Restoration of anti-bacterial innate immune cell function lags behind nutritional recovery among children convalescing from complicated severe acute malnutrition

Children recovering after hospitalisation with complicated severe acute malnutrition (SAM) have a high risk of infectious mortality and morbidity. In a cross-sectional cohort of SAM inpatients in Zambia and Zimbabwe (cases, n=125) and well-nourished children from the same communities (controls, n=73) we evaluate anti-bacterial innate immune cell function to determine whether abnormalities may be an underlying factor in subsequent adverse clinical outcomes and ponderal growth gains. We go on to characterise how innate immune cell function changes over 48 weeks of post-discharge rehabilitation in a longitudinal cohort (n=83). We find that blood immune cell composition, monocyte and neutrophil bacterial binding capacity, and upregulation of monocyte surface marker expression and soluble immune mediator secretion in response to bacterial antigen stimulation are dysregulated by complicated SAM. We did not find evidence that inpatient immune function differed in cases who experienced subsequent adverse clinical outcomes (clinic visits or death, readmission, persistent SAM at 48 weeks). However, pro-inflammatory cytokine (IL-6, IL-8 and TNFα) secretion in response to E. coli lipopolysaccharide and heat-killed Salmonella typhimurium during hospitalisation was positively associated with subsequent gains in mid-upper arm circumference, an indicator of nutritional recovery. Relative to initial immune function during hospitalisation, bacterial binding capacity and anti-bacterial pro-inflammatory cytokine secretion of cases had reciprocal patterns; the former declined whilst the latter increased over the post-discharge follow-up period with both normalising towards ranges in controls. These changes continued to be evident in cases who had recovered from SAM to a healthy nutritional status (weight-for-height Z score≥-2). Collectively, our data suggest that restoration of immune function following complicated SAM lags behind nutritional recovery. Thus, children who are no longer wasted may nevertheless continue to have deficient anti-bacterial innate immunity weeks to months after hospital admission for SAM.