Children with Noncritical Infections have Increased Intestinal Permeability, Endotoxemia and Altered Innate Immune Responses

Abstract

Background: Children with critical illness have increased intestinal permeability and a period of immunoparalysis, mediated by elevated circulating endotoxin. Whether children with less severe infections have similar changes is uncertain. Methods: We conducted a proof-of-concept pilot study, enrolling children 6-59 months of age hospitalized for noncritical infections (cases, n = 11) and noninfected controls (n = 19). Intestinal permeability was measured by lactulose-mannitol recovery. Plasma endotoxin, blood monocyte and neutrophil immunophenotypes and cytokine elaboration following 24-hour whole-blood culture with antigens targeting distinct innate pathogen recognition receptor signaling pathways were evaluated. Results: Cases had higher intestinal permeability and plasma endotoxin levels than controls. Among cases versus controls, fewer monocytes expressed human leukocyte antigen DR isotype (HLA-DR) (87.1% vs. 96.4%, P = 0.001), and more expressed CD64 (99.6% vs. 97.6%, P = 0.041). Following zymosan stimulation of whole blood, cases versus controls produced less interleukin 1 beta (IL-1β) (median 1101 vs. 2604 pg/mL, P= 0.048) and tumor necrosis factor alpha (TNF-α) (2342 vs. 5130 pg/mL, P = 0.031). Children with higher (≥0.1 endotoxin unit (EU)/mL) versus lower (<0.1 EU/mL) circulating endotoxin had fewer monocytes expressing CD86 (69.8% vs. 92.4%, P = 0.003) and less expression of CD64 following 24-hour zymosan stimulation (median fluorescence intensity (MFI) 1514 vs. 2196, P = 0.022). Conclusions: Children hospitalized with noncritical infections had increased intestinal permeability, endotoxemia and altered monocyte phenotype and function. Collectively, these changes are typical of immunoparalysis seen in children with critical illness and may increase the risk of subsequent infections.