Table 2.
Metabolomics studies of sepsis focusing on survival/death.
| Study (Year) | Sample Type | Participants (Survivors:Non-Survivors) |
Age Group | Analytical Technique | Statistical Analysis Methods | Raised in Non-Survivors | Reduced in Non-Survivors |
|---|---|---|---|---|---|---|---|
| Jones et al. [88] (2022) c | Serum | 113:39 | Adults | UHPLC-MS (targeted) |
PCA, PLSDA, FET MW-U test, MELR, Cox PHR, KMSA | 14,15-dihydroxyeicosatrienoic acid (DHET) | - |
| Mierzchala-Pasierb et al. [37] (2021) | Serum and urine | 11:4 | Adults | UPLC-MS (targeted) |
MW-U test, Cox PHR analysis | Serum 4-hydroxyproline and Glutamine | - |
| Li et al. [42] (2021) c | Serum | 74:10 | Paediatric | HPLC-MS (targeted) |
ANOVA, t-test, PCA, OPLS-DA, HCA, LR | Adenine, indolelactic acid, LPS (18:1/0:0), Ile-Tyr, kynurenine, glutamate, acetylcarnitine, tyrosine, tryptophan, palmitoylcarnitine, methionine, proline, acetylneuraminate and N2,N2-dimethylguanosine | PC (14:0/0:0,17:0/0:0, O-18:1/0:0), PI (18:0/22:5,18:0/22:6) |
| Reisinger et al. [39] (2021) c |
Serum | 34:19 30:16 on days 3 and 7 |
Adults |
1H-NMR (untargeted) and Bruker IVDr lipoprotein analysis |
LR, LMM, FET, Χ2 or MW-U test, PCA, PLS and OPLS-DA correlations | - | BCAAs (valine, leucine, isoleucine) |
| Jaurila et al. [27] (2020) |
Serum | 33:11 | Adults |
1H-NMR (targeted) |
MW-U or t-test, FET, correlations | Lactate and citrate | - |
| Khaliq et al. [89] (2020) c |
Plasma | 12:8 | Adults | LC-MS/MS (targeted) and industrial clinical chemistry system |
PCA, mixed effects type-III ANOVA, Tukey HSD test, Random forests, linear SVMs | Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and troponin T, putrescine, acylcarnitines (mostly short-chain acylcarnitines), amino acids (aspartate, tyrosine, phenylalanine, histidine) on days 0–3 or at any specific timepoint | HDCH, LDCH, 4 LPCs, 28 PCs, 11 SM-OH (C14:1, C16:1, C22:2, C23:0), SM (C16:0, C18:0, C18:1, C20:2, C22:3, C24:0, C26:0) on days 0–3 or at any specific timepoint |
| Wang et al. [16] (2020) c |
Plasma | 134:54 | Adults | LC-MS (targeted) |
MW-U test, PLS-DA, ROC analysis | Isoleucine, alanine, acetylcarnitine, lactic acid pyruvic acid | LPG (22:0), and LPC (24:0) |
| Evans et al. [90] (2019) f |
Serum | 7:4 | Adults | LC-MS (untargeted) |
MW-U test, Student’s t-test, generalised estimation equations | N-Methyl-phenylalanine, glucosamine, isoleucyl-proline/leucyl proline, histamine, adipoyl-L-carnitine, methoxytryptophol, fibrinopeptide A, N,N-dimethylguanosine, N-(3-acetamidopropyl)pyrrolidin-2-one, allysine | N-Acetyl-L-phenylalanine, phenylalanyl-tyrosine |
|
Chung et al. [91] (2019) c |
Plasma | Derivation—69:21 Validation—96:24 |
Adults | UHPLC-MS (targeted) |
Cox PHR, t-test, LR, ROC curves, KMSA | Acetylcarnitine (in both cohorts) | - |
| Huang et al. [92] (2019) e |
Plasma | 63:30 | Adults | UPLC-UV (targeted) |
Χ2, MW-U, KWT and t-test, KMSA, Cox PHR, ROC | Leucine and phenylalanine | - |
|
Liu et al. [75] (2019) b |
Serum | 40:29 at 0 h 32:19 at 24 h |
Adults |
1H-NMR (untargeted and targeted) |
PCA, OPLS-DA, t-test, ROC analysis | Lactate, pyruvate, alanine, glutamate, glutamine, lysine, 1-methylhistidine, tyrosine, phenylalanine, citrate at 0 h and 24 h. Methionine, fumarate, acetate, urea and 3-hydroxybutyrate at 0 h. Creatinine, 3-hydroxyisovalerate and lipids at 24 h | N-acetyl glycoproteins—0 h and 24 h |
| Cambiaghi et al. [93] (2018) c |
Plasma | 9:8 | Adults | LC-MS/MS (targeted) |
