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The life cycle of the malaria parasite in the human body is intimately tied to the clinical problems it produces (see part 1 of Malaria and the human body). These clinical problems can be predicted from these three main aspects of host–parasite interaction:
In most cases, malaria is a febrile illness with a wide range of symptoms that include headache, rigors, muscle pains, lassitude, and cough – most of which probably reflect activation of cytokines.
The episode is usually limited, either by the host's response or by treatment, but in a proportion of cases the disease progresses to become severe and life threatening.
Although complex, the clinical picture of severe malaria is dominated by three main problems: anaemia, respiratory distress and coma, and these can be seen as resulting from the interaction of the three main components of the host–parasite interaction discussed above.
Thus, severe anaemia may result from rapid parasite growth and red blood cell destruction (although the removal of uninfected red blood cells by an overenthusiastic immune system, and the suppression of the bone marrow response by cytokines, also play a role).
Reduced oxygen delivery to tissues caused by a combination of small vessel obstruction, and exacerbated by reduced oxygen-carrying capacity due to anaemia, leads to a profound metabolic acidosis (where the blood becomes too acidic). This in turn leads to respiratory distress, a compensatory mechanism by which the patient breathes harder to try to 'blow off' carbon dioxide to reduce the acidity.
The most well known and feared manifestation of severe malaria is cerebral malaria, in which the patient goes into coma and often has convulsions.
In some cases, coma seems to be the body's response to overwhelming metabolic disturbance, particularly the metabolic acidosis described above. But in other cases the general features described above are specifically focused in the brain, with massive packing of blood vessels by infected parasites, leading to a variety of local effects, including tissue damage, cytokine activation and other poorly understood cellular pathology.
Prevention and treatment
The key to reducing malaria deaths is prevention of infection. Historically, emphasis was on reducing the numbers of mosquitoes by a combination of environmental hygiene and residual insecticide spraying. While still important in many settings, these approaches are often of limited use in widespread rural communities which bear the brunt of the malaria threat. Here, the current emphasis is on individual protection by sleeping under insecticide-impregnated bednets, an approach demonstrated to have major effects in reducing childhood mortality.
The prevention of mosquito biting is only ever partial, however, and in most circumstances the major barrier between malaria infection and death is the early use of antimalarial drugs as soon as the patient has fever. Here the major problem is the development of resistance to chloroquine, a cheap and effective drug.
There is a desperate need for the development of new, safe affordable antimalarials. Once severe malaria has developed, antimalarial drugs still have a role but just as important is rapid management of the problems discussed above: blood transfusion for anaemia, fluid therapy to correct acidosis and the treatment of convulsions to limit subsequent brain damage.
While malaria has been eradicated from some areas of the world, these were essentially regions where the balance between transmission and control was already precarious. There is no prospect of eradication with currently available measures in the core areas of malaria's range, where the dynamics of transmission massively favour the parasite.
In sub-Saharan Africa in particular, there will continue to be a race between the development of new approaches to control and the parasite's ability to evade them.
Currently the parasite has the upper hand. Central to attempts to reverse this are the search for novel antimalarial drugs and the development of vaccines.
But malaria is complex and successful, and all the easy options have been exhausted.
New approaches depend critically on developing a holistic view which integrates our understanding of malaria, from the most basic realities of life for those who are its victims to the most fundamental aspects of the parasite's biology, and it is here that the information from the genome project will play a critical role.
Professor Kevin Marsh is Director of the KEMRI-Wellcome Trust Research Programme, which is based in Kilifi and Nairobi, Kenya.
Page of 2; 2/9/04
[WTD023880] Malaria and the human body, part 2: Tackling illness.doc