Longitudinal associations of plasma amino acid levels with recovery from malarial coma.
Amino acids
Blantyre coma score
Cerebral malaria
Generalized linear mixed-effects model
Glyceryl lipid ethers
Tetrahydrobiopterin
Journal
Malaria journal
ISSN: 1475-2875
Titre abrégé: Malar J
Pays: England
ID NLM: 101139802
Informations de publication
Date de publication:
23 Aug 2024
23 Aug 2024
Historique:
received:
14
05
2024
accepted:
13
08
2024
medline:
24
8
2024
pubmed:
24
8
2024
entrez:
23
8
2024
Statut:
epublish
Résumé
Disordered amino acid metabolism is observed in cerebral malaria (CM). This study sought to determine whether abnormal amino acid concentrations were associated with level of consciousness in children recovering from coma. Twenty-one amino acids and coma scores were quantified longitudinally and the data were analysed for associations. In a prospective observational study, 42 children with CM were enrolled. Amino acid levels were measured at entry and at frequent intervals thereafter and consciousness was assessed by Blantyre Coma Scores (BCS). Thirty-six healthy children served as controls for in-country normal amino acid ranges. Logistic regression was employed using a generalized linear mixed-effects model to assess associations between out-of-range amino acid levels and BCS. 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 analysed at each sampling time. Longitudinal data is provided for associations between abnormal amino acid levels and recovery from CM. Of 10 amino acids significantly associated with BCS, elevated phenylalanine may be a surrogate for impaired clearance of ether lipid mediators of inflammation and may contribute to CM pathogenesis.
Sections du résumé
BACKGROUND
BACKGROUND
Disordered amino acid metabolism is observed in cerebral malaria (CM). This study sought to determine whether abnormal amino acid concentrations were associated with level of consciousness in children recovering from coma. Twenty-one amino acids and coma scores were quantified longitudinally and the data were analysed for associations.
METHODS
METHODS
In a prospective observational study, 42 children with CM were enrolled. Amino acid levels were measured at entry and at frequent intervals thereafter and consciousness was assessed by Blantyre Coma Scores (BCS). Thirty-six healthy children served as controls for in-country normal amino acid ranges. Logistic regression was employed using a generalized linear mixed-effects model to assess associations between out-of-range amino acid levels and BCS.
RESULTS
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 analysed at each sampling time.
CONCLUSION
CONCLUSIONS
Longitudinal data is provided for associations between abnormal amino acid levels and recovery from CM. Of 10 amino acids significantly associated with BCS, elevated phenylalanine may be a surrogate for impaired clearance of ether lipid mediators of inflammation and may contribute to CM pathogenesis.
Identifiants
pubmed: 39180112
doi: 10.1186/s12936-024-05077-9
pii: 10.1186/s12936-024-05077-9
doi:
Substances chimiques
Amino Acids
0
Types de publication
Journal Article
Observational Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
253Subventions
Organisme : NIH/NIAID
ID : K23 AI 116869
Informations de copyright
© 2024. The Author(s).
Références
Marsh K, Forster D, Waruiru C, Mwangi I, Winstanley M, Marsh V, et al. Indicators of life-threatening malaria in African children. N Engl J Med. 1995;332:1399–404.
pubmed: 7723795
doi: 10.1056/NEJM199505253322102
WHO. World Malaria Report 2021. Geneva: World Health Organization; 2021.