Elastic net LR, LDA, PLS-DA | Day 7 to day 1 ratios of PCaa (C34:3, C36:3, C36:6, C42:1, C42:5), PCaeC30:1, SDMA, total dimethylarginine, proline, tyrosine | Day 7 to Day 1 ratios of LPC aC24:0, methionine, PCaa (C40:6, C42:6, C42:2), PCae (C30:2 and C42:5) |
| Winkler et al. [49] (2018) c |
Plasma | 89:31 | Adults | LC-MS/MS (targeted) |
Χ2, MW-U test, KWT, KMSA | SDMA on days 1, 3 and 7, ADMA on days 1 and 3 | - |
| Cirstea et al. [58] (2017) c,e |
186:14—Day 28 172:28—Day 90 |
Adults | Photometric analysis | KMSA, ROC analysis | - | HDCH | |
| Dalli et al. [94] (2017) b |
Plasma | 13:9 | Adults | LC-MS/MS (targeted) |
Wilcoxon paired signed rank test, FET, PLS-DA | PGF2α (on days 0, 3 and 7), RvD5 (on days 3 and 7), RvE1, 17-HDHA, 18-HEPE, 15-HETE (on days 1 and 3), LTB4, RvE2,4S,14S-diHDHA and 5S,15S-diHETE (on day 7), 17R-PD1, 7-HDHA and 15-HEPE (on day 1), 17-epi-RvD1, 17-epi-PD1, 5-HETE and 5S,12S-diHETE (on day 3). | - |
|
Wang et al. [95] (2017) c |
Plasma | CAPSOD—90:31 HAI–VAP—20:16 |
Adults | LC-MS/MS (targeted) |
MW-U test, HCA, SVMs, ROC curves | Methylthioadenosine (MTA) in both cohorts | - |
| Sharma et al. [44] (2017) b |
Plasma | 20:13—Day 1 14:9—Day7 |
Adults | LC-MS/MS (targeted) and enzymatic colorimetry | ANOVA, Tukey HSD test | No significant difference in lipoproteins. |
|
| Liu et al. [73] (2016) b |
Serum | 21:29 | Adults | UPLC-MS (untargeted) |
ANOVA, Tukey HSD test | Citrate, succinate, malate, α-ketoglutartae, amino acids (proline, BCAAAs, glutamine, glutamate, phenylalanine, betaine, creatine, creatinine, tyrosine), lactate, bile acids (GUDCA, GUDCS, GCDCA, GCA, UDCA), acyl carnitines (C6, C10, C12), indoxylactate, indoxysulfate, LPC 14:0 | Ornithine, citrulline, argininosuccinate, acetylcarnitine, FFA (16:0,18:0), LPE (18:0,18:2,20:3,20:4), acylcarnitines (C16, C18) |
| Ferrario et al. [96] (2016) c,e |
Plasma | 9:11 (90-day mortality) 11:9 (28-day mortality) |
Adults | LC-MS/MS (targeted) |
Unpaired Wilcoxon and paired Wilcoxon signed rank test, Multivariate Elastic Net regression analysis | Acetylcarnitine (on day 1) and kynurenine (on day 7)—based on 28-Day mortality. | PCs and LPCs species (on days 1 and 7)—based on 28-day and 90-day mortality. Six saturated long-chain LPC (aC16:0, aC18:0) and polyunsaturated very long-chain PC (aaC32:3, aaC34:4, aaC36:4, aeC40:1) at day 7—on both 28 and 90-day mortality. |
| Garcia-Simon et al. [80] (2015) d | Urine | 48:12 | Adults |
1H-NMR (targeted and untargeted) |
ANOVA, PCA, PLS-DA, LR, ROC analysis | Ethanol, glucose, hippurate and an unknown metabolite (located at 1.40–1.45 ppm)—at 0 h and 24 h | Phenylalanine &arginine at 0 h and 24 h. Glutamine and methionine at 0 h |
| Su et al. [38] (2015) c |
Serum | 20:15 | Adults | LC-MS/MS (targeted) |
ANOVA, Χ2 test, t-test, Pearson correlation, ROC analysis | α-aminoadipic acid, ethanolamine, cystathionine, and phenylalanine—at certain time points | Taurine (on days 10 and 14), BCAA/AAA ratio (on day 14), SAA (on days 7, 10, and 14) whilst arginine, glutamic acid, serine, and tryptophan at certain timepoints |
| Lee et al. [97] (2015) c |
Serum | 65:52 | Adults | Commercial kits with automated analysers | LMM, MW-U test or Student’s t-test, Cox PHR, ROC analysis | - | Cholesterol, TG, HDL, LDL, and Apo A-I—On days 0, 1, 3 and 7 |
| Mickiewicz et al. [32] (2015) |
Serum and plasma | 8:8 | Adults |
1H-NMR (targeted) and cytokine and chemokine kits |
PCA, OPLS-DA, ROC analysis | 2-hydroxyisovalerate, fructose, IL-8, IL-9 and growth-regulated oncogene alpha (GRO-α). | Tumour necrosis factor (TNF)-β, beta-nerve growth factor (β-NGF) and dimethylamine |
