Intestinal Injury Biomarkers Predict Mortality in Pediatric Severe Malaria
Maithri L Sarangam1, Ruth Namazzi2,3, Dibyadyuti Datta4
1University of Washington, Seattle, Washington, USA.
Abstract:
Severe malaria (SM) increases the risk of invasive bacterial infection, and there is evidence to suggest increased gastrointestinal permeability. Studies have shown sequestration of infected erythrocytes in intestinal microvasculature, and in vivo studies of rectal mucosa have demonstrated disruption of microvascular blood flow. However, the extent of intestinal injury in pediatric malaria is not well characterized. In this study, two serum biomarkers of intestinal injury, trefoil factor 3 (TFF3) and intestinal fatty acid binding protein (I-FABP), were analyzed in 598 children with SM and 120 healthy community children (CC), 6 months to 4 years of age. Serum was collected at enrollment and 1 month for laboratory studies, and participants were monitored for 12 months. Intestinal injury biomarkers were significantly elevated in children with SM, with 18.1% having levels of TFF3 and/or I-FABP greater than the 99th percentile of CC levels. TFF3 levels continued to be elevated at 1 month, while I-FABP levels were comparable to CC levels. Both markers predicted in-hospital mortality {odds ratio (OR) (95% confidence interval [CI]), 4.4 (2.7, 7.3) and 2.3 (1.7, 3.1)} for a natural log increase in TFF3 and I-FABP, respectively. TFF3 was also associated with postdischarge mortality (OR, 2.43 [95% CI, 1.1, 4.8]). Intestinal injury was associated with acute kidney injury (AKI), acidosis (P < 0.001 for both), and angiopoietin 2, a maker of endothelial activation. In conclusion, intestinal injury is common in pediatric severe malaria and is associated with an increased mortality. It is strongly associated with AKI, acidosis, and endothelial activation. IMPORTANCE In children with severe malaria, intestinal injury is a common complication associated with increased mortality. Intestinal injury is associated with acute kidney injury, acidosis, and endothelial activation. Interventions promoting intestinal regeneration and repair represent novel approaches to improve outcomes.
Insights
Intestinal injury is common in children with severe malaria, increasing mortality risk. Biomarkers trefoil factor 3 (TFF3) and intestinal fatty acid binding protein (I-FABP) indicate injury and predict outcomes, highlighting the need for gut repair interventions.
Area of Science:
- Pediatric infectious diseases
- Gastroenterology
- Biomarker research
Background:
- Severe malaria (SM) is linked to invasive bacterial infections and increased gastrointestinal permeability.
- Evidence suggests microvascular dysfunction in the gut during pediatric malaria, but intestinal injury extent is unclear.
Purpose of the Study:
- To investigate the prevalence and clinical significance of intestinal injury in children with severe malaria.
- To analyze serum biomarkers trefoil factor 3 (TFF3) and intestinal fatty acid binding protein (I-FABP) as indicators of intestinal injury in pediatric SM.
Main Methods:
- Serum samples from 598 children with SM and 120 healthy community children (CC) aged 6 months to 4 years were analyzed.
- Measurements of TFF3 and I-FABP were taken at enrollment and 1 month, with participants monitored for 12 months.
- Statistical analysis correlated biomarker levels with mortality, acute kidney injury (AKI), acidosis, and endothelial activation markers.
Main Results:
- Children with SM showed significantly elevated TFF3 and I-FABP levels compared to CC.
- TFF3 remained elevated at 1 month post-enrollment, while I-FABP normalized.
- Both TFF3 and I-FABP predicted in-hospital mortality; TFF3 also predicted post-discharge mortality.
- Intestinal injury correlated strongly with AKI, acidosis, and angiopoietin 2 (endothelial activation).
Conclusions:
- Intestinal injury is a frequent complication in pediatric severe malaria, significantly associated with increased mortality.
- Intestinal injury is strongly linked to acute kidney injury, acidosis, and endothelial activation.
- Targeting intestinal regeneration and repair may offer novel therapeutic strategies to improve outcomes in pediatric SM.
