Severe Falciparum Malaria in Children: Current Understanding of Pathophysiology and Supportive Treatment
Introduction
Malaria is one of the most common and important parasitic diseases worldwide. About 40% of the world’s population lives in malaria-endemic areas (Sturchler, 1990), and malaria is responsible for up to 500 million episodes of clinical infection and 2.7 million deaths every year (World Health Organisation, 1996). Plasmodium falciparum is the principal cause of severe disease, since the other species of malaria rarely cause death or persistent sequelae. P. falciparum may infect humans at any time from conception to adulthood. Malarial infection probably results in 3.5 million low birth-weight infants every year (Steketee et al., 1996), since an estimated 24 million pregnant women live in malaria-endemic areas. Children living in sub-Saharan Africa bear the brunt of the disease, as they are exposed to malaria frequently after birth, and either die from complications or experience clinical episodes of infection for many years until the slow and capricious development of antimalarial immunity (Edington, 1967). This balance between acquisition of immunity and development of severe disease has continued for thousands of years.
Since the first description of malarial parasites in a sufferer by Laveran in Constantine, Algeria in 1880, there have been considerable advances in the understanding of disease mechanisms in malaria Laveran 1880, White and Ho 1992. These advances have resulted from detailed studies in patients, animal models of infection, biochemical, cellular, and molecular investigations. These studies have illuminated our understanding of disease processes, although none have succeeded so far in reducing mortality from severe infection. Mortality from treated severe malaria in children is between 5 and 15% Waller et al. 1995, Marsh et al. 1995, and the current management of severe malaria has changed surprisingly little, in spite of rapid scientific advances in malariology.
Measures to eradicate malaria have been ineffective (World Health Organisation, 1993). After the initial successes in the 1960s, insecticides have failed to curb transmission by anopheline mosquitoes (World Health Organisation, 1993). Insecticide-impregnated bednets have reduced mortality and morbidity in malarious areas Nevill et al. 1996, D’Alessandro et al. 1995c, but their efficacy may not be sustainable D’Alessandro et al. 1995b, Greenwood 1997. Results of recent trials with the current generation of malaria vaccines have been unimpressive D’Alessandro et al. 1995a, Alonso et al. 1994, although newer prototypes are under continuous investigation Stoute et al. 1997, Targett 1995. Therefore, it probably will require a concerted combination of measures, including antimalarials, vaccines, and vector control, before a reduction in infection and mortality can be maintained. Furthermore, reducing the transmission of malaria in an endemic area runs the concomitant risk of reducing the development of antimalarial immunity in the population. This reduction in “herd immunity” eventually may result in the rapid spread of severe infection if control measures fail, so that longer-term study of preventive interventions will be crucial to assessment of their true and sustainable worth. The goal of effective prevention is not yet achievable, and consequently, we will still need to manage cases of severe malaria in the foreseeable future.
The early effective treatment of falciparum infection is critical in preventing the progression to severe, life-threatening disease. Falciparum malaria has become increasingly refractory to chloroquine, the cheapest and most widely available antimalarial Krishna and White 1996, Zucker et al. 1996. In Southeast Asia, multidrug resistance is rapidly spreading Pukrittayakamee et al. 1994a, White 1992, increasing the likelihood of severe disease. In Africa, widespread chloroquine resistance has increased the incidence of some complications such as anaemia (because of inability to cure infections) (Lackritz et al., 1992), and other related problems are anticipated to worsen as higher-grade resistance becomes entrenched.
Newer antimalarial treatment regimens testing, for example, the efficacy of artemether against quinine in children with severe malaria, have not confirmed any advantage for artemether in terms of survival (van Hensbroek et al., 1996a). Yet, in vitro, the artemisinin derivatives are some of the most rapidly parasiticidal drugs, with the broadest stage-specificity of action (Murphy et al., 1995b; ter Kuile et al., 1993), and indeed, in vivo, they clear circulating parasites much faster than other antimalarials (Hien and White, 1993). This observation, that the use of more rapidly parasiticidal drugs may not affect mortality, points to alternative directions for further research designed to reduce mortality in children with malaria. These alternative approaches are based on detailed studies of the pathophysiology of infection (White and Ho, 1992), and are aimed at reversing or ameliorating those disease processes that may contribute directly to a fatal outcome, in spite of the rapid administration of effective antimalarials to the patient. These adjunctive therapies are designed to support severely ill children until the underlying disease can be reversed by the antimalarial treatment. This review focuses on key pathophysiological observations made in children with severe malaria that may guide the eventual development of such adjunctive therapies.