Seydel KB, Kampondeni SD, Valim C, Potchen MJ, Milner DA, Muwalo FW, et al. Brain swelling and death in children with cerebral malaria. N Engl J Med. 2015;372:1126–37.
pubmed: 25785970
pmcid: 4450675
doi: 10.1056/NEJMoa1400116
Potchen MJ, Kampondeni SD, Seydel KB, Haacke EM, Sinyangwe SS, Mwenechanya M, et al. 1.5 Tesla magnetic resonance imaging to investigate potential etiologies of brain swelling in pediatric cerebral malaria. Am J Trop Med Hyg. 2018;98:497–504.
pubmed: 29313473
pmcid: 5929182
doi: 10.4269/ajtmh.17-0309
Kampondeni S, Seydel KB, Zhang B, Small DS, Birbeck GL, Hammond CA, et al. Amount of brain edema correlates with neurologic recovery in pediatric cerebral malaria. Pediatr Infect Dis J. 2020;39:277–82.
pubmed: 32168246
doi: 10.1097/INF.0000000000002573
Poespoprodjo JR, Douglas NM, Ansong D, Kho S, Anstey NM. Malaria. Lancet. 2023;402:2328–45.
pubmed: 37924827
doi: 10.1016/S0140-6736(23)01249-7
Darling TK, Mimche PN, Bray C, Umaru B, Brady LM, Stone C, et al. EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria. PLoS Pathog. 2020;16: e1008261.
pubmed: 31999807
pmcid: 6991964
doi: 10.1371/journal.ppat.1008261
Moxon C, Alhamdi Y, Storm J, Toh J, Ko JY, Murphy G, et al. Parasite histones mediate blood-brain barrier disruption in cerebral malaria. Clin Med. 2020;20(Suppl 2):s96–7.
doi: 10.7861/clinmed.20-2-s96
White NJ, Warrell DA, Chanthavanich P, Looareesuwan S, Warrell MJ, Krishna S, et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med. 1983;309:61–6.
pubmed: 6343877
doi: 10.1056/NEJM198307143090201
Planche T, Krishna S. Severe malaria: metabolic complications. Curr Mol Med. 2006;6:141–53.
pubmed: 16515507
doi: 10.2174/156652406776055177
Herdman MT, Sriboonvorakul N, Leopold SJ, Douthwaite S, Mohanty S, Hassan MM, et al. The role of previously unmeasured organic acids in the pathogenesis of severe malaria. Crit Care. 2015;19:317.
pubmed: 26343146
pmcid: 4561438
doi: 10.1186/s13054-015-1023-5
Leopold SJ, Apinan S, Ghose A, Kingston HW, Plewes KA, Hossain A, et al. Amino acid derangements in adults with severe falciparum malaria. Sci Rep. 2019;9:6602.
pubmed: 31036854
pmcid: 6488658
doi: 10.1038/s41598-019-43044-6
Conroy AL, Tran TM, Bond C, Opoka RO, Datta D, Liechty EA, et al. Plasma amino acid concentrations in children with severe malaria are associated with mortality and worse long-term kidney and cognitive outcomes. J Infect Dis. 2022;226:2215–25.
pubmed: 36179241
pmcid: 10205609
doi: 10.1093/infdis/jiac392
Dinarello CA. Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med. 1984;311:1413–8.
pubmed: 6208485
doi: 10.1056/NEJM198411293112205
Lundblad RL. Biotechnology of plasma proteins. Ist. Boca Raton: CRC Press; 2012. p. 460.
doi: 10.1201/b12368
van Gassel RJJ, Baggerman MR, van de Poll MCG. Metabolic aspects of muscle wasting during critical illness. Curr Opin Clin Nutr Metab Care. 2020;23:96–101.
pubmed: 31904602
pmcid: 7015189
doi: 10.1097/MCO.0000000000000628
Lopansri BK, Anstey NM, Stoddard GJ, Mwaikambo ED, Boutlis CS, Tjitra E, et al. Elevated plasma phenylalanine in severe malaria and implications for pathophysiology of neurological complications. Infect Immun. 2006;74:3355–9.
pubmed: 16714564
pmcid: 1479261
doi: 10.1128/IAI.02106-05
Rubach MP, Zhang H, Florence SM, Mukemba JP, Kalingonji AR, Anstey NM, et al. Kinetic and cross-sectional studies on the genesis of hypoargininemia in severe pediatric Plasmodium falciparum malaria. Infect Immun. 2019;87:e00655-e718.
