Although many species of malarial parasite exist, only Plasmodium falciparum, vivax, ovale, and malariae are classically associated with human infection. The former two species are most frequently associated with malarial disease in humans, with severe malarial disease almost exclusively associated with P. falciparum infection. Falciparum malaria is responsible for considerable morbidity (300-500 million annual clinical cases) and death across the globe, with a particular burden of mortality among children in sub-Saharan Africa. Infection with P. vivax is rarely fatal, but is associated with considerable morbidity outside the African continent. It should also be recalled that malaria causes social and economic disruption on a uniquely large scale [1].

Severe adult malaria is a clinical syndrome originally classified using 10 defining and 5 supportive (often overlapping) clinical features unified by the presence of asexual malarial parasites in the peripheral blood smear [2]. Based on observations of children in coastal Kenya, paediatric severe malaria has similarly been distilled into three main (again often overlapping) clinical syndromes, anaemia, respiratory distress (an indicator of an underlying metabolic acidosis) and impairment of consciousness [3]. These clinical syndromes are discussed below.

In the review mentioned above [3], the authors' judicious use of the term impaired consciousness, rather than cerebral malaria (CM), promoted the useful concept that the neurological features (and in-turn the underlying mechanisms) associated with severe malaria are not necessarily unique to malarial disease. Indeed, over 60 years ago, it was noted that the clinical features of malaria can resemble those exhibited in patients with fulminant bacterial or viral infections [4].

Severe malaria has been intensively studied, and there appears to be a complex interplay between host infection and disease. This is highlighted by the different clinical manifestations of severe malaria exhibited by children and adults. These differences are undoubtedly, in part, a function of patient age. However, age is just one of a series of interacting factors, e.g. geographical region, level of malaria transmission, degree of previous malaria exposure, length of illness prior to treatment and host immunity that may influence the clinical presentation of severe malaria. This variation in clinical presentation has been mirrored by a similar multitude of proposals regarding the functional mechanisms underlying pathogenesis of severe malaria.

One concept of pathogenesis consistently articulated has been the 'mechanical theory'. Historically, this theory was developed from two fundamental differences between P. falciparum and P. vivax infection. Firstly, erythrocytes parasitised with P. vivax do not sequester. Secondly, death following P. vivax infection is rare. Consequently, pathogenesis is believed to be due to obstruction of micro-vascular flow by erythrocytes containing mature-stage falciparum parasites adhering to the endothelium (termed sequestration).

More recently the 'cytokine theory of disease' has also gained credence. This theory can be applied to disease following both falciparum and vivax infection. The lower mortality associated with P. vivax being explained by a relatively milder degree of pro-inflammatory imbalance during the host's response to P. vivax infection.

The main theme of this chapter is to examine the increased understanding of the functions of inflammatory cytokines gained over the past 15 years, and explore how these insights are changing attitudes in malarial disease research. We also discuss how two theories (mechanical and cytokine) can, as proposed first in a recognisable form at least 65 years ago [5], be complementary.

Table 1. Comparison of Kenyan children and Papua-New Guinea adults admitted to hospital using the WHO classification

Kenyan children [7]

Adults Papua-New Guinea [19a ]





Defining criteria Coma*

Severe anemia** Pulmonary oedema Hypoglycaemia Circulatory collapse Renal Failure Spontaneous bleeding Haemoglobinaemia Acidosis

Repeated convulsions



50 21.4

17.1 10


37.5 100

Supporting criteria

Impaired consciousness 8.2

Jaundice 4.7

Prostration 12.2

Hyperpyrexia 10.6

Hyperparasitaemia 8.9

20 40



* Childhood coma is defined by a Blantyre coma score a 2.

** The childhood definition for severe anemia does not include a cut off for parasitaemia. Modified from [11].

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