher risk of in-hospital mortality (14% vs. 60%, P < 0.001). Independent risk factors associated with increased risk of ARDS development included intermediate (2–3.9 mmol/L) (P = 0.04) and high (≥4) serum lactate levels (P = 0.008), Lung Injury Prediction score (P < 0.001), and microbiologically proven infection (P = 0.01). ConclusionsIn patients presenting to the ED with severe sepsis, the rate of sepsis-associated ARDS development varied across the continuum of care. Acute respiratory distress syndrome developed rapidly and was associated with significant mortality. Elevated serum lactate levels in the ED and a recently validated clinical prediction score were independently associated with the development of ARDS in severe sepsis.
The epidemiology, management, and outcomes of acute respiratory distress syndrome (ARDS) differ between children and adults, with lower mortality rates in children despite comparable severity of ...hypoxemia. However, the relationship between age and mortality is unclear.
We aimed to define the association between age and mortality in ARDS, hypothesizing that it would be nonlinear.
We performed a retrospective cohort study using data from two pediatric ARDS observational cohorts (
= 1,236), multiple adult ARDS trials (
= 5,547), and an adult observational ARDS cohort (
= 1,079). We aligned all datasets to meet Berlin criteria. We performed unadjusted and adjusted logistic regression using fractional polynomials to assess the potentially nonlinear relationship between age and 90-day mortality, adjusting for sex, Pa
/Fi
, immunosuppressed status, year of study, and observational versus randomized controlled trial, treating each individual study as a fixed effect.
There were 7,862 subjects with median ages of 4 years in the pediatric cohorts, 52 years in the adult trials, and 61 years in the adult observational cohort. Most subjects (43%) had moderate ARDS by Berlin criteria. Ninety-day mortality was 19% in the pediatric cohorts, 33% in the adult trials, and 67% in the adult observational cohort. We found a nonlinear relationship between age and mortality, with mortality risk increasing at an accelerating rate between 11 and 65 years of age, after which mortality risk increased more slowly.
There was a nonlinear relationship between age and mortality in pediatric and adult ARDS.
Objective Oxidant stress pathway activation during ischemia reperfusion injury may contribute to the development of primary graft dysfunction (PGD) after lung transplantation. We hypothesized that ...oxidant stress gene variation in recipients and donors is associated with PGD. Methods Donors and recipients from the Lung Transplant Outcomes Group (LTOG) cohort were genotyped using the Illumina IBC chip filtered for oxidant stress pathway genes. Single nucleotide polymorphisms (SNPs) grouped into SNP sets based on haplotype blocks within 49 oxidant stress genes selected from gene ontology pathways and literature review were tested for PGD association using a sequencing kernel association test. Analyses were adjusted for clinical confounding variables and population stratification. Results Three hundred ninety-two donors and 1038 recipients met genetic quality control standards. Thirty percent of patients developed grade 3 PGD within 72 hours. Donor NADPH oxidase 3 ( NOX3 ) was associated with PGD ( P = .01) with 5 individual significant loci ( P values between .006 and .03). In recipients, variation in glutathione peroxidase ( GPX1 ) and NRF-2 ( NFE2L2 ) was significantly associated with PGD ( P = .01 for both). The GPX1 association included 3 individual loci ( P values between .006 and .049) and the NFE2L2 association included 2 loci ( P = .03 and .05). Significant epistatic effects influencing PGD susceptibility were evident between 3 different donor blocks of NOX3 and recipient NFE2L2 ( P = .026, P = .017, and P = .031). Conclusions Our study has prioritized GPX1 , NOX3 , and NFE2L2 genes for future research in PGD pathogenesis, and highlights a donor-recipient interaction of NOX3 and NFE2L2 that increases the risk of PGD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Late-onset (more than 48 h after ICU admission) acute respiratory distress syndrome (ARDS) is associated with shorter survival time and higher mortality; however, the underlying molecular targets ...remain unclear. As the
gene family is known to drive inflammation, immunity, and tissue fibrosis, all of which are closely related to the pathogenesis and prognosis of ARDS, we aim to investigate the associations of the
family with late-onset ARDS and 28-day survival. Genetic (
= 380), epigenetic (
= 185), transcriptional (
= 160), and protein (
= 300) data of patients with ARDS were extracted from the MEARDS (Molecular Epidemiology of ARDS) cohort. We used sure independence screening to identify late onset-related genetic biomarkers and constructed a genetic score on the basis of eight SNPs, which was associated with risk for late-onset ARDS (odds ratio OR, 2.72;
= 3.81 × 10
) and survival (hazard ratio HR, 1.28;
= 0.008). The associations were further externally validated in the iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk) (OR
, 2.49
= 0.006; HR
, 1.87
= 0.045) and MESSI (Molecular Epidemiology of Severe Sepsis in the ICU) (OR
, 4.12
= 0.026; HR
, 1.45
= 0.036) cohorts. Furthermore, we functionally interrogated the six mapped genes of eight SNPs in the multiomics data and noted associations of
(
family member 9A) in epigenetic (OR
, 2.95
= 9.91 × 10
; HR
, 1.53
= 0.011) and protein (OR
, 1.42
= 0.035; HR
, 1.38
= 0.011) data. The mediation analysis indicated that the effects of
on ARDS survival were mediated by late onset (HR
, 1.12
= 0.014 for genetic data; HR
, 1.05
= 0.030 for protein data). The essential roles of
in immunity and fibrosis may explain the different trajectories of recovery and dysfunction between early- and late-onset ARDS, providing clues for ARDS treatment.
