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Children With Noncritical Infections Have Increased Intestinal Permeability, Endotoxemia and Altered Innate Immune
Jonathan P Sturgeon1,2, Claire D Bourke1, Andrew J Prendergast1,2
1From the Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, United Kingdom.
Insights
Children hospitalized with infections show increased intestinal permeability and endotoxemia, similar to critical illness. This altered immune response may heighten their risk for future infections.
Area of Science:
- Pediatric infectious diseases
- Immunology
- Gastroenterology
Background:
- Children with critical illness exhibit increased intestinal permeability and immunoparalysis due to elevated endotoxin.
- It remains unclear if children with less severe infections experience similar physiological changes.
Purpose of the Study:
- To investigate intestinal permeability, endotoxemia, and immune cell function in children hospitalized with noncritical infections.
- To compare these parameters with healthy controls and explore correlations with endotoxin levels.
Main Methods:
- A pilot study involving children aged 6-59 months with noncritical infections (cases) and healthy controls.
- Measurements included intestinal permeability (lactulose-mannitol recovery), plasma endotoxin, and monocyte/neutrophil immunophenotypes.
- Assessed cytokine production (IL-1β, TNF-α) after whole-blood stimulation.
Main Results:
- Cases showed higher intestinal permeability and plasma endotoxin than controls.
- Monocytes in cases had altered expression of HLA-DR and CD64.
- Cases produced less IL-1β and TNF-α post-stimulation, and higher endotoxin correlated with altered monocyte markers.
Conclusions:
- Children hospitalized for noncritical infections display increased intestinal permeability, endotoxemia, and altered monocyte function.
- These findings suggest a state of immunoparalysis, mirroring that in critical illness.
- This immune alteration could increase susceptibility to subsequent infections.
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.
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