Abstract
Severely ill children in low- and middle-income countries (LMICs) experience high rates of mortality from a broad range of infectious diseases, with the risk of infection-related death compounded by co-existing undernutrition. How undernutrition and acute illness impact immune responses in young children in LMICs remains understudied, and it is unclear what aspects of immunity are compromised in this highly vulnerable population. To address this knowledge gap, we profiled longitudinal whole blood cytokine responses to Toll-like receptor (TLR) ligands among severely ill children (n=63; 2-23 months old) with varied nutritional backgrounds, enrolled in the CHAIN Network cohort from Kampala, Uganda, and Kilifi, Kenya, and compared these responses to similar-aged well children in local communities (n=41). Cytokine responses to ligands for TLR-4 and TLR-7/8, as well as Staphylococcus enterotoxin B (SEB), demonstrated transient impairment in T cell function among acutely ill children, whereas innate cytokine responses were exaggerated during both acute illness and following clinical recovery. Nutritional status was associated with the magnitude of cytokine responses in all stimulated conditions. Among children who died following hospital discharge or required hospital re-admission, exaggerated production of interleukin-7 (IL-7) to all stimulation conditions, as well as leukopenia with reduced lymphocyte and monocyte counts, were observed. Overall, our findings demonstrate exaggerated innate immune responses to pathogen-associated molecules among acutely ill young children that persist during recovery. Heightened innate immune responses to TLR ligands may contribute to chronic systemic inflammation and dysregulated responses to subsequent infectious challenges. Further delineating mechanisms of innate immune dysregulation in this population should be prioritized to identify novel interventions that promote immune homeostasis and improve outcomes.
Highlights
Sepsis continues to be a significant cause of pediatric morbidity and mortality worldwide
In this study we examined resting and stimulated whole blood cytokine responses among young children living in lowand middle- income countries (LMICs), including children who required hospitalization for severe illness and well children recruited from local communities
The Toll-like receptor (TLR) agonists utilized in this study served as a method of interrogating functional host immune responses that may have been deranged as a result of severe acute illness and undernutrition, both common among children in LMICs
Summary
Sepsis continues to be a significant cause of pediatric morbidity and mortality worldwide. Antiinflammatory and tissue-repair immune responses are elicited during both acute and convalescent phases of severe illness [39], and may contribute to secondary infections among patients who survive their initial infection. This post-sepsis response has been described as “immunoparalysis”, or a state of cellular senescence, where immune cells remain locked in a functionally impaired state by either extrinsic (repeated pathogenic insult, global DAMP expression) or intrinsic (altered T cell repertoires, increased inhibitory receptor expression) factors [40]. Interrogation of immune responses among highly vulnerable young children during severe illness is a critical first step to the identification of specific immunologic pathways associated with poor versus thriving outcomes, and in the development of novel interventions to improve pediatric post-hospitalization outcomes in LMICs
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