pubmed: 30718287
pmcid: 6434111
doi: 10.1128/IAI.00655-18
Molyneux ME, Taylor TE, Wirima JJ, Borgstein A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med. 1989;71:441–59.
pubmed: 2690177
WHO. Severe falciparum malaria. Trans R Soc Trop Med Hyg. 2000;94:S1–90.
doi: 10.1016/S0035-9203(00)90300-6
Armstrong BG, Sloan M. Ordinal regression models for epidemiologic data. Am J Epidemiol. 1989;129:191–204.
pubmed: 2910061
doi: 10.1093/oxfordjournals.aje.a115109
Norris CM, Ghali WA, Saunders LD, Brant R, Galbraith D, Faris P, et al. Ordinal regression model and the linear regression model were superior to the logistic regression models. J Clin Epidemiol. 2006;59:448–56.
pubmed: 16632132
doi: 10.1016/j.jclinepi.2005.09.007
Hedeker D. A mixed-effects multinomial logistic regression model. Stat Med. 2003;22:1433–46.
pubmed: 12704607
doi: 10.1002/sim.1522
Ugwu CLJ, Zewotir TT. Using mixed effects logistic regression models for complex survey data on malaria rapid diagnostic test results. Malar J. 2018;17:453.
pubmed: 30518399
pmcid: 6282337
doi: 10.1186/s12936-018-2604-y
Umlauf N, Adler D, Kneib T, Lang S, Zeileis A. Structured additive regression models: an R interface to BayesX. Stat Softw. 2015;63:1–46.
Team RC. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2021.
Cabin RJ, Mitchell RJ. To Bonferroni or not to Bonferroni: when and how are the questions. Ecol Soc Am. 2000;81:246–8.
Batte A, Berrens Z, Murphy K, Mufumba I, Sarangam ML, Hawkes MT, et al. Malaria-associated acute kidney injury in African children: prevalence, pathophysiology, impact, and management challenges. Int J Nephrol Renovasc Dis. 2021;14:235–53.
pubmed: 34267538
pmcid: 8276826
doi: 10.2147/IJNRD.S239157
Basler T, Meier-Hellmann A, Bredle D, Reinhart K. Amino acid imbalance early in septic encephalopathy. Intensive Care Med. 2002;28:293–8.
pubmed: 11904658
doi: 10.1007/s00134-002-1217-6
Bröer S, Bröer A. Amino acid homeostasis and signalling in mammalian cells and organisms. Biochem J. 2017;474:1935–63.
pubmed: 28546457
doi: 10.1042/BCJ20160822
Anstey NM, Weinberg JB, Hassanali MY, Mwaikambo ED, Manyenga D, Misukonis MA, et al. Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. J Exp Med. 1996;184:557–67.
pubmed: 8760809
doi: 10.1084/jem.184.2.557
Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, McNeil YR, et al. Recovery of endothelial function in severe falciparum malaria: relationship with improvement in plasma L-arginine and blood lactate concentrations. J Infect Dis. 2008;198:602–8.
pubmed: 18605903
doi: 10.1086/590209
Harper AE, Miller RH, Block KP. Branched-chain amino acid metabolism. Annu Rev Nutr. 1984;4:409–54.
pubmed: 6380539
doi: 10.1146/annurev.nu.04.070184.002205
Staten MA, Bier DM, Matthews DE. Regulation of valine metabolism in man: a stable isotope study. Am J Clin Nutr. 1984;40:1224–34.
pubmed: 6439027
doi: 10.1093/ajcn/40.6.1224
Castillo L, Yu YM, Marchini JS, Chapman TE, Sanchez M, Young VR, et al. Phenylalanine and tyrosine kinetics in critically ill children with sepsis. Pediatr Res. 1994;35:580–8.
pubmed: 8065841
pmcid: 7102387
doi: 10.1203/00006450-199405000-00009
Rubach MP, Mukemba J, Florence S, Lopansri BK, Hyland K, Volkheimer AD, et al. Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria: association with disease severity. PLoS Pathog. 2015;11: e1004655.
pubmed: 25764173
pmcid: 4357384
doi: 10.1371/journal.ppat.1004655
Blau N, Thony B, Cotton RGH, Hyland K. Disorders of tetrahydrobiopterin and related biogenic amines. In: CR Scriver AB, WS Sly, D Valle, (eds.) The Metabolic and molecular bases of inherited disease. 8 edn. Vol II. New York: McGraw-Hill; 2001.
