The role of previously unmeasured organic acids in the pathogenesis of severe malaria.
BACKGROUND
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.
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. mtherdman@gmail.com.
M Trent
MT
Herdman
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Natthida@tropmedres.ac.|Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand. Natthida@tropmedres.ac.|Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Natthida@tropmedres.ac.
Natthida
N
Sriboonvorakul
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. stije@tropmedres.ac.
Stije J
SJ
Leopold
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. samdouthwaite.1@googlemail.com.
Sam
S
Douthwaite
Ispat General Hospital, Rourkela, Orissa, India. sanjibmalaria@rediffmail.com.
Sanjib
S
Mohanty
Chittagong Medical College Hospital, Chittagong, Bangladesh. mahtabnipu@yahoo.com.
M Mahtab Uddin
MM
Hassan
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. richard@tropmedres.ac.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. richard@tropmedres.ac.
Richard J
RJ
Maude
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. hugh@tropmedres.ac.|Global Health Division, Menzies School of Health Research, Darwin, Australia. hugh@tropmedres.ac.
Hugh W F
HW
Kingston
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Katherine@tropmedres.ac.
Katherine
K
Plewes
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Jib@tropmedres.ac.|Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Jib@tropmedres.ac.
Prakaykaew
P
Charunwatthana
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. oye@tropmedres.ac.
Kamolrat
K
Silamut
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Charlie@tropmedres.ac.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Charlie@tropmedres.ac.
Charles J
CJ
Woodrow
Aniruddha
A
Ghose
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. nok@tropmedres.ac.|Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. nok@tropmedres.ac.
Kesinee
K
Chotinavich
Chittagong Medical College Hospital, Chittagong, Bangladesh. amir_hossain_ctg@yahoo.com.
Md Amir
MA
Hossain
Dev Care Foundation, Dhaka, Bangladesh. drmafaiz@gmail.com.
M Abul
MA
Faiz
Ispat General Hospital, Rourkela, Orissa, India. sarojrkl@gmail.com.
Saroj
S
Mishra
Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand. Natchanun.L@chula.ac.th.
Natchanun
N
Leepipatpiboon
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. nickwdt@tropmedres.ac.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. nickwdt@tropmedres.ac.
Nicholas J
NJ
White
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Nickd@tropmedres.ac.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Nickd@tropmedres.ac.
Nicholas P J
NP
Day
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. joel@tropmedres.ac.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. joel@tropmedres.ac.
Joel
J
Tarning
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. arjen@tropmedres.ac.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. arjen@tropmedres.ac.
Arjen M
AM
Dondorp
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000138:Acidosis / Q000150:complications; D000293:Adolescent; D000328:Adult; D000368:Aged; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates / Q000097:blood; D007656:Ketoglutaric Acids / Q000652:urine; D019344:Lactic Acid / Q000097:blood; D016778:Malaria, Falciparum / Q000097:blood / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000652:urine; D008297:Male; D008314:Malonates / Q000652:urine; D013058:Mass Spectrometry; D008764:Methylmalonic Acid / Q000652:urine; D008875:Middle Aged; D010666:Phenylpropionates / Q000097:blood; D011446:Prospective Studies; D012720:Severity of Illness Index; D055815:Young Adult
D006885:Hydroxybutyrates; D007656:Ketoglutaric Acids; D008314:Malonates; D010666:Phenylpropionates; C001418:4-hydroxyphenyllactic acid; D019344:Lactic Acid; C038080:ethylmalonic acid; D008764:Methylmalonic Acid; C031570:2-hydroxybutyric acid; D020155:3-Hydroxybutyric Acid