Intestinal Inflammatory Biomarkers and Outcome in Pediatric Clostridium difficile Infections

Abstract

To identify specific fecal biomarkers for symptomatic Clostridium difficile infection and predictors of poor outcomes. We enrolled 65 children with positive C difficile testing (cases) and 37 symptomatic controls. We also analyzed stool samples from colonized and non-colonized asymptomatic children. We performed enzyme immunoassays to determine fecal interleukin (IL)-8, lactoferrin, and phosphorylated-p38 protein concentrations, and quantitative polymerase chain reaction to determine IL-8 and chemokine ligand (CXCL)-5 RNA relative transcript abundances, and C difficile bacterial burden. Of 68 asymptomatic controls, 16 were colonized with C difficile. Phosphorylated-p38 was specific for C difficile infection but lacked sensitivity. Fecal cytokines were elevated in samples from symptomatic children, whether cases or controls. In children with C difficile infection, fecal CXCL-5 and IL-8 messenger RNA abundances at diagnosis correlated with persistent diarrhea after 5 days of C difficile infection therapy and with treatment with vancomycin. When children with concomitant viral gastroenteritis were excluded, these correlations persisted. Time-to-diarrhea resolution was significantly longer in patients with elevated fecal cytokines at diagnosis. A logistic regression model identified high CXCL-5 messenger RNA abundance as the only predictor of persistent diarrhea. Conversely, fecal C difficile bacterial burden was not different in symptomatic and asymptomatic children and did not correlate with any clinical outcome measure. Fecal inflammatory cytokines may be useful in distinguishing C difficile colonization from disease and identifying children with C difficile infection likely to have prolonged diarrhea.