| Kamisoglu et al. [84] (2015) c | Plasma | 90:31 | Adults | LC-Q-orbitrap-MS and DSQ GC-MS (untargeted) |
Welch’s t-test, Kolmogorov–Smirnov test | 2-methylbutyroylcarnitine tiglylcarnitine, acetylcarnitine, hexanoylcarnitine octanoylcarnitine, propionylcarnitine, butyrylcarnitine, decanoylcarnitie, cis-4-decenoyl carnitine at 0 h and 24 h whilst deoxycarnitine only at 24 h. | 1-eicosatrienoyl-GPC (20:3), 1-palmitoleoyl-GPC (16:1), 2-palmitoyl GPC (16:0) at 0 h and 24 h. 1-palmitoyl-GPC (16:0) 1-stearoyl-GPC (18:0), 1-oleoyl-GPC (18:1), 1-linoleoyl-GPC (18:2), 1-arachidonyl-GPC (20:4) at 24 h. |
| Mickiewicz et al. [25] (2014) |
Serum | 4:4 | Adults |
1H-NMR (targeted) |
PCA, OPLS-DA, ROC analysis | 20 metabolites were significant in differentiating survivors from non-survivors (results not reported) | - |
|
Rogers et al. [72] (2014) c |
Plasma | RoCI—60:30 CAPSOD—115:34 |
Adults | GC-MS and LC-MS (targeted) |
LR, Bayesian networks | Kynurenine lactate, p-HPhLA, ornithine, 3-hydroxyisovalerate, 2-hydroxyisovalerate, N-acetylalanine, sucrose, N-acetylserine, xanthine, allantoin, N2,N2-dimethylguanosine, 1-methylimidazoleacetate, glycocholate, GCDCA, TCDCA, taurocholate, cortisol, carnitines (C3, C4, C5, C5-OH, C5:1 and C6), γ-glutamylphenyl-alanine, γ-glutamyl-tyrosine—in both cohorts. | 1-arachidonoyl-GPC (20:4), 1-arachidonoyl-GPE (20:4),), 1-palmitoyl-GPC (16:0), 2-palmitoyl-GPC (16:0), 1-linoleoyl-GPC (18:2), 1-stearoyl-GPC (18:0))—in both cohorts |
| Su et al. [34] (2014) a |
Serum | 26:9 | Adults | LC-MS/MS (targeted) |
MW-U, ROC analysis, PCA, PLS and OPL-DA | S-succinyl glutathione, GPC, PG (22:2(13Z,16Z)/0:0), S-(3-methylbutanoyl)dihydrolipoamide-E) |
- |
| Mickiewicz et al. [23] (2013) |
Serum | 10:10—Model 1 13:10—Model 2 |
Infants, Toddlers, School Age |
1H-NMR (untargeted and targeted) |
PCA, PLS-DA, OPLS-DA, ROC analysis | Eleven metabolites from model 1 and eighteen metabolites from model 2 were significant in separating survivors from non-survivors. (Metabolites not reported) | - |
|
Langley et al. [70] (2013) c |
Plasma | Derivation set—90:31 CAPSOD—34:18 RoCI—36:25 |
Adults | UPLC-MS/MS (Targeted and untargeted) and GC-MS (untargeted) |
ANOVA, LR, SVMs | Seventeen amino acid catabolites (lactate, p-HPhLA, 4-hydroxyproline, 3-methoxytyrosine), sixteen carnitine esters (Cis-4-decenoylcarnitine, 2-methylbutyroylcarnitine, butyroylcarnitine, hexanoylcarnitine), citrate, malate, pyruvate, dihydroxyacetone, phosphate, eleven nucleic acid catabolites, and four FFAs | Seven GPC and GPE esters, anabolic steroids, cortisone |
|
Seymour et al. [71] (2013) e |
Plasma | 15:15 | Adults | UHPLC-MS/MS and GC-MS (untargeted) |
Wilcoxon signed rank and t-test, random forests with supervised classification | Urea, cortisol, cortisone, fumarate, Kynurenate, 2-Py, pyridoxate, cofactors/vitamins, taurocholate, sulfated bile acids, sulfated hormones, N2, N2-dimethylguanosine, N1-methyladenosine, pseudouridine, allantoin, 10-hepatodecenoic acid, N6-carbamoylthreonyladenosine | GPEs and xenobiotics (paraxanthine and caffeine) |
| Gaddnas et al. [47] (2009) d |
Serum | 33:11 | Adults | Radioimmunological assays | Χ2 test, FET, MW-U, ROC | Procollagen type III aminoterminal propeptides and crosslinked telopeptides of type I collagen | - |
| Chien et al. [98] (2005) d |
Serum | 44:19 | Adults | Enzymatic and turbidimetric methods using kits | MW-U, FET, multivariate LR, KMSA | - | HDCH and Apo-A1 (on days 1 to 4) |
| Vermont et al. [99] (2005) |
Serum | 46:10 | Paediatrics | Enzymatic colorimetric assay | Non-parametric test, FET | - | Total cholesterol |
