• 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.

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.

In total, up to 840 patients may be enrolled in this study.