NMR-based metabolic profiling provides diagnostic and prognostic information in critically ill children with suspected infection

Abstract

Sepsis, defined as life-threatening organ dysfunction caused by infection is difficult to distinguish clinically from infection or post-operative inflammation. We hypothesized that in a heterogeneous group of critically ill children, there would be different metabolic profiles between post-operative inflammation, bacterial and viral infection and infection with or without organ dysfunction. 1D 1H nuclear magnetic resonance spectra were acquired in plasma samples from critically ill children. We included children with bacterial (n = 25) and viral infection (n = 30) and controls (n = 58) (elective cardiac surgery without infection). Principal component analysis was used for data exploration and partial least squares discriminant analysis models for the differences between groups. Area under receiver operating characteristic curve (AUC) values were used to evaluate the models. Univariate analysis demonstrated differences between controls and bacterial and viral infection. There was excellent discrimination between bacterial and control (AUC = 0.94), and viral and control (AUC = 0.83), with slightly more modest discrimination between bacterial and viral (AUC = 0.78). There was modest discrimination (AUC = 0.73) between sepsis with organ dysfunction and infection with no organ dysfunction. In critically ill children, NMR metabolomics differentiates well between those with a post-operative inflammation but no infection, and those with infection (bacterial and viral), and between sepsis and infection.

Patient Stratification in Sepsis: Using Metabolomics to Detect Clinical Phenotypes, Sub-Phenotypes and Therapeutic Response

“…It is suggested that mitochondrial dysfunction in sepsis leads to the accumulation of glycolysis and tricarboxylic acid (TCA) cycle metabolites such as lactate, pyruvate and citric acid [ 16 ], and the pathways which lead to the accumulation of these metabolites are shown in Figure 1 . Several studies in Table 1 consistently showed that sepsis patients had increased levels of glycolysis metabolites including lactate [ 21 , 22 , 23 , 24 , 25 ] and pyruvate [ 21 , 26 ] compared to healthy controls [ 21 , 22 , 23 ] or those with SIRS [ 24 , 25 , 26 ]. Lin et al showed elevation of seven TCA metabolites as well as two TCA cycle derivatives including DL-gamma-methylketoglutaramate isomer and dimethyl fumarate in sepsis compared to healthy controls [ 21 ], which suggests upregulation of the TCA cycle in septic patients.…”

“…S-(3-methylbutanoyl)-dihydrolipoamide-E, a metabolite involved in the degradation of BCAAs ( Figure 1 ) was elevated in sepsis patients compared to SIRS [ 34 ]. Moreover, the levels of isoleucine and leucine were reduced in septic infant [ 25 ] and paediatric populations [ 24 ] compared to controls, perhaps suggesting differences in metabolism between children and adults. Alterations in aromatic amino acids may relate to the increase in oxidative stress ( Figure 1 ) with phenylalanine being higher in septic patients compared to healthy controls [ 21 , 37 , 38 ] those with SIRS [ 20 , 25 , 32 ] and in mechanically ventilated patients with pneumonia compared with those with brain injuries [ 40 ].…”

“…Additionally, metabolomic studies in children revealed that phenylalanine levels were elevated in septic paediatric populations including toddlers and school age children compared to healthy controls [ 23 ] and those with SIRS [ 23 , 24 ]. Moreover, septic patients also had higher levels of creatinine, creatine, proline (involved in the synthesis of DNA, ornithine and polyamines via pyrrolline-5-carboxylate [ 35 ]), total dimethylarginine (a competitive inhibitor of nitric oxide (NO) [ 49 ]), kynurenine (a breakdown product of tryptophan [ 50 ]) and cystathionine (involved in synthesis of antioxidants [ 51 ]) compared to SIRS [ 20 , 25 , 32 , 38 ], whilst alanine (a substrate for glucose synthesis in the liver and energy substrate for leucocytes [ 35 ]), lysine (a regulator of NO synthesis [ 35 ]), 2-aminobutyrate, threonine (an inhibitor of apoptosis and stimulator of lymphocyte proliferation [ 35 ]), glutamine (a regulator of glutathione production [ 35 ]), glutamate and creatine phosphate were reduced compared to SIRS [ 25 , 32 , 40 ] and severe sepsis [ 38 ] ( Figure 1 ).…”

“…Toddlers and school age children showed increased levels of arginine in septic populations compared to healthy controls or those with SIRS [ 23 ]. Urea, the end product of the urea cycle, was elevated in both septic adult [ 25 , 32 ] and paediatric [ 24 ] populations compared to SIRS [ 24 , 25 , 32 ] which might suggest renal dysfunction resulting in reduced elimination due to acute kidney injury, which is common in sepsis ( Figure 1 ).…”

Recent application of metabolomics in the diagnosis, pathogenesis, treatment, and prognosis of sepsis

“…Arturas Grauslys used NMR to study 55 infected children (25 bacterial infections, 30 viral infections) and 58 uninfected children undergoing heart surgery. The results showed that metabolomics can distinguish children with infection from children with postoperative inflammation but no infection [40]. James R. Anderson used NMR technology to analyze the synovial tissue of horses.…”