Severe Falciparum Malaria in Children: Current Understanding of Pathophysiology and Supportive Treatment

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Abstract

Severe falciparum malaria is one of the most lethal parasitic infections in the world and is responsible for more than one million deaths in African children per year. Changes to management over the last 40 years have not improved survival. A reduction in the mortality and morbidity may only come about by a better understanding of the pathophysiological processes that are responsible for severe disease and that determine the outcome before antimalarials have had time to work. This review discusses potential adjunctive therapies for severe malaria that are under development following such detailed clinical and pathophysiological studies.

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.

References (430)

  • W. Berman et al.

    The effects of exchange transfusion on intracranial pressure in patients with Reye syndrome

    J. Pediatr.

    (1975)
  • D.B. Bethell et al.

    Electrocardiographic monitoring in severe falciparum malaria

    Trans. R. Soc. Trop. Med. Hyg.

    (1996)
  • F.S. Bondi

    The incidence and outcome of neurological abnormalities in childhood cerebral malariaa long term follow-up of 62 surviviors

    Trans. R. Soc. Trop. Med. Hyg.

    (1992)
  • C.H. Brandts et al.

    Effect of paracetamol on parasite clearance time in Plasmodium falciparum malaria

    Lancet

    (1997)
  • D.R. Brewster et al.

    Neurological sequelae of cerebral malaria in children

    Lancet

    (1990)
  • J. Carlson et al.

    Human cerebral malariaassociation with erythrocyte rosetting and lack of anti-rosetting antibodies

    Lancet

    (1990)
  • J. Carlson et al.

    Natural protection against severe Plasmodium falciparum malaria due to impaired rosette formation

    Blood

    (1994)
  • I.A. Clark et al.

    The cytokine theory of human cerebral malaria

    Parasitol. Today

    (1994)
  • I.A. Clark et al.

    Oxygen-derived free radicals in the pathogenesis of parasitic disease

    Adv. Parasitol.

    (1986)
  • I.A. Clark et al.

    Role of TNF in cerebral malaria

    Lancet

    (1991)
  • I.A. Clark et al.

    Possible central role of nitric oxide in conditions clinically similar to cerebral malaria

    Lancet

    (1992)
  • U. D’Alessandro et al.

    Efficacy trial of malaria vaccine SPf66 in Gambian infants

    Lancet

    (1995)
  • U. D’Alessandro et al.

    Mortality and morbidity from malaria in Gambian children after introduction of an impregnated bednet programme

    Lancet

    (1995)
  • U. D’Alessandro et al.

    A comparison of the efficacy of insecticide-treated and untreated bed nets in preventing malaria in Gambian children

    Trans. R. Soc. Trop. Med. Hyg.

    (1995)
  • B.S. Das et al.

    Increased cerebrospinal fluid protein and lipid peroxidation products in patients with cerebral malaria

    Trans. R. Soc. Trop. Med. Hyg.

    (1991)
  • T.M.E. Davis et al.

    Glucose turnover in severe falciparum malaria

    Metabolism

    (1993)
  • N.P. Day et al.

    The effects of dopamine and adrenaline infusions on acid-base balance and systemic haemodynamics in severe infection

    Lancet

    (1996)
  • E. Dekker et al.

    The relationship between glucose production and plasma glucose concentration in children with falciparum malaria

    Trans. R. Soc. Trop. Med. Hyg.

    (1996)
  • H.J. de Silva et al.

    Delayed cerebellar ataxia following falciparum malarialack of evidence for antibody mediation

    Trans. R. Soc. Trop. Med. Hyg.

    (1992)
  • S.H. Abdalla

    Iron and folate status in Gambian children with malaria

    Ann. Trop. Paediatr.

    (1990)
  • S. Abdalla et al.

    The direct antiglobulin test in P. falciparum malaria

    Br. J. Haematol.

    (1982)
  • S. Abdalla et al.

    The anaemia of P. falciparum malaria

    Br. J. Haematol.

    (1980)
  • J.H. Adams et al.

    A family of erythrocyte binding proteins of malaria parasites

    Proc. Natl. Acad. Sci. USA

    (1992)
  • Ahmad, S. H., Moonis, R., Kidwai, T., Khan, T. A., Khan, H. M. and Shahab, T. (1986) Cerebral malaria in children. 53:...
  • M. Aikawa

    Human cerebral malaria

    Am. J. Trop. Med. Hyg.

    (1988)
  • G.O. Akpede et al.

    Convulsions with malariafebrile or indicative of cerebral involvement?

    J. Trop. Pediatr.

    (1993)
  • R.J. Allan et al.

    Plasmodium falciparum varies in its ability to induce tumor necrosis factor

    Infect. Immun.

    (1993)
  • R.J. Allan et al.

    Strain variation in tumor necrosis factor induction by parasites from children with acute falciparum malaria

    Infect. Immun.

    (1995)
  • S.J. Allen et al.

    Severe malaria in children in Papua New Guinea

    Q. J. Med.

    (1996)
  • B.J. Angus et al.

    Short reportrosette formation in Plasmodium ovale infection

    Am. J. Trop. Med. Hyg.

    (1996)
  • Anonymous

    Renal lesions in human malaria

    Br. Med. J.

    (1976)
  • Anonymous

    Man over monkey [editorial]

    Lancet i:

    (1987)
  • N.M. Anstey et al.

    Nitric oxide in Tanzanian children with malariainverse relationship between disease severity and nitric oxide production/nitric oxide synthetase type 2 expression

    J. Exp. Med.

    (1996)
  • A.I. Arieff et al.

    General considerations in metabolic encephalopathies and systemic disorders affecting the nervous system

  • M. Armengaud et al.

    Étude pourtant sur 448 cas de paludisme chez l’Africain de la région Dakaroı̈se

    Bull. Soc. Med. Afr. Noire Lang. Fr.

    (1962)
  • Khin-Maung-U. Aung-Kyaw-Zaw et al.

    Endotoxaemia in complicated falciparum malaria

    Trans. R. Soc. Trop. Med. Hyg.

    (1988)
  • B. Badibanga et al.

    Étude des principaux facteurs immunologiques et de la barrière hemato-meniné, au cause de la malaria cérébrale chez l’enfant en pays d’endemie (Zaire)

    Ann. Soc. Belg. Med. Trop.

    (1986)
  • H. Barennes et al.

    Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria

    Br. J. Clin. Pharmacol.

    (1996)
  • C.A. Bate et al.

    Inhibitory immunoglobulin M antibodies to tumor necrosis factor-inducing toxins in patients with malaria

    Infect. Immun.

    (1994)
  • D.R. Bell et al.

    Parasites which migrate to the brain [letter]

    Lancet i:

    (1976)
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