Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response

Wong, Hector R.; Cvijanovich, Natalie Z.; Anas, Nick; Allen, Geoffrey L.; Thomas, Neal J.; Bigham, Michael T.; Weiss, Scott L.; Fitzgerald, Julie C.; Checchia, Paul A.; Meyer, Keith; Quasney, Michael W.; Hall, Mark W.; Gedeit, Rainer; Freishtat, Robert J.; Nowak, Jeffrey; Lutfi, Riad; Gertz, Shira J.; Grunwell, Jocelyn R.; Lindsell, Christopher J.

doi:10.1097/ccm.0000000000002932

Cited by 46 publications

(34 citation statements)

References 24 publications

(49 reference statements)

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“…Univariate analysis further confirmed that high expression of GCR alpha decreased the odds of a complicated course (Table 3 ). This finding is consistent with our previous transcriptional studies showing that patients with a complicated course had downregulation of genes in the glucocorticoid signaling pathway [ 11 , 16 ]. Other groups have also shown reduced GCR alpha expression in pediatric patients critically ill with septic shock [ 22 ].…”

Section: Discussionsupporting

confidence: 93%

“…Many reviews have summarized these studies [ 2 – 5 ]. Some studies have suggested benefit [ 6 ], but subsequent trials have not been able to confirm these findings [ 7 ], whereas other studies suggest that there may be harm due to administration of corticosteroids [ 8 – 11 ]. This was further reiterated with two recent large studies published side by side in the New England Journal of Medicine , again showing conflicting results [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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The glucocorticoid receptor and cortisol levels in pediatric septic shock

2018

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BackgroundThere 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.MethodsWe 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.ResultsWe 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).ConclusionsWe 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.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2177-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

The glucocorticoid receptor and cortisol levels in pediatric septic shock

2018

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“…Several groups have published transcriptomic metrics to identify sepsis immune endotypes that may be useful for risk stratification or, eventually, as a companion diagnostic for immune treatments (40,(54)(55)(56)(57)(58). Further, transcriptomic risk stratification is not limited to sepsis; a 63-mRNA metric of blood leukocyte gene expression was recently shown to be accurate in blunt trauma patients to identify those likely to have complicated clinical trajectories (59).…”

Section: Transcriptomics In Risk Stratificationmentioning

confidence: 99%

Diagnosing and Managing Sepsis by Probing the Host Response to Infection: Advances, Opportunities, and Challenges

Gunsolus

Sweeney²,

Liesenfeld³

et al. 2019

J Clin Microbiol

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Sepsis is a major source of mortality and morbidity globally. Accurately diagnosing sepsis remains challenging due to the heterogeneous nature of the disease, and delays in diagnosis and intervention contribute to high mortality rates. Measuring the host response to infection enables more rapid diagnosis of sepsis than is possible through direct detection of the causative pathogen, and recent advances in host response diagnostics and prognostics hold promise for improving outcomes. The current review discusses recent advances in the technologies used to probe the host response to infection, particularly those based on transcriptomics. These are discussed in the context of contemporary approaches to diagnosing and prognosing sepsis, and recommendations are made for successful development and validation of host response technologies.

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“…Predictive enrichment strategy involves identifying endotypes (subclasses of a disease or syndrome as defined by function or biology) by analyzing gene expression [18]. This highly sophisticated method has revealed that the endotype of patients with sepsis changes over time, possibly affecting the response of these patients to treatment [19]. If this dynamic change of endotype is seen in patients with septic DIC, it may not be beneficial to administer rhsTM to all patients with septic DIC for a uniform duration.…”

Section: Main Textmentioning

confidence: 99%

Should we treat sepsis-induced DIC with anticoagulants?

Inata

2020

j intensive care

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Background: Disseminated intravascular coagulation (DIC) is a common complication in sepsis because of crosstalk between the immune system and the coagulation system. Several anticoagulant agents have been tested in an attempt to improve the survival of patients with sepsis and sepsis-induced DIC. Here, we discuss the rationale against using anticoagulation therapy in septic DIC. Main body of the abstract: Coagulopathy and DIC are associated with increased mortality in sepsis. Several anticoagulant agents have been tested in an attempt to improve the survival of patients with sepsis and sepsisinduced DIC, but have proven largely ineffective. This is because of two major factors. First, the coagulation system is complex and closely related to the immune system. When we manipulate one of the factors involved in these systems, we may disturb the delicate homeostasis between them. A second factor may be failure to identify patients who will benefit from anticoagulation therapy. This may be attributed partly to the fact that there is no gold standard for the diagnosis of DIC, and there are consequently several diagnostic criteria, none of which are specifically designed for sepsis-induced DIC. Application of precision medicine, of the kind currently being applied in other intensive care fields, may be the key to overcoming these challenges. Until we know the precise target population, we should not use anticoagulation therapy in sepsis-induced DIC outside a research setting. Short conclusion: There is no strong evidence to support the effectiveness of routine anticoagulation therapy in sepsis-induced DIC, and it should not be used clinically until more is known regarding the population of patients who may benefit from it.

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Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response

Abstract: A substantial proportion of children with septic shock transition endotypes during the acute phase of illness. The risk of poor outcome and the response to corticosteroids change with changes in endotype assignment. Patients persisting as endotype A are at highest risk of poor outcomes.

Cited by 46 publications

References 24 publications

The glucocorticoid receptor and cortisol levels in pediatric septic shock

The glucocorticoid receptor and cortisol levels in pediatric septic shock

Diagnosing and Managing Sepsis by Probing the Host Response to Infection: Advances, Opportunities, and Challenges

Should we treat sepsis-induced DIC with anticoagulants?

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