Background
Septic shock is a leading cause of morbidity and mortality in children, with over 7000 pediatric deaths due to sepsis in the USA each year [
1,
2]. Septic shock is characterized by a dysregulated systemic immune response to infection that results in organ dysfunction. The failure of more than one organ, termed “multiple organ dysfunction syndrome (MODS),” confers a > 10-fold increase in risk of mortality in critically ill children [
3]. Current management guidelines for pediatric sepsis largely focus on supportive care, including fluid resuscitation and vasoactive medications, in addition to early empiric antibiotics [
4]. Hydrocortisone is frequently prescribed as an adjunctive treatment for children with septic shock who have known adrenal insufficiency, those with a history of recent corticosteroid use, and those who remain hemodynamically unstable despite fluid resuscitation and initiation of vasoactive support [
5,
6]. The use of hydrocortisone in septic shock, however, remains controversial, with clinical trials in adults yielding conflicting results [
7‐
9]. The current version of the pediatric Surviving Sepsis guidelines is unable to recommend for or against hydrocortisone use, largely due to a lack of evidence. The first prospective clinical trial of hydrocortisone use in pediatric septic shock is currently underway (NCT03401398).
The immune response to pediatric critical illness is highly dynamic, with acquired immune suppression frequently accompanying systemic inflammation. When severe, this compensatory immune suppression is termed “immunoparalysis.” We and others have consistently shown that immunoparalysis is associated with adverse outcomes from critical illness in children including sepsis, trauma, and cardiopulmonary bypass [
10‐
13]. We recently observed, in a prospective, single-center, 102-subject cohort of children with severe sepsis/septic shock, that both immunoparalysis and hydrocortisone treatment were associated with longer duration of organ dysfunction. Prior transcriptomic work has suggested the possibility of a differential effect of hydrocortisone on pediatric sepsis outcomes depending on the host immune phenotype [
14]. We therefore designed this secondary analysis of our data set to test the hypothesis that the relationships between hydrocortisone treatment and duration of MODS will be variable, depending on the presence or absence of immunoparalysis.
Discussion
Ours is the first study to examine the relationships between the functional immune response, hydrocortisone use, and clinical outcomes in septic children. We were able to identify differential risk for prolonged organ dysfunction in children treated with hydrocortisone depending on their immune function in the acute phase of sepsis, with children with immunoparalysis demonstrating more prolonged MODS. Our data are in agreement with previously published mRNA studies [
14] and highlight the need to incorporate prospective immunophenotyping into the design of future clinical trials of hydrocortisone in septic children.
Severe sepsis/septic shock remains a major source of morbidity and mortality worldwide. A recent multi-national point prevalence study found a 25% mortality associated with pediatric severe sepsis [
22] while another US multi-center study found a strong correlation between higher organ dysfunction scores and lower health-related quality of life in pediatric survivors of septic shock [
23]. The mainstays of pediatric sepsis management include early fluid resuscitation, timely antibiotic administration, and hemodynamic support [
6,
24,
25] though hydrocortisone is frequently used as adjuvant therapy in children with fluid and catecholamine-resistant shock as well as those with a priori risk factors for adrenal insufficiency. Hydrocortisone use in sepsis remains highly controversial, however. Evidence suggests that low-dose hydrocortisone treatment is associated with a shorter time to shock reversal in septic adults [
26], but its reported effects on mortality have been inconsistent and at least one study has suggested an increase in nosocomial infection risk with hydrocortisone use [
8]. Retrospective, observational pediatric data raise the possibility of equivocal or even harmful effects of hydrocortisone in the treatment of sepsis [
27‐
29], but data from pediatric randomized controlled trials are, as yet, lacking. The current version of the pediatric Surviving Sepsis guidelines recommends neither for nor against the use of hydrocortisone [
4].
