Severe and Cerebral Malaria Investigated Through Host Metabolomics

Study Overview
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Brief Summary
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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.

Official Title
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Microvascular and Metabolic Dysregulation in the Pathogenesis of Severe and Cerebral Malaria Investigated Through Host Metabolomics

Conditions
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Severe Malaria

Intervention / Treatment
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* Other: Observation


Participation Criteria
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Eligibility Criteria
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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: Heart rate > 90 beats per minute; Respiratory rate > 20 breaths per minute, a PaCO2 of < 32 mmHg, or the use of mechanical ventilation for an acute respiratory process; Tympanic temperature > 38°C or < 36 °C; 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: Peripheral venous bicarbonate < 15 mmol/L 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.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Severe/Cerebral Malaria<br>Intensive monitoring | Other: Observation<br> <br> |
| Uncomplicated Malaria<br>Intensive monitoring | Other: Observation<br> <br> |
| Sepsis<br>Intensive monitoring | Other: Observation<br> <br> |
| Acidosis<br>Intensive monitoring | Other: Observation<br> <br> |
| Encephalitis<br>Intensive monitoring | Other: Observation<br> <br> |
| Healthy Individuals<br>Monitoring | Other: Observation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterisation of patterns of metabolic dysregulation in severe malaria | Interrelationship between disturbances in metabolic pathways associated with acidosis and cerebral malaria | 4-6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pathogenesis, Microvascular function, Metabolic dysregulation, Metabolomics