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

IntroductionSevere 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.MethodsIn 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.ResultsPatients 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).ConclusionsNewly 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.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-1023-5) contains supplementary material, which is available to authorized users.     

Levamisole inhibits sequestration of infected red blood cells in patients with falciparum malaria

BACKGROUND: Sequestration of infected red blood cells (iRBCs) in the microcirculation is central to the pathophysiology of falciparum malaria. It is caused by cytoadhesion of iRBCs to vascular endothelium, mediated through the binding of Plasmodium falciparum erythrocyte membrane protein-1 to several endothelial receptors. Binding to CD36, the major vascular receptor, is stabilized through dephosphorylation of CD36 by an alkaline phosphatase. This is inhibited by the alkaline phosphatase-inhibitor levamisole, resulting in decreased cytoadhesion. METHODS: Patients with uncomplicated falciparum malaria were randomized to receive either quinine treatment alone or treatment with a single 150-mg dose of levamisole as an adjunct to quinine. Peripheral blood parasitemia and parasite stage distribution were monitored closely over time. RESULTS: Compared with those in control subjects, peripheral blood parasitemias of mature P. falciparum parasites increased during the 24 h after levamisole administration (n=21; P=.006). The sequestration ratio (between observed and expected peripheral blood parasitemia) of early trophozoite and midtrophozoite parasites increased after levamisole treatment, with near complete prevention of early trophozoite sequestration and >65% prevention of midtrophozoite sequestration. CONCLUSION: These findings strongly suggest that levamisole decreases iRBC sequestration in falciparum malaria in vivo and should be considered as a potential adjunctive treatment for severe falciparum malaria. TRIAL REGISTRATION: Current Controlled Trials identifier: 15314870.     

A systematic overview of published antimalarial drug trials

Systematic database searches identified 435 antimalarial drug treatment trials, involving 82,616 patients, conducted and published between 1966 and December 2002. Of these trials 72% were randomised; 64 (15%) trials involved severe malaria, 47 (11%) studied Plasmodium vivax, 3 Plasmodium malariae or Plasmodium ovale, and the remainder (74%) assessed treatment responses in uncomplicated falciparum malaria. Twelve trials (2.7%) specifically evaluated antimalarial treatments in pregnant women. Overall 49% of trials were conducted in Asia (29% from Thailand alone) and 42% in Africa. Half of all the patients studied had been in trials published in the past 7 years. There has been a recent rise in the proportion of trial enrolling children, and a tripling in the average number of patients recruited per trial (from approximately 100 in the 1970s to 300 currently). Chloroquine was given to over half the patients in antimalarial drug trials (n = 53552) compared with artemisinin derivatives (n = 12463), mefloquine-sulphadoxine-pyrimethamine (n = 9153), mefloquine (n = 5546) and sulphadoxine-pyrimethamine (n = 5909). The quality of safety and efficacy data for recently evaluated drugs contrasts with a relative paucity of data for older 'established' compounds.     

Pharmacokinetic Interactions between Primaquine and Chloroquine

Chloroquine combined with primaquine has been the standard radical curative regimen for Plasmodium vivax and Plasmodium ovale malaria for over half a century. In an open-label crossover pharmacokinetic study, 16 healthy volunteers (4 males and 12 females) aged 20 to 47 years were randomized into two groups of three sequential hospital admissions to receive a single oral dose of 30 mg (base) primaquine, 600 mg (base) chloroquine, and the two drugs together. The coadministration of the two drugs did not affect chloroquine or desethylchloroquine pharmacokinetics but increased plasma primaquine concentrations significantly (P ≤ 0.005); the geometric mean (90% confidence interval [CI]) increases were 63% (47 to 81%) in maximum concentration and 24% (13 to 35%) in total exposure. There were also corresponding increases in plasma carboxyprimaquine concentrations (P ≤ 0.020). There were no significant electrocardiographic changes following primaquine administration, but there was slight corrected QT (QTc) (Fridericia) interval lengthening following chloroquine administration (median [range] = 6.32 [−1.45 to 12.3] ms; P < 0.001), which was not affected by the addition of primaquine (5.58 [1.74 to 11.4] ms; P = 0.642). This pharmacokinetic interaction may explain previous observations of synergy in preventing P. vivax relapse. This trial was registered at ClinicalTrials.gov under reference number {"type":"clinical-trial","attrs":{"text":"NCT01218932","term_id":"NCT01218932"}}NCT01218932.     

