Longitudinal associations of plasma amino acid levels with recovery from malarial coma

Abstract

Background: Disordered amino acid metabolism is observed in cerebral malaria (CM). We sought to determine whether abnormal amino acid concentrations were associated with level of consciousness in children recovering from coma. We quantified 21 amino acids and coma scores longitudinally and analyzed data for associations.

Methods: In a prospective observational study, we enrolled 42 children with CM. We measured amino acid levels at entry and at frequent intervals thereafter and assessed consciousness by Blantyre Coma Scores (BCS). Thirty-six healthy children served as controls for in-country normal amino acid ranges. We employed logistic regression using a generalized linear mixed-effects model to assess associations between out-of-range amino acid levels and BCS.

Results: At entry 16/21 amino acid levels were out-of-range. Longitudinal analysis revealed 10/21 out-of-range amino acids were significantly associated with BCS. Elevated phenylalanine levels showed the highest association with low BCS. This finding held when out-of-normal-range data were analyzed at each sampling time.

Discussion: We provide longitudinal data for associations between abnormal amino acid levels and recovery from CM. Of 10 amino acids significantly associated with BCS, we propose that elevated phenylalanine may be a surrogate for impaired clearance of ether lipid mediators of inflammation contributing to CM pathogenesis.

Keywords: Blantyre coma score; amino acids; cerebral malaria; generalized linear mixed-effects model; glyceryl lipid ethers; tetrahydrobiopterin.

Figure 1.

Effect of sampling time on having an amino acid level outside of, or within, the normal range. Results at each sampling time are OR (95% confidence intervals). Odd ratios in yellow cells highlight times significantly associated with an amino acid level outside the normal range; blue cells show times significantly associated with an amino acid level within the normal range; white cells show times with no significant association. Odds ratios less than one denote association with a level out-of-range, while odds ratios greater than one denote association with an amino acid level within the normal range.

Figure 2.

Box plot showing median coma scores with variance measures at sampling intervals. Boxes represent the interquartile range (IQR). Dark lines in boxes represent the median of the data at the times given. Vertical lines extending from the boxes indicate the minimum and maximum values within 1.5 times the IQR.