Translational gap in pediatric septic shock management: an ESPNIC perspective.
Ontology highlight
ABSTRACT:
SUBMITTER: Morin L
PROVIDER: S-EPMC6598895 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
Publications
Translational gap in pediatric septic shock management: an ESPNIC perspective.
Morin Luc L Kneyber Martin M Jansen Nicolaas J G NJG Peters Mark J MJ Javouhey Etienne E Nadel Simon S Maclaren Graeme G Schlapbach Luregn Jan LJ Tissieres Pierre P
Annals of intensive care 20190628 1
<h4>Background</h4>The Surviving Sepsis Campaign and the American College of Critical Care Medicine guidelines have provided recommendations for the management of pediatric septic shock patients. We conducted a survey among the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) members to assess variations to these recommendations.<h4>Methods</h4>A total of 114 pediatric intensive care physicians completed an electronic survey. The survey consisted of four standardized clinical c ...[more]
Similar Datasets
Project description:The pediatric sepsis syndrome remains a common cause of morbidity, mortality, and health care utilization costs worldwide. The initial resuscitation and management of pediatric sepsis is focused on 1) rapid recognition of abnormal tissue perfusion and restoration of adequate cardiovascular function; 2) eradication of the inciting invasive infection, including prompt administration of empiric broad-spectrum antimicrobial medications; and 3) supportive care of organ system dysfunction. Efforts to improve early and aggressive initial resuscitation and ongoing management strategies have improved outcomes in pediatric severe sepsis and septic shock, though many questions still remain as to the optimal therapeutic strategies for many patients. In this article, we will briefly review the definitions, epidemiology, clinical manifestations, and pathophysiology of sepsis and provide an extensive overview of both current and novel therapeutic strategies used to resuscitate and manage pediatric patients with severe sepsis and septic shock.
| S-EPMC4395852 | biostudies-literature
Project description:In an ongoing translational research program involving microarray-based expression profiles in pediatric septic shock, we have now conducted longitudinal studies focused on the temporal expression profiles of canonical signaling pathways and gene networks. Genome-level expression profiles were generated from whole blood-derived RNA samples of children with septic shock (n = 30 individual patients) corresponding to days 1 and 3 of admission to the pediatric intensive care unit. Based on sequential statistical and expression filters, day 1 and day 3 of septic shock were characterized by differential regulation of 2,142 and 2,504 gene probes, respectively, relative to normal control patients. Venn analysis demonstrated 239 unique genes in the day 1 data set, 598 unique genes in the day 3 data set, and 1,906 genes common to both data sets. Analyses targeted toward derivation of biological function from these data sets demonstrated time-dependent, differential regulation of genes involved in multiple canonical signaling pathways and gene networks primarily related to immunity and inflammation. Notably, multiple and distinct gene networks involving T cell- and MHC antigen-related biological processes were persistently downregulated from day 1 to day 3. Further analyses demonstrated large scale and persistent downregulation of genes corresponding to functional annotations related to zinc homeostasis. These data represent the largest reported cohort of patients with septic shock, which has undergone longitudinal genome-level expression profiling. The data further advance our genome-level understanding of pediatric septic shock and support novel hypotheses that can be readily tested at both the experimental and translational levels. Keywords: Inflammation; sepsis; innate immunity; T cells; MHC antigen Keywords: to be updated
2007-06-14 | GSE8121 | GEO
Project description:ObjectivesPediatric septic shock continues to be an important public health problem. Several investigative groups have applied genetic and genomic approaches as a means of identifying novel pathways and therapeutic targets, discovery of sepsis-related biomarkers, and identification of septic shock subclasses. This review will highlight studies in pediatric sepsis with a focus on gene association studies and genome-wide expression profiling.Data sourcesA summary of published literature involving gene association and expression profiling studies specifically involving pediatric sepsis and septic shock.SummarySeveral polymorphisms of genes broadly involved in inflammation, immunity, and coagulation have been linked with susceptibility to sepsis, or outcome of sepsis in children. Many of these studies involve meningococcemia, and the strongest association involves a functional polymorphism of the plasminogen activator inhibitor-1 promoter region and meningococcal sepsis. Expression profiling studies in pediatric septic shock have identified zinc supplementation and inhibition of matrix metalloproteinase-8 activity as potential, novel therapeutic approaches in sepsis. Studies focused on discovery of sepsis-related biomarkers have identified interleukin-8 as a robust outcome biomarker in pediatric septic shock. Additional studies have demonstrated the feasibility and clinical relevance of gene expression-based subclassification of pediatric septic shock.ConclusionsPediatric sepsis and septic shock are increasingly being studied by genetic and genomic approaches and the accumulating data hold the promise of enhancing our future approach to this ongoing clinical problem.