Prevalence and diversity of human rotavirus among Thai adults

Rotavirus infections have become one of the most common causes of infectious gastroenteritis in children. Although rotavirus infections have been intensively studied in infants and young children, the study in adults has been limited. As such, this study assessed the prevalence of rotaviruses and performed the molecular characterization of rotaviruses circulating in Thai adults experiencing acute gastroenteritis between January 2018 and December 2018. Group A human rotaviruses were detected in 100 feces samples by rapid immunochromatography. The peak incidence of infection occurred in February and began to decline in the summer months. From January 2018 to December 2018, there were 1344 acute gastroenteritis adult cases in the Hospital for Tropical Diseases, Bangkok, Thailand. Among these, 310 cases were rotavirus-suspected cases. Only 100 samples tested positive for rotavirus via an immunochromatography test. Twentynine out of the 100 rotavirus-positive samples were further characterized by real-time polymerase chain reaction. The G3[P8] strain was identified as the most prevalent (31.0%) followed by G1P[8], G8P[8] and G9P[8], and G2P[8], which accounted for 20.8%, 17.2%, and 13.8%, respectively. Because of the detection of rare rotavirus genotypes, such as G8, the surveillance of rotavirus epidemiology is crucial in monitoring new emergences of rotavirus strains, leading to a better understanding of the effects of strain variation for further vaccine development.     

Does Artesunate Prolong the Electrocardiograph QT Interval in Patients with Severe Malaria?

Several antimalarials can cause significant prolongation of the electrocardiograph QT interval, which can be associated with an increased risk of potentially lethal ventricular arrhythmias. High doses of artemether and artemotil have been associated with QT prolongation in dogs, raising the possibility of a class effect with the artemisinin derivatives. Serial electrocardiograms were recorded, and QTc interval was calculated before and after administration of artesunate by intravenous injection in patients with severe falciparum malaria in Bangladesh. Of 21 adult patients with severe malaria enrolled, 8 (38%) died. The mean QTc interval was unaffected by bolus intravenous artesunate (2.4 mg/kg). In two patients, the QTc interval exceeded 0.5 seconds, but in both cases, an alternative explanation was plausible. No effect was observed on the JTc or PR interval, QRS width, blood pressure, or heart rate. Intravenous artesunate does not have significant cardiovascular effects in patients with severe falciparum malaria.     

Hyponatremia in Severe Malaria: Evidence for an Appropriate Anti-diuretic Hormone Response to Hypovolemia

Although hyponatremia occurs in most patients with severe malaria, its pathogenesis, prognostic significance, and optimal management have not been established. Clinical and biochemical data were prospectively collected from 171 consecutive Bangladeshi adults with severe malaria. On admission, 57% of patients were hyponatremic. Plasma sodium and Glasgow Coma Score were inversely related (r_s = −0.36, P < 0.0001). Plasma antidiuretic hormone concentrations were similar in hyponatremic and normonatremic patients (median, range: 6.1, 2.3–85.3 versus 32.7, 3.0–56.4 pmol/L; P = 0.19). Mortality was lower in hyponatremic than normonatremic patients (31.6% versus 51.4%; odds ratio [95% confidence interval]: 0.44 [0.23–0.82]; P = 0.01 by univariate analysis). Plasma sodium normalized with crystalloid rehydration from (median, range) 127 (123–140) mmol/L on admission to 136 (128–149) mmol/L at 24 hours (P = 0.01). Hyponatremia in adults with severe malaria is common and associated with preserved consciousness and decreased mortality. It likely reflects continued oral hypotonic fluid intake in the setting of hypovolemia and requires no therapy beyond rehydration.