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Increased intestinal permeability, endotoxaemia present in children with noncritical infections

Stephen Padilla
12 Jul 2019

Children with noncritical infections and no gastrointestinal symptoms show similar gut and innate immune cell alterations as those with severe sepsis or organ failure, according to a study. Such changes are associated with increased morbidity and mortality and with a higher risk of future infections.

“Children hospitalized with noncritical infections had increased intestinal permeability, endotoxaemia, and altered monocyte phenotype and function,” researchers said. “Collectively, these changes are typical of immunoparalysis seen in children with critical illness and may increase the risk of subsequent infections.”

This proof-of-concept pilot study enrolled 11 children aged 6–59 months hospitalized for noncritical infections and 19 noninfected controls, among whom intestinal permeability was measured by lactulose–mannitol recovery.

Researchers evaluated 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.

Intestinal permeability and plasma endotoxin levels were higher in infected children than controls. Fewer monocytes expressed human leukocyte antigen DR isotype (HLA-DR; 87.1 percent vs 96.4 percent; p=0.001) and more expressed CD64 (99.6 percent vs 97.6 percent; p=0.041) in infected children as compared with controls. [Pediatr Infect Dis J 2019;38:741-748]

Infected children vs controls also produced less interleukin 1 beta (IL-1β; median, 1,101 vs 2,604 pg/mL; p=0.048) and tumour necrosis factor alpha (TNF-α; 2,342 vs 5,130 pg/mL; p=0.031) following zymosan stimulation of whole blood.

Moreover, fewer monocytes expressed CD86 (69.8 percent vs 92.4 percent; p=0.003) and CD64 was less expressed (median fluorescence intensity 1,514 vs 2,196; p=0.022) in children with higher (≥0.1 endotoxin unit (EU)/mL) vs lower (<0.1 EU/mL) circulating endotoxin following 24-hour zymosan stimulation.

Increased intestinal permeability appears to present with multifactorial pathogenesis, according to researchers. For instance, regarding gastrointestinal infections, mechanical damage to the epithelium as well as loss of tight junction integrity and villous atrophy arise from local inflammatory processes that cause cytokine-dependent changes in the enterocyte cytoskeleton. [J Pediatr Gastroenterol Nutr 1989;8:466-473; Nat Rev Immunol 2009;9:799-809; J Gastroenterol Hepatol 2007;22:464-471]

In terms of critical illness or sepsis, hypoperfusion of the gut occurs, leading to epithelial hypoxic injury, acidosis and disarrangement of the mucosal cytoskeleton. For noncritical infections outside the gut, where there is adequate perfusion, intestinal permeability is poorly described, researchers said. [J Gastroenterol Hepatol 2007;22:464-471]

On the other hand, murine models of pneumonia and children with measles have shown increased intestinal permeability, although the presence of diarrhoea in 30 percent of measles cases signifies difficulty in establishing the mechanism underlying such observation, they noted. [Crit Care Med 2000;28:2573-2577; Arch Dis Child 1986;61:739-743; Am J Clin Nutr 1987;45:1433-1441]

“Future studies should investigate the molecular triggers of these observed changes, how long they persist, and the clinical implications during and after hospitalization,” researchers said. “Such studies are warranted because children with noncritical infections represent a much larger population of children presenting to hospital than children with critical illness.”

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