Section snippets
Development of infection
Clinical symptoms and signs of malaria occur when P. falciparum-infected erythrocytes multiply asexually (Marchiafava and Bignami, 1894). The hepatic stages and gametocytes are asymptomatic. The cause of P. falciparum’s virulence in comparison with other human parasites is unknown, but its multiplicative capacity and ability to sequester in the deep vascular beds are thought to contribute.
Pathology
The finding of relatively mature parasites within the deep vascular bed at post mortem was made soon after the discovery of the parasite (Marchiafava and Bignami, 1894), and gave rise to the “mechanical” hypothesis for the pathogenesis of severe malaria. This hypothesis has dominated the thinking of severe malaria during this century. We will first discuss the pathological basis of this theory, describing the pathology of severe malaria, after which we will further discuss the mechanistic
Mechanical Hypothesis
The mechanical hypothesis assumes that organs will be affected in proportion to the overall number of PRBCs sequestered in tissues, as well as their relative proportions within different tissue capillary beds. Thus, CM arises because of sequestration of PRBCs in cerebral capillaries and postcapillary venules, whereas patients who may have similar numbers of sequestered parasites in other tissues, but not the brain, would not be expected to develop a full-blown cerebral syndrome. Patients, of
Pathogenesis—parasite factors
The macroscopic consequences of falciparum infection have been recognised for over a century, but the cellular and molecular mechanisms that give rise to the fundamental pathophysiological process of sequestration have only begun to unravel in the past few years. Infection with P. falciparum changes the host red cell in many and profound ways. One of these is by altering the surface property of infected cells to make it “sticky.” This increased adhesiveness manifests itself in ways that can be
Severe Malaria
The parasite and host features that determine why a child who has been living in a malaria-endemic area and who is likely to have had extensive previous exposure to infection progresses to develop severe disease are still largely undefined. The clinical manifestations of severe malaria are determined by the degree of immunity in the affected child, as well as genotypic predispositions. African children growing up in endemic areas are exposed to malaria from infancy, and in some areas, may
Fever
Fever is a characteristic feature of falciparum malaria, although parasitisation is not inevitably associated with fever. In malaria-endemic areas, many children are afebrile despite being parasitaemic, even with relatively high parasitaemias. There is, however, a broad relationship between the level of parasitaemia and fever in these areas, so that it is possible to determine a threshold of parasitaemia (usually 2000–20,000 parasites/μL) that has an optimum sensitivity and specificity for the
Adjunctive measures
Good nursing care is crucial to the management of children with severe malaria Murphy et al. 1995a, Krishna and White 1989. Children should be transferred to a dedicated (intensive care type) unit wherever possible and cared for by experienced nurses. Those children who develop signs of deepening coma or abnormal brainstem signs should be considered for assisted ventilation, if facilities exist for this supportive measure. These children should not be made normocapnic, since this may
Discussion and future studies
Many potentially important pathophysiological events have been identified in severe malarial infection, but the testing of appropriate interventions to reverse them still remains one of the most challenging tasks for investigators. In order to test adjunctive therapies rigorously, very large clinical trials are needed, and the infrastructure and expertise to implement such studies, even if funding were to be made available, is frequently lacking. Thus, to demonstrate a reduction in mortality
Acknowledgements
We thank all of our colleagues with whom we have carried out investigations into malaria, in Kenya, Thailand, The Gambia, and Ghana, and Professor M. Bland, St. George’s Medical School, for help in constructing Table 3. CRJCN holds a Wellcome Trust Career Post in Tropical Medicine (No. 050533) and SK is a Wellcome Trust Senior Research Fellow in Clinical Science.
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