Hyland K. Estimation of tetrahydro, dihydro and fully oxidised pterins by high-performance liquid chromatography using sequential electrochemical and fluorometric detection. J Chromatogr. 1985;343:35–41.
pubmed: 4066860
doi: 10.1016/S0378-4347(00)84565-X
Kaufman CS. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: CR Scriver AB, WS Sly, D Valle, (eds). The metabolic and molecular bases of inherited disease. 8
Werner ER. Three classes of tetrahydrobiopterin-dependent enzymes. Pteridines. 2013;24:7–11.
doi: 10.1515/pterid-2013-0003
Watschinger K, Werner ER. Alkylglycerol monooxygenase. IUBMB Life. 2013;65:366–72.
pubmed: 23441072
pmcid: 3617469
doi: 10.1002/iub.1143
Sailer S, Keller MA, Werner ER, Watschinger K. The emerging physiological role of AGMO 10 years after its gene identification. Life. 2021;11:88.
pubmed: 33530536
pmcid: 7911779
doi: 10.3390/life11020088
Dorninger F, Forss-Petter S, Wimmer I, Berger J. Plasmalogens, platelet-activating factor and beyond - ether lipids in signaling and neurodegeneration. Neurobiol Dis. 2020;145: 105061.
pubmed: 32861763
pmcid: 7116601
doi: 10.1016/j.nbd.2020.105061
Erdlenbruch B, Alipour M, Fricker G, Miller DS, Kugler W, Eibl H, et al. Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries. Br J Pharmacol. 2003;140:1201–10.
pubmed: 14597599
pmcid: 1574140
doi: 10.1038/sj.bjp.0705554
Erdlenbruch B, Jendrossek V, Eibl H, Lakomek M. Transient and controllable opening of the blood-brain barrier to cytostatic and antibiotic agents by alkylglycerols in rats. Exp Brain Res. 2000;135:417–22.
pubmed: 11146820
doi: 10.1007/s002210000553
Stafforini DM, McIntyre TM, Zimmerman GA, Prescott SM. Platelet-activating factor, a pleiotrophic mediator of physiological and pathological processes. Crit Rev Clin Lab Sci. 2003;40:643–72.
pubmed: 14708958
doi: 10.1080/714037693
Gupta S, Seydel K, Miranda-Roman MA, Feintuch CM, Saidi A, Kim RS, et al. Extensive alterations of blood metabolites in pediatric cerebral malaria. PLoS ONE. 2017;12: e0175686.
pubmed: 28426698
pmcid: 5398544
doi: 10.1371/journal.pone.0175686
Lacerda-Queiroz N, Rodrigues DH, Vilela MC, Rachid MA, Soriani FM, Sousa LP, et al. Platelet-activating factor receptor is essential for the development of experimental cerebral malaria. Am J Pathol. 2012;180:246–55.
pubmed: 22079430
doi: 10.1016/j.ajpath.2011.09.038
Lacerda-Queiroz N, Rachid MA, Teixeira MM, Teixeira AL. The role of platelet-activating factor receptor (PAFR) in lung pathology during experimental malaria. Int J Parasitol. 2013;43:11–5.
pubmed: 23260771
doi: 10.1016/j.ijpara.2012.11.008
Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS, Fosiko NG, et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med. 2004;10:143–5.
pubmed: 14745442
doi: 10.1038/nm986