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Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response
Hector R Wong1,2, Natalie Z Cvijanovich3, Nick Anas4
1Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.
Insights
Children with septic shock can change between endotypes A and B within three days. Endotype changes impact outcomes and corticosteroid response, with persistent endotype A indicating the highest mortality risk.
Area of Science:
- Pediatric critical care medicine
- Immunology
- Genetics
Background:
- Septic shock endotypes A and B were previously identified based on 100 genes.
- These endotypes are associated with differing outcomes and corticosteroid responsiveness.
Purpose of the Study:
- To determine if septic shock endotypes change during the initial three days of illness in children.
- To investigate the association between endotype changes, corticosteroid response, and patient outcomes.
Main Methods:
- An observational cohort study involving 375 children with septic shock.
- Measurement of 100 endotyping genes at day 1 and day 3 of illness.
- Multivariable logistic regression analysis adjusted for illness severity, age, and comorbidity.
Main Results:
- A significant proportion of children transitioned between endotypes A and B from day 1 to day 3 (42% from A to B, 32% from B to A).
- Endotype A at day 1 was linked to increased mortality risk, modified by day 3 endotype.
- Corticosteroids increased mortality risk for patients who remained endotype A.
Conclusions:
- Septic shock endotypes are dynamic during the acute illness phase in children.
- Endotype shifts influence patient outcomes and corticosteroid efficacy.
- Persistent endotype A is associated with the highest risk of adverse outcomes.
Objective:
We previously identified septic shock endotypes A and B based on 100 genes reflecting adaptive immunity and glucocorticoid receptor signaling. The endotypes differ with respect to outcome and corticosteroid responsiveness. We determined whether endotypes change during the initial 3 days of illness, and whether changes are associated with outcomes.
Design:
Observational cohort study including existing and newly enrolled participants.
Setting:
Multiple PICUs.
Patients:
Children with septic shock.
Interventions:
None.
Measurements And Main Results:
We measured the 100 endotyping genes at day 1 and day 3 of illness in 375 patients. We determined if endotype assignment changes over time, and whether changing endotype is associated with corticosteroid response and outcomes. We used multivariable logistic regression to adjust for illness severity, age, and comorbidity burden. Among the 132 subjects assigned to endotype A on day 1, 56 (42%) transitioned to endotype B by day 3. Among 243 subjects assigned to endotype B on day 1, 77 (32%) transitioned to endotype A by day 3. Assignment to endotype A on day 1 was associated with increased odds of mortality. This risk was modified by the subsequent day 3 endotype assignment. Corticosteroids were associated with increased risk of mortality among subjects who persisted as endotype A.
Conclusions:
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.
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