| Drobnik et al. [48] (2003) d |
Plasma | 63:39 | Adults | LC-MS/MS (targeted) |
MW-U test, ROC curves | Cer-SM ratios—on day 4 and day 11. Cer-SM to LPC-PC ratios—on day 1, 4 and 11 |
LPC-PC ratios—on day 4 and day 11 |
| van Leeuwen et al. [53] (2003) | Plasma | 10:7 | Adults | DGU and enzymatic methods | ANOVA, t-test, MLRA | No significant differences in lipoproteins | - |
| Sprung et al. [100] (1991) |
Plasma | 10:5 | Adults | Postcolumn IEC with ninhydrin detection | Spearman’s correlations, t-test | AAAs (tyrosine, phenylalanine), SAAs (taurine, methionine, and cysteine), ammonia and GABA | - |
| Roth et al. [81] (1982) |
Plasma | 7:7 | Adults | Automatic amino acid analyser (Liquimat III) | Student’s t-test | Muscle valine and leucine and plasma levels of glucose, glucagon, phosphoserine, cysteine, valine, phenylalanine and 3-methylhistidine | Muscle glutamine, proline and lysine |
Studies with validation cohorts are highlighted in bold. Abbreviations, UPLC-MS: ultra-performance liquid chromatography–mass spectrometry; UPLC-UV: ultra-performance liquid chromatography coupled to ultraviolet detector; UHPLC-MS: ultra-high performance liquid chromatography–mass spectrometry; GC-MS: gas chromatography coupled to time-of-flight mass spectrometry; DSQ GC-MS: dual-stage quadrupole gas chromatography-mass spectrometer; LC-MS/MS: liquid chromatography–tandem mass spectrometry; LC-Q-orbitrap-MS: liquid chromatography with quadrupole orbitrap mass spectrometry; IEC: ion-exchange chromatography, DGU: density gradient ultracentrifugation; PHR: proportional hazards regression; MW-U: Mann–Whitney U; LR: logistic regression; LMM: linear mixed model; MELR: mixed effect LR; MLRA: multiple-level regression analysis; HCA: hierarchical clustering analysis; LDA: linear discriminant analysis; PLS-DA: partial least squares discriminant analysis; PCA: principal component analysis; OPLS-DA: orthogonal projections to latent structures discriminant analysis; ANOVA: analysis of variance; HSD: honestly significant difference;; H-MCR: hierarchical multivariate curve resolution; KMSA: Kaplan-Meier survival analysis; ROC: receiver operating characteristic; Χ2: chi-square; FET: Fisher’s exact test; KWT: Kruskal-Wallis test; SVMs: support vector machines; AAAs: aromatic amino acids; BCAAs: branched-chain amino acids; aa: diacyl; ae: acyl-alkyl; PC: phosphatidylcholine; PG: phosphatidylglycerol LPC: lysophosphatidylcholine; PI: phosphatidyinositol; LPE: lysophosphatidyethanolamine; GPE: glycerophosphatidylethanolamine; GPC: glycerophopholcholine; Cer: ceramide, SM: sphingomyelin; Rv: resolvins; PGF2α: prostaglandin F2α; LT: leukotrienes; PD1: protectin D1; p-HPhLA: p-(hydroxyphenyl)-lactic acid; 2-Py = N1-methyl-2-pyridone-5-carboxamide; TCDCA: taurochenodeoxycholate; GCDCA: glycochenodeoxycholate; FAs: fatty acids; FFAs: free fatty acids; TG: triglyceride; HDL: high-density lipoprotein; LDL: low-density lipoprotein; HDCH: HDL cholesterol; LDCH: LDL cholesterol; Apo-A1: apolipoprotein-A1; TCA: tricarboxylic acid; SDMA: symmetric dimethylarginine; ADMA: asymmetric dimethylarginine; GABA: gamma-aminobutyric acid; HDHA: hydroxydocosahexaenoate; HEPE: hydroxyeicosapentaenoate; HETE: hydroxyeicosatetraenoate; CAPSOD: community acquired pneumonia and sepsis outcome diagnostics; RoCI: Brigham and Women’s Hospital Registry of Critical Illness. Symbols a–f represent censoring time point of mortality assessment; a 24-h mortality; b 7-day mortality; c 28-day mortality; d 30-day mortality; e 90-day mortality; f 1-year mortality.