severe and cerebral malaria investigated through host metabolomics

Conditions: Severe Malaria

Summary: * the aim is to describe disease mechanisms of severe and cerebral malaria and identify new targets for adjunctive therapies. * despite treatment between 10-30% of patients with severe malaria die. * metabolic acidosis and cerebral malaria are major complications associated with mortality across all age groups. still, their underlying pathogenesis remains incompletely understood. * using a metabolomics approach, this study aims to characterise the spectrum of acids accumulating during acidosis, and investigate patterns of metabolic dysregulation associated with coma and seizures.


Eligibility criteria:
severe/cerebral malaria: * any p. falciparum parasitaemia detected by asexual stages on a peripheral blood-slide or a positive rapid diagnostic test in combination with one or more modified who criteria for severe malaria (hien et al, 1996) * \< 24 hours after treatment commencement with either parenteral artemisinin or quinine * age \> 12 years * full informed written consent obtained uncomplicated malaria: * any level of plasmodium parasitaemia, detected by asexual stages on a peripheral blood-slide or a positive rapid diagnostic test without any of the complications of severe malaria stated above. * age \> 12 years * full informed written consent obtained sepsis: * clinical signs of infection in combination with any two of the following signs: 1. heart rate \> 90 beats per minute; 2. respiratory rate \> 20 breaths per minute, a paco2 of \< 32 mmhg, or the use of mechanical ventilation for an acute respiratory process; 3. tympanic temperature \> 38°c or \< 36 °c; 4. white-cell count of \> 12x109/l or \< 4x109/l, or a differential count showing 10% immature neutrophils ; * negative peripheral blood slide for any stages of malaria parasites or a negative rapid diagnostic test for falciparum and vivax malaria * \[as bacterial culture is not routinely available at the study site, positivity of cultures is not required\] * age \> 12 years * full informed written consent obtained acidosis: * clinical suspicion of metabolic acidosis in combination with any of the following: 1. peripheral venous bicarbonate \< 15 mmol/l 2. peripheral venous base excess \< -3 mmol/l * negative peripheral blood slide for any stages of malaria parasites or a negative rapid diagnostic test for falciparum and vivax malaria; and not meeting any of the inclusion criteria for sepsis as stated above. * age \> 12 years * full informed written consent obtained encephalitis: * gcs \< 11/15 * documented fever \> 38°c * onset of symptoms \< 2 weeks, with an indication a lumbar puncture as part of the diagnostic work up * negative peripheral blood slide for any stages of malaria parasites or a negative rapid diagnostic test for falciparum and vivax malaria * age \> 12 years * full informed written consent obtained healthy volunteers: * no chronic or acute disease * no fever in the past 2 weeks * age \> 16 years * full informed written consent obtained exclusion criteria: * known pre-existing chronic medical conditions including advanced hepatic disease.

Keywords: pathogenesis microvascular function metabolic dysregulation metabolomics