Amino acid derangements in adults with severe falciparum malaria

Stije J Leopold,Sujat Paul,Siribha Apinan,Arjen M Dondorp,Amir Hossain,Anupam Barua,Nicholas J White,Katherine A Plewes,Asok Kumar Dutta,Markus Winterberg,Aniruddha Ghose,Nicholas P J Day,Joel Tarning,Abdus Sattar,Hugh W Kingston

doi:10.1038/s41598-019-43044-6

Abstract

Amino acid derangements are common in severe falciparum malaria and have been associated with endothelial dysfunction (L-arginine), metabolic acidosis (alanine and lactate), and disease severity (phenylalanine and tryptophan metabolites). Whether these amino acid perturbations reflect isolated pathogenic mechanisms or if they are part of overall changes in amino acid metabolism is unclear. To investigate this, we prospectively simultaneously quantified a broad range of plasma free amino acids (PFAA) using HPLC-MRM-Mass spectrometry in relation to presenting symptoms in adults with severe malaria (n = 88), septicaemia (n = 88), uncomplicated malaria (n = 71), and healthy controls (n = 48) from Bangladesh. The total plasma concentration of measured amino acids was significantly reduced in each of the patient groups when compared to normal levels observed in healthy local controls: uncomplicated malaria −54%, severe malaria −23%, and sepsis −32%, (p = <0.001). Inspection of amino acid profiles revealed that in each group the majority of amino acids were below normal levels, except for phenylalanine. Among patients with severe malaria, L-lactate was strongly associated with an increase of the total amino acid concentration, likely because this reflects tissue hypoxia. Our data confirm previously described amino acid abnormalities, likely resulting from overall changes in the concentration of PFAA.

Highlights

The pathophysiology of severe falciparum malaria is linked to derangements in amino acid metabolism
We observed a strong effect of L-lactate on the total plasma free amino acids (PFAA) concentrations in patients with severe falciparum malaria, where incremental levels of L-lactate were significantly associated with increased total concentrations of PFAA
Patients who were in a deeper coma were more likely to have higher total PFAA levels. In this prospective observational cohort of patients with malaria and sepsis we investigated the patterns and determinants of plasma free amino acid derangements during severe infection

Summary

Participants

We observed a significant reduction of the median concentration of PFAA in all patient groups when compared to healthy individuals, in patients with uncomplicated malaria (Table 2 and Fig. S1). A total of 10 out of 21 measured amino acids were significantly elevated in patients who died from severe malaria compared to those who survived their infection. These changes included a significant increase in plasma alanine Determinants of total plasma amino acid levels in adults with severe falciparum malaria We modelled the effects of L-lactate on the total concentration of PFAA using multivariate regression analysis, adjusting for factors that could explain an energy deficit or malnutrition. Patients who were in a deeper coma were more likely to have higher total PFAA levels

Discussion

Findings

Methods and Materials