Corticosteroids are associated with repression of adaptive immunity gene programs in pediatric septic shock

Abstract

Rationale: Corticosteroids are prescribed commonly for patients with septic shock, but their use remains controversial and concerns remain regarding side effects.

Objectives: To determine the effect of adjunctive corticosteroids on the genomic response of pediatric septic shock.

Methods: We retrospectively analyzed an existing transcriptomic database of pediatric septic shock. Subjects receiving any formulation of systemic corticosteroids at the time of blood draw for microarray analysis were classified in the septic shock corticosteroid group. We compared normal control subjects (n = 52), a septic shock no corticosteroid group (n = 110), and a septic shock corticosteroid group (n = 70) using analysis of variance. Genes differentially regulated between the no corticosteroid group and the corticosteroid group were analyzed using Ingenuity Pathway Analysis.

Measurements and main results: The two study groups did not differ with respect to illness severity, organ failure burden, mortality, or mortality risk. There were 319 gene probes differentially regulated between the no corticosteroid group and the corticosteroid group. These genes corresponded predominately to adaptive immunity-related signaling pathways, and were down-regulated relative to control subjects. Notably, the degree of down-regulation was significantly greater in the corticosteroid group, compared with the no corticosteroid group. A similar pattern was observed for genes corresponding to the glucocorticoid receptor signaling pathway.

Conclusions: Administration of corticosteroids in pediatric septic shock is associated with additional repression of genes corresponding to adaptive immunity. These data should be taken into account when considering the benefit to risk ratio of adjunctive corticosteroids for septic shock.

Figure 1.

Gene expression mosaics for 319 gene probes differentially regulated between the septic shock no corticosteroid group and the septic shock corticosteroid group. Each gene expression mosaic depicts that same 319 gene probes at the identical coordinates. The degree of red intensity correlates with increased gene expression, whereas the degree of blue intensity correlates with decreased gene expression.

Figure 2.

Box-and-whisker plots depicting the relative mRNA expression values for genes corresponding to the respective signaling pathways shown in Table 2. *P < 0.05 versus the septic shock no corticosteroid group. CCR = chemokine receptor; CTLA = cytotoxic T- lymphocyte antigen; iCOS = inducible T-cell costimulator (CD278); iNOS = inducible nitric oxide synthetase; NFAT = nuclear factor of activated T cells; PKC = protein kinase C.

Figure 3.

Top scoring network represented by the 319 gene probes differentially regulated between the septic shock no corticosteroid group and the septic shock corticosteroid group. Red intensity indicates increased expression and green intensity indicates decreased expression in the corticosteroid group, relative to the no corticosteroid group. The genes corresponding to the respective nodes are provided in Table E2.