Prof. Arjen Dondorp: The treatment of severe malaria

Q: What is severe malaria?

AD: Malaria is a disease caused by a parasite called Plasmodium which lives in red blood cells. There are four species of Plasmodium that can cause human disease, and one other species that easily jumps from the monkey to human beings. Of those 5 types, Plasmodium falciparum is the one that most commonly causes severe disease in patients that are not immune to the disease. It can then develop within a few days to a very severe condition affecting many vital organs, for instance the brain, causing coma or cerebral malaria; it can affect kidneys causing renal failure and lungs causing respiratory failure; it can make the blood very acidotic and causes severe anaemia as well as death. So then it is really an emergency disease.

Q: Is malaria different in South East Asia than Africa, and is it different in Cambodia and Thailand?

AD: Yes there are differences between sub-Saharan Africa and Asia in that the transmission of the disease in Africa is much more intense than in Asia. In many parts he or she will build up immunity in the first years of his or her life, so you hardly see any severe disease after the age of five. Whereas in Asia people are bitten maybe once a year by an infected mosquito so they don’t have time to build up immunity. There you see disease in young adults or in any ages. This also makes the manifestations of the disease slightly different in adults: adults can develop cerebral malaria and very acidotic blood, but also renal failure, pulmonary failure whereas children also often develop coma and acidosis but tend to have more severe anaemia than adult patients. Then your question whether it is specifically different in Cambodia and Thailand: these are areas of low transmission so severe malaria is mainly a disease of young adults; but anti-malarial drug resistance tends to somehow, for reasons we don’t completely understand, start in that part of the world. So the treatment of malaria is in general more difficult in that part of the world.

Q: What are the most important lines of research that have developed over the last five or ten years?

AD: There is a lot of research going on in severe malaria and we more and more understand the mechanisms of the disease - or why a child or an adult gets so severely ill from malaria. The focus is much more around deaths. The real changes are in the smallest blood vessels of the patients because they get completely clogged with these red blood cells that have the mature forms of the parasite; those red blood cells get very sticky and adhere to the lining of the small blood vessels causing a mechanical blockage of blood flow there. This also activates the endothelium which has a lot of secondary effects. Therapies are directed to either kill the parasite at an early stage so that it cannot mature, get sticky and obstruct the small blood vessels, and there are new therapies called adjuvant therapies that you give in addition to anti-malarial drugs which specifically target this mechanism of cyto-adherence?

Q: What are the most promising treatments?

AD: Our own research over the last few years has been in more potent acting anti-malarial drugs killing young parasites and these are the artemisinin drugs. We tested a specific derivative of those drugs called artesunate that you can give directly into the blood stream. That has proven to be very successful for the treatment of severe malaria. We have done very large trials and shown that in adults with severe malaria it reduces mortality by 35% compared to the old treatment with quinine and in children, African children with severe malaria, by 23%. So that’s a huge gain.

Q: Why does your line of research matter? Why should we put money into it?

AD: Malaria is still a very important disease; malaria control has been very successful over the last decade and malaria mortality worldwide has gone down. But still 428 000 people, mainly African children, die from malaria each year so it is a very important disease. We still need better treatments to reduce this high mortality rate and there are still important questions to answer in the mechanism of disease that we need to know in order to develop these better treatments.

Q: How does your research fit into translational medicine within the department?

AD: Well there are many translational aspects to the research we do. A lot of the research starts in the laboratory trying to look for new treatments in models, and then those new drugs have to be tested out in the field. Once they are shown to work, they need to be translated in the field in which they are really used. Then it is important to get them into guidelines such as the WHO guidelines for treatment of severe malaria - for instance with these new artemisinin derivatives. What is also important is that the general care of children and adults with severe malaria is improved. We also have teaching programmes to have structured implementation of strategies that are cost effective and cheap so that they can be used in resource poor settings. And with all those measures we hope to improve the survival of these people with severe malaria.