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The role of previously unmeasured organic acids in the pathogenesis of severe malaria.

Herdman MT, Sriboonvorakul N, Leopold SJ, Douthwaite S, Mohanty S, Hassan MM, Maude RJ, Kingston HW, Plewes K, Charunwatthana P, Silamut K, Woodrow CJ, Ghose A, Chotinavich K, Hossain MA, Faiz MA, Mishra S, Leepipatpiboon N, White NJ, Day NP, Tarning J, Dondorp AM - Crit Care (2015)

Bottom Line: In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated.Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6-7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5-7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81).Further characterisation of their sources and metabolic pathways is now needed.

View Article: PubMed Central - PubMed

Affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. mtherdman@gmail.com.

ABSTRACT

Introduction: Severe falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria.

Methods: In this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death.

Results: Patients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean ± SD) was elevated in severe malaria (8.2 mEq/L ± 4.5) and severe sepsis (8.6 mEq/L ± 7.7) compared with uncomplicated malaria (6.0 mEq/L ± 5.1) and encephalopathy (6.6 mEq/L ± 4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and β-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6-7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5-7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81).

Conclusions: Newly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.

No MeSH data available.


Related in: MedlinePlus

Plasma concentrations of organic acids in severe malaria, stratified by disease outcome. Comparisons are drawn between patients who survived to discharge (n=99) and those who died (n=39). For all four acids, plasma concentrations were significantly higher among patients who later died, by unpaired t test of log-transformed concentrations (P<0.001 for LA, HPLA and β-HBA; P=0.001 for α-HBA). Error bars represent medians and interquartile ranges. Abbreviations: LA lactic acid, HPLA hydroxyphenyllactic acid, α-HBA α-hydroxybutyric acid, β-HBA β-hydroxybutyric acid
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Fig3: Plasma concentrations of organic acids in severe malaria, stratified by disease outcome. Comparisons are drawn between patients who survived to discharge (n=99) and those who died (n=39). For all four acids, plasma concentrations were significantly higher among patients who later died, by unpaired t test of log-transformed concentrations (P<0.001 for LA, HPLA and β-HBA; P=0.001 for α-HBA). Error bars represent medians and interquartile ranges. Abbreviations: LA lactic acid, HPLA hydroxyphenyllactic acid, α-HBA α-hydroxybutyric acid, β-HBA β-hydroxybutyric acid

Mentions: Admission plasma concentrations of LA, HPLA, α-HBA and β-HBA were each higher in patients with severe malaria who later died than in those who survived (Fig. 3). Of the four detectable acids, HPLA had the highest prognostic utility with an AUROCC of 0.79 (95 % CI 0.70–0.87), followed by LA with an AUROCC of 0.77 (95 % CI 0.69–0.86). The AUROCC for SBD was 0.75 (95 % CI 0.65-0.85), and the AUROCC for pH was 0.74 (95 % CI 0.64–0.83). Urine LA and HPLA also had prognostic value, but less than that of their plasma concentrations (data not shown).Fig. 3


The role of previously unmeasured organic acids in the pathogenesis of severe malaria.

Herdman MT, Sriboonvorakul N, Leopold SJ, Douthwaite S, Mohanty S, Hassan MM, Maude RJ, Kingston HW, Plewes K, Charunwatthana P, Silamut K, Woodrow CJ, Ghose A, Chotinavich K, Hossain MA, Faiz MA, Mishra S, Leepipatpiboon N, White NJ, Day NP, Tarning J, Dondorp AM - Crit Care (2015)

Plasma concentrations of organic acids in severe malaria, stratified by disease outcome. Comparisons are drawn between patients who survived to discharge (n=99) and those who died (n=39). For all four acids, plasma concentrations were significantly higher among patients who later died, by unpaired t test of log-transformed concentrations (P<0.001 for LA, HPLA and β-HBA; P=0.001 for α-HBA). Error bars represent medians and interquartile ranges. Abbreviations: LA lactic acid, HPLA hydroxyphenyllactic acid, α-HBA α-hydroxybutyric acid, β-HBA β-hydroxybutyric acid
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4561438&req=5

Fig3: Plasma concentrations of organic acids in severe malaria, stratified by disease outcome. Comparisons are drawn between patients who survived to discharge (n=99) and those who died (n=39). For all four acids, plasma concentrations were significantly higher among patients who later died, by unpaired t test of log-transformed concentrations (P<0.001 for LA, HPLA and β-HBA; P=0.001 for α-HBA). Error bars represent medians and interquartile ranges. Abbreviations: LA lactic acid, HPLA hydroxyphenyllactic acid, α-HBA α-hydroxybutyric acid, β-HBA β-hydroxybutyric acid
Mentions: Admission plasma concentrations of LA, HPLA, α-HBA and β-HBA were each higher in patients with severe malaria who later died than in those who survived (Fig. 3). Of the four detectable acids, HPLA had the highest prognostic utility with an AUROCC of 0.79 (95 % CI 0.70–0.87), followed by LA with an AUROCC of 0.77 (95 % CI 0.69–0.86). The AUROCC for SBD was 0.75 (95 % CI 0.65-0.85), and the AUROCC for pH was 0.74 (95 % CI 0.64–0.83). Urine LA and HPLA also had prognostic value, but less than that of their plasma concentrations (data not shown).Fig. 3

Bottom Line: In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated.Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6-7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5-7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81).Further characterisation of their sources and metabolic pathways is now needed.

View Article: PubMed Central - PubMed

Affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. mtherdman@gmail.com.

ABSTRACT

Introduction: Severe falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria.

Methods: In this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death.

Results: Patients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean ± SD) was elevated in severe malaria (8.2 mEq/L ± 4.5) and severe sepsis (8.6 mEq/L ± 7.7) compared with uncomplicated malaria (6.0 mEq/L ± 5.1) and encephalopathy (6.6 mEq/L ± 4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and β-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6-7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5-7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81).

Conclusions: Newly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.

No MeSH data available.


Related in: MedlinePlus