Pathophysiology and Treatment of Severe Malaria

Extracting DNA in Dr. Malika Imwong's Molecular Malariology Laboratory

A major achievement of the Malaria Department has been the successful completion of two very large trials in Asian adults (SEAQUAMAT) and African children (AQUAMAT) showing the parenteral artesunate compared to quinine reduces mortality with 35% in adults and 23% in children with severe falciparum malaria. These trials have defined the optimal antimalarial treatment for severe malaria, now adopted worldwide. Recently a thus far unrecognized but potentially important side effect of artesunate in severe malaria was described in returning travellers: a severe drop in haemoglobin more than a week after treatment of severe malaria. The team at KIMORU, led by Caterina Fanello and Marie Onyamboko, investigate how important this side effect is for African children. The team from DRC also work on uncomplicated paediatric malaria and malaria in pregnancy in collaboration with the Kinshasa School of Public Health in the Democratic Republic of Congo.

Now that parenteral artesunate has proven to be the best drug for severe malaria in all age groups and all settings, further reductions in the mortality of this deadly disease will have to come from better supportive ICU-type care and adjuvant therapies beyond antimalarial treatment. For the later it is crucial to identify the pivotal patho-physiological mechanism causing severe illness.

Currently, Hugh Kingston, Katherine Plewes and Richard Maude lead seasonal work on severe malaria in MORU study sites in Chittagong and Ramu in Bangladesh in collaboration with Professor M Abul Faiz and the Chittagong Medical College Hospital and with Drs Sanjib Mohanty and Sarosh Mishra at Ispat General Hospital in Rourkela, India.

The Malaria Department has carried out extensive research to quantify the importance of microvascular obstruction by sequestration of parasitized red blood cells through adhesion to the vascular endothelium and to other infected and uninfected red blood cells, as well as through a reduction in red blood cell deformability.

We have developed methods to observe microvascular changes in patients with severe malaria, including studies on malaria specific retinopathy and microscopic observations of rectal capillaries  using “orthogonal polarizing spectroscopy”. These studies have confirmed the central role of microvascular obstruction in the pathophysiology of severe malaria.

The Unit is now conducting trials with drugs that reverse and prevent the sequestration of parasitized red blood cells in the micro-vasculature of vital organs. Dr. Prakaykaew Charunwatthana has coordinated studies in Mae Sot, Mae Ramad Hospital, Thailand on levamisole and sevuparin, which both counteract cytoadherence.  In addition, trials with drugs acting as nitric oxide-donors in order to improve microvascular function are underway.

Another very important contributor to disease severity in malaria is metabolic acidosis. Dr Stije Leopold in close collaboration with the Pharmacology Department investigates the molecules contributing to this acid load and their sources. This may also provide us with novel targets for intervention.

Intravascular haemolysis is inherently present in patients with severe malaria, causing haem-mediated oxidative stress. We are investigating the importance of different haem fractions, and are evaluating paracetamol as renal protective therapy in patients with severe malaria and intravascular haemolysis oxidative stress mediated renal impairment.