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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

Urine concentrations of organic acids corrected for renal function. Black bars above the scatterplots denote significantly different participant groups identified with Tukey’s test and P<0.05. Error bars represent medians and interquartile ranges. Abbreviations: CrCl creatinine clearance, LA lactic acid, HPLA hydroxyphenyllactic acid, α-HBA α-hydroxybutyric acid, β-HBA β-hydroxybutyric acid
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Fig2: Urine concentrations of organic acids corrected for renal function. Black bars above the scatterplots denote significantly different participant groups identified with Tukey’s test and P<0.05. Error bars represent medians and interquartile ranges. Abbreviations: CrCl creatinine clearance, LA lactic acid, HPLA hydroxyphenyllactic acid, α-HBA α-hydroxybutyric acid, β-HBA β-hydroxybutyric acid

Mentions: Of the eight candidate acids sought by LC-MS, four were present at detectable levels in both plasma and urine: LA, α-HBA, β-HBA and HPLA. EMA, MMA and α-KGA were undetectable in plasma but were detectable in urine. MA was undetectable in both plasma and urine. Table 3 summarises the observed range of acids detected in plasma and urine specimens taken from the study groups at the time of admission. Figures 1 and 2 compare plasma and corrected urine concentrations, respectively, between study groups.Table 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)

Urine concentrations of organic acids corrected for renal function. Black bars above the scatterplots denote significantly different participant groups identified with Tukey’s test and P<0.05. Error bars represent medians and interquartile ranges. Abbreviations: CrCl creatinine clearance, 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

Fig2: Urine concentrations of organic acids corrected for renal function. Black bars above the scatterplots denote significantly different participant groups identified with Tukey’s test and P<0.05. Error bars represent medians and interquartile ranges. Abbreviations: CrCl creatinine clearance, LA lactic acid, HPLA hydroxyphenyllactic acid, α-HBA α-hydroxybutyric acid, β-HBA β-hydroxybutyric acid
Mentions: Of the eight candidate acids sought by LC-MS, four were present at detectable levels in both plasma and urine: LA, α-HBA, β-HBA and HPLA. EMA, MMA and α-KGA were undetectable in plasma but were detectable in urine. MA was undetectable in both plasma and urine. Table 3 summarises the observed range of acids detected in plasma and urine specimens taken from the study groups at the time of admission. Figures 1 and 2 compare plasma and corrected urine concentrations, respectively, between study groups.Table 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