Children with Congenital Heart Disease and Post-Operative PICS (Persistent Inflammation, Immunosuppression, and Catabolism Syndrome) Demonstrate Both Pro- and Anti-Inflammatory Cytokine Profiles
Natalya Beneschott, Sandy Yoder, Eric Brady, Amanda Williams, C Buddy CreechAbstract
Background
Critically ill patients have variable recovery from surgery or sepsis, and some may develop complications that include dysregulated inflammation, blunted immune responses, recurrent infections, and malnutrition. This phenotype of persistent inflammation, immunosuppression, and catabolism syndrome (PICS) is associated with an increased risk of healthcare-associated infections, poor wound healing, and indolent organ failure. A retrospective review of cardiac critical care unit deaths attributed to culture-confirmed sepsis at our institution identified PICS in >75% of cases. Despite the prevalence, the immune dysregulation in PICS has been incompletely characterized.
Methods
Twenty-seven hospitalized children aged 1 month to 7 years underwent CHD surgical repair and were enrolled. Participants were grouped into four broad categories: children who rapidly recovered from children, children at risk for PICS, children with confirmed bacterial infections, and children who met PICS criteria (lymphopenia, elevated CRP, and hypoalbuminemia). Participants underwent weekly blood sampling for up to one month after enrollment, except for the group experiencing rapid recovery who provided a single sample. Seventy-one blood samples were obtained. Plasma cytokines were measured using a 25-plex antibody bead panel (Human Immunotherapy Fixed Panel, Luminex®). Immunophenotyping of peripheral blood mononuclear cells was performed using standard flow cytometric standards. Non-parametric Wilcoxon rank-sum testing was performed using GraphPad Prism.
Results
Compared to the severity and duration of adult lymphopenia in PICS (ALC < 1000), lymphopenia in pediatric PICS was transient and moderate. The pro-inflammatory cytokines IL-1α (p = 0.01), IL-6 (p = 0.04), IP-10 (p = 0.01), IFNγ (p = 0.03), and GM-CSF (p = 0.01) were increased in participants with PICS when compared to those without PICS. The anti-inflammatory cytokines PD-L1 (p = 0.02), IL-1RA (p = 0.002) and IL-10 (p = 0.003) were also increased in PICS.
Conclusions
Children with PICS demonstrate a cytokine profile that is both pro-inflammatory and anti-inflammatory, demonstrating the immune dysregulation characteristic of PICS. Future pediatric studies are needed in children to refine the case definition for PICS and to identify potential strategies for intervention.