| S-EPMC3329642 | biostudies-literature
Project description:For nearly a decade, our research group has had the privilege of developing and mining a multicenter, microarray-based, genome-wide expression database of critically ill children (≤10 y of age) with septic shock. Using bioinformatic and systems biology approaches, the expression data generated through this discovery-oriented, exploratory approach have been leveraged for a variety of objectives, which are reviewed here. Fundamental observations include widespread repression of gene programs corresponding to the adaptive immune system and biologically significant differential patterns of gene expression across developmental age groups. The data have also identified gene expression-based subclasses of pediatric septic shock having clinically relevant phenotypic differences. The data have also been leveraged for the discovery of novel therapeutic targets, as well as for the discovery and development of novel stratification and diagnostic biomarkers. Almost a decade of genome-wide expression profiling in pediatric septic shock is now demonstrating tangible results. The studies have progressed from an initial discovery-oriented and exploratory phase to a new phase in which the data are being translated and applied to address several areas of clinical need.
| S-EPMC3615026 | biostudies-literature
Project description:We previously generated genome-wide expression data (microarray) from children with septic shock having the potential to lead the field into novel areas of investigation. Herein we seek to validate our data through a bioinformatic approach centered on a validation patient cohort. Forty-two children with a clinical diagnosis of septic shock and 15 normal controls served as the training data set, while 30 separate children with septic shock and 14 separate normal controls served as the test data set. Class prediction modeling using the training data set and the previously reported genome-wide expression signature of pediatric septic shock correctly identified 95-100% of controls and septic shock patients in the test data set, depending on the class prediction algorithm and the gene selection method. Subjecting the test data set to an identical filtering strategy as that used for the training data set, demonstrated 75% concordance between the two gene lists. Subjecting the test data set to a purely statistical filtering strategy, with highly stringent correction for multiple comparisons, demonstrated <50% concordance with the previous gene filtering strategy. However, functional analysis of this statistics-based gene list demonstrated similar functional annotations and signaling pathways as that seen in the training data set. In particular, we validated that pediatric septic shock is characterized by large-scale repression of genes related to zinc homeostasis and lymphocyte function. These data demonstrate that the previously reported genome-wide expression signature of pediatric septic shock is applicable to a validation cohort of patients.
| S-EPMC2440641 | biostudies-literature
Project description:Polymorphisms of the glucocorticoid receptor gene are associated with outcome and corticosteroid responsiveness among patients with inflammatory disorders. We conducted a candidate gene association study to test the hypothesis that these polymorphisms are associated with outcome and corticosteroid responsiveness among children with septic shock.We genotyped 482 children with septic shock for the presence of two glucocorticoid receptor polymorphisms (rs56149945 and rs41423247) associated with increased sensitivity and one glucocorticoid receptor polymorphism (rs6198) associated with decreased sensitivity to corticosteroids. The primary outcome variable was complicated course, defined as 28-day mortality or the persistence of two or more organ failures 7 days after a septic shock diagnosis. We used logistic regression to test for an association between corticosteroid exposure and outcome, within genotype group, and adjusted for illness severity.Multiple PICUs in the United States.Standard care.There were no differences in outcome when comparing the various genotype groups. Among patients homozygous for the wild-type glucocorticoid receptor allele, corticosteroids were independently associated with increased odds of complicated course (odds ratio, 2.30; 95% CI, 1.01-5.21; p = 0.047).Based on these glucocorticoid receptor polymorphisms, we could not detect a beneficial effect of corticosteroids among any genotype group. Among children homozygous for the wild-type allele, corticosteroids were independently associated with increased odds of poor outcome.
