Biomarkers of Growth Faltering and Neurodevelopmental Delay in Children who are HIV-Exposed but Uninfected: A Systematic Review.

INTRODUCTION: Children who are HIV-exposed but uninfected (CHEU) are at risk of linear growth faltering and neurodevelopmental delay. Circulating biomarkers associated with these adverse outcomes may elucidate pathways of injury. OBJECTIVE: To identify biomarkers associated with growth faltering and neurodevelopmental delay in CHEU. METHODS: We performed a systematic review of electronic databases MEDLINE (1946-April 2021), EMBASE (1974-April 2021), Scopus (2004-April 2021), and PubMed (1985-April 2021), following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The systematic review was registered on the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42021238363). RESULTS: We found seven studies associating biomarker abnormalities and growth outcomes in CHEUs and two studies on biomarker abnormalities and neurodevelopmental delay. Biomarker abnormalities associated with growth restriction were: C-reactive protein (CRP), tumour necrosis factor (TNF), interferon-gamma (IFN-γ), interleukin (IL)-12p70, IFN-γ-induced protein-10 (CXCL10/IP-10), lipopolysaccharide binding protein (LBP), insulin-like growth factor-1 (IGF-1), and IGF-binding protein-1 (IGFBP-1). Biomarkers associated with motor, language, and cognitive delay were CRP, IFN-γ, IL-1ß, -2, -4, -6, -10, -12p70, neutrophil gelatinase-associated lipocalin (NGAL), granulocyte-macrophage colony-stimulating factor (GM-CSF), and matrix metalloproteinase- 9 (MMP-9). CONCLUSION: Elevated markers of inflammation (acute phase reactants, pro-inflammatory cytokines, chemokines) and intestinal microbial translocation are associated with growth faltering. Elevated markers of inflammation are associated with adverse neurodevelopment.

Dysregulation of angiopoietin-Tie-2 axis in ugandan children hospitalized with pneumonia.

OBJECTIVE: Pneumonia is the leading cause of death in children under 5, with the highest burden in resource-limited countries. Endothelial activation occurs in pneumonia and can be assessed using quantitative levels of biomarkers angiopoietin (Ang)-1 and Ang-2. We examined admission levels of Ang-1 and Ang-2 in pediatric pneumonia and their association with disease severity and outcome. METHODS: Prospective cohort study of children with hypoxemic pneumonia admitted to two hospitals in Uganda. Clinical, radiographic, and microbiologic characteristics were measured at admission. Disease severity was assessed using the Respiratory Index of Severity in Children (RISC). Plasma levels of Ang-1 and Ang-2 were quantified by enzyme-linked immunosorbent assay. Vital signs, oxygen supplementation, and mortality were assessed prospectively. RESULTS: We included 65 patients (43% female) with median age 19 months (IQR 8-24). Admission Ang-2/Ang-1 ratio directly correlated with RISC (ρ = 0.32, p = 0.008) and lactate level (ρ = 0.48, p < 0.001). Ang-2/Ang-1 ratio was higher in pneumococcal pneumonia than viral RTI (0.19 [IQR: 0.076-0.54] vs. 0.078 [IQR: 0.027-0.11]; p = 0.03). Elevated Ang-2/Ang-1 ratio (>0.084) was associated with prolonged tachypnea (HR 0.50 (95%CI 0.29-0.87), p = 0.02), fever (HR 0.56 (95%CI 0.33 to 0.96), p = 0.02), longer duration of oxygen therapy (HR 0.59 (95%CI 0.35-0.99), p = 0.04), and hospital stay (HR 0.43 (95%CI 0.25-0.74), p = 0.001). The Ang-2/Ang-1 ratio at admission was higher in fatal cases relative to survivors (0.36 [IQR: 0.17-0.58] vs. 0.077 [IQR: 0.025-0.19]; p = 0.05) CONCLUSION: Endothelial activation in hypoxemic pediatric pneumonia, reflected by high plasma Ang-2/Ang-1 ratio, is associated with disease severity, prolonged recovery time, and mortality.