While it is used in septic patients primarily for its hemodynamic-supporting mineralocorticoid activity, hydrocortisone does have some glucocorticoid activity which has the potential to exacerbate or perpetuate sepsis-induced immune suppression. The host immune response to sepsis is highly dynamic. The initial pro-inflammatory response is quickly accompanied by a compensatory downregulation of systemic immune function. This is termed “immunoparalysis” when severe and is characterized by a marked reduction of the ability of whole blood to produce TNFα upon ex vivo stimulation with LPS. We and others have repeatedly shown associations between reduction in the TNFα response and adverse outcomes including nosocomial infection, prolonged organ dysfunction, and death in critically ill children [
13,
16,
18]. We recently published the results of a single-center, prospective immune phenotyping study of 102 children with severe sepsis/septic shock in which the use of hydrocortisone and severe reduction in the TNFα response were both associated with longer durations of MODS [
17]. The degree to which hydrocortisone influences the host immune response in this setting is unknown. The current study represents a secondary analysis of this cohort, with emphasis on the relationships between hydrocortisone use, immunoparalysis, and MODS.
Our observation that hydrocortisone use was associated with a differential outcome depending on the subject’s immunophenotype is complementary to a recent biomarker study conducted by Wong et al. Their group developed a panel of 5 plasma proteins (the PERSEVERE panel) that has been validated to risk-stratify children with acute septic shock [
30]. They also developed a 100-gene leukocyte transcriptomic panel that segregates children with acute septic shock into endotypes that are characterized by under-activation (endotype A) or overactivation (endotype B) of genes related to adaptive immunity and glucocorticoid receptor signaling [
31]. In a secondary analysis of 288 children with acute septic shock, subjects in the intermediate and high-risk PERSEVERE groups who exhibited endotype B, hydrocortisone use was associated with a more than 10-fold reduction in in the risk of death or prolonged MODS. Hydrocortisone use was not associated with clinical outcomes in subjects with endotype A. This suggested that hydrocortisone benefit may be limited to children with a more activated immune state. Our study takes this line of reasoning further and, for the first time, provides evidence of an association between hydrocortisone use and
worse outcomes in children who have severe functional innate immune impairment. It is therefore possible that prior clinical trials of hydrocortisone use in sepsis may have failed to correctly identify beneficial or harmful effects due to an inability to adjust for subjects’ immunologic state. Since immunoparalysis is typically occult, and biomarkers of immunoparalysis are not currently measured in the clinical laboratory, it will be crucial to include prospective immune phenotyping in the design of future clinical trials of hydrocortisone in septic children.
Additionally, our results showed that receipt of a RBC transfusion was also associated with a higher risk of a longer duration of MODS, an observation that was recently the subject of another secondary analysis of this data set [
32]. We also found that the presence of baseline immune compromise was associated with fewer MODS days in patients with immunoparalysis. In this patient population, immune suppression may be a modifiable risk factor through the tapering of immunosuppressive medication. Further, the presence of known baseline immune compromise may prompt earlier and more aggressive sepsis treatment. This is an area of active investigation.
This study was limited by its single center design and small sample size. Despite this, we were able to demonstrate significant associations between hydrocortisone use, immune function, and outcomes. The use of hydrocortisone in this study was not protocolized, and the resulting variability in prescription may have influenced our results. Perhaps most importantly, the majority of subjects who received hydrocortisone in our cohort underwent immune function testing after having received at least one dose of hydrocortisone. It is therefore unclear if hydrocortisone contributed to the development of immunoparalysis or if subjects at high risk for immunoparalysis are also more likely to receive hydrocortisone. The cause-and-effect relationship between hydrocortisone and innate immune suppression in critically ill children is an active area of investigation for our research group. The presence of a differential relationship between hydrocortisone use and outcomes depending on the host immune response, however, remains a key confounder of future clinical trials of hydrocortisone in pediatric sepsis. Lastly, this study focuses primarily on the TNFα response, which represents only one measure of immune function. While other aspects of immune function including phagocytosis, intracellular killing, antigen presentation, adaptive immune responses, and immunologic memory may be of interest in this population, a large body of literature suggests that the TNFα response is a highly clinically relevant readout of immune function in septic children.
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