| S-EPMC5380529 | biostudies-literature
Project description:Sepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles. The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses. Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires. Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences. Trial Registration This is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.
| S-EPMC10709863 | biostudies-literature
Project description:BackgroundSepsis is a highly heterogeneous syndrome, that has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles.MethodsThe subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA-sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses.ResultsPatients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells, and less diverse T-Cell receptor repertoires.ConclusionsTwo subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences.Trial registrationThis is a secondary analysis of data generated as part of the observational CAF PINT ancillary of the HALF PINT study (NCT01565941). Registered 29 March 2012.
| S-EPMC10491329 | biostudies-literature
Project description:Rationale: We previously generated genome-wide expression data in children with septic shock, based on whole blood-derive RNA, having the potential to lead the field into novel areas of investigation. Objective: Herein we seek to validate our data through a bioinformatic approach centered on a validation patient cohort. Methods: Microarray- and bioinformatics-centered analyses involving our previous data as a training data set (n = 42) and a new, validation cohort (n = 30) as the test data set. Measurements and Main Results: Class prediction modeling using the training data set and the previously reported genome-wide expression signature of pediatric septic shock correctly identified 93 to 100% of septic shock patients in the test data set, depending on the class prediction algorithm and the gene selection method. Subjecting the test data set to an identical filtering strategy as that used for the training data set, demonstrated 72% concordance between the two gene lists. Subjecting the test data set to a purely statistical filtering strategy, with highly stringent correction for multiple comparisons, demonstrated less than 50% concordance with the previous gene filtering strategy. However, functional analysis of this statistics-based gene list demonstrated similar functional annotations and signaling pathways as that seen in the learning data set. In particular, we validated that pediatric septic shock is characterized by large scale repression of genes related to zinc homeostasis and lymphocyte function. Conclusions: These data demonstrate that the previously reported genome-wide expression signature of pediatric septic shock is applicable to a validation cohort of patients. Keywords: Inflammation; sepsis; innate immunity; T cells; MHC antigen; zinc
2007-12-01 | GSE9692 | GEO
Project description:BACKGROUND:There is controversy around the prescription of adjunct corticosteroids in patients with fluid-refractory septic shock, and studies provide mixed results, showing benefit, no benefit, and harm. Traditional means for evaluating whether a patient receives corticosteroids relied on anecdotal experience or measurement of serum cortisol production following stimulation. We set out to measure both serum cortisol and the intracellular signaling receptor for cortisol, the glucocorticoid receptor (GCR), in this group of patients. METHODS:We enrolled pediatric patients admitted to the pediatric intensive care unit with a diagnosis of systemic inflammatory response syndrome (SIRS), sepsis, or septic shock as well as healthy controls. We measured serum cortisol concentration and GCR expression by flow cytometry in peripheral blood leukocytes on the day of admission and day 3. RESULTS:We enrolled 164 patients for analysis. There was no difference between GCR expression comparing SIRS, sepsis, and septic shock. When all patients with septic shock were compared, those patients with a complicated course, defined as two or more organ failures at day 7 or death by day 28, had lower expression of GCR in all peripheral blood leukocytes. Further analysis suggested that patients with the combination of low GCR and high serum cortisol had higher rates of complicated course (75%) compared with the other three possible combinations of GCR and cortisol levels: low GCR and low cortisol (33%), high GCR and high cortisol (33%), and high GCR and low cortisol (13%; P <0.05). CONCLUSIONS:We show that decreased expression of the GCR correlated with poor outcome from septic shock, particularly in those patients with high serum cortisol. This is consistent with findings from transcriptional studies showing that downregulation of GCR signaling genes portends worse outcome.
| S-EPMC6162875 | biostudies-other