Plasmalogens are a class of phospholipids containing vinyl ether linked aliphatic groups at the sn-1 position. Plasmalogens are known to contain 16- and 18-carbon aliphatic groups at the sn-1 ...position. Here, we reveal that the human neutrophil plasmenylethanolamine pool uniquely includes molecular species with very long carbon chain (VLC) aliphatic groups, including 20-, 22- and 24-carbon vinyl ether linked aliphatic groups at the sn-1 position. We identified these novel VLC plasmalogen species by electrospray ionization mass spectrometry methods. VLC plasmalogens were only found in the neutrophil plasmenylethanolamine pool. During neutrophil activation, VLC plasmenylethanolamines undergo myeloperoxidase-dependent oxidation to produce VLC 2-chlorofatty aldehyde and its oxidation product, 2-chlorofatty acid (2-ClFA). Furthermore, plasma concentrations of VLC 2-ClFA are elevated in human sepsis. These studies demonstrate for the first time VLC plasmenylethanolamine molecular species, their myeloperoxidase-mediated chlorolipid products and the presence of these chlorolipids in human sepsis.
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•Novel very long chain (VLC) plasmenylethanolamine molecular species are discovered in human neutrophils.•VLC plasmenylethanolamines undergo myeloperoxidase dependent oxidation to produce new VLC chlorinated lipids.•VLC 2-chlorofatty acids are elevated in human sepsis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multisystem organ failure and viral sepsis characterized by respiratory failure, arrhythmias, thromboembolic complications, and ...shock with high mortality. Autopsy and preclinical evidence implicate aberrant complement activation in endothelial injury and organ failure. Erythrocytes express complement receptors and are capable of binding immune complexes; therefore, we investigated complement activation in patients with COVID-19 using erythrocytes as a tool to diagnose complement activation. We discovered enhanced C3b and C4d deposition on erythrocytes in COVID-19 sepsis patients and non-COVID sepsis patients compared with healthy controls, supporting the role of complement in sepsis-associated organ injury. Our data suggest that erythrocytes may contribute to a precision medicine approach to sepsis and have diagnostic value in monitoring complement dysregulation in COVID-19-sepsis and non-COVID sepsis and identifying patients who may benefit from complement targeted therapies.
Abstract Purpose Acute kidney injury (AKI) is a common source of morbidity after trauma. We sought to determine novel risk factors for AKI, by Acute Kidney Injury Network (AKIN) criteria, in ...critically ill trauma patients. Materials and Methods A prospective cohort of 400 patients admitted to the intensive care unit of a level 1 trauma center was followed for the development of AKI over 5 days. Results Acute kidney injury developed in 147 (36.8%) of 400 patients. In multivariable regression analysis, independent risk factors for AKI included African American race (odds ratio OR, 1.86; 95% confidence interval CI, 1.08-3.18; P = .024), body mass index of 30 kg/m2 or greater (OR, 4.72 versus normal body mass index; 95% CI, 2.59-8.61; P < .001), diabetes mellitus (OR, 3.26; 95% CI, 1.30-8.20; P = .012), abdominal Abbreviated Injury Scale score of 4 or more (OR, 3.78; 95% CI, 1.79-7.96; P < .001), and unmatched packed red blood cells administered during resuscitation (OR, 1.13 per unit; 95% CI, 1.04-1.23; P = .004). Acute Kidney Injury Network stages 1, 2, and 3 were associated with hospital mortality rates of 9.8%, 13.7%, and 30.4%, respectively, compared with 3.8% for those without AKI ( P < .001). Conclusions Acute kidney injury in critically ill trauma patients is associated with substantial mortality. The findings of African American race, obesity, and blood product administration as independent risk factors for AKI deserve further study to elucidate underlying mechanisms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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