Pharmacol. Ther. Vol. 79, No. 1, pp. 1–53, 1998 ISSN 0163-7258/98 $19.00 Copyright © 1998 Elsevier Science Inc. PII S0163-7258(98)00008-4 Associate Editor: P. Winstanley Severe Falciparum Malaria in Children: Current Understanding of Pathophysiology and Supportive Treatment Charles R. J. C. Newton*‡ and Sanjeev Krishna†‡ *NEUROSCIENCE’S UNIT, INSTITUTE OF CHILD HEALTH, WOLFSON CENTRE, MECKLENBURGH SQUARE, LONDON WC1N 2AP, UK †DIVISION OF INFECTIOUS DISEASES, DEPARTMENT OF CELL AND MOLECULAR SCIENCES, ST. GEORGE’S HOSPITAL MEDICAL SCHOOL, CRANMER TERRACE, LONDON SW17 0RE, UK 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. pharmacol. ther. 79(1):1–53, 1998. © 1998 Elsevier Science Inc. KEY WORDS. Falciparum malaria, pathophysiology, children, adjunct therapy. CONTENTS 1. INTRODUCTION ...............2 6. CLINICAL DEFINITIONS AND 2. DEVELOPMENT OF INFECTION ........3 PRESENTATIONS ............. 14 2.1. MULTIPLICATIVE CAPACITY ......3 6.1. SEVERE MALARIA ......... 14 2.2. SEQUESTRATION OF PARASITISED 6.2. CEREBRAL MALARIA ....... 16 RED BLOOD CELLS ............ 4 6.2.1. DEFINITION OF CEREBRAL 3. PATHOLOGY .................4 MALARIA . .16 3.1. PATHOLOGY OF INFECTION ......4 6.2.2. COMA SCORES . .18 3.2. MACROSCOPIC APPEARANCES .....5 6.2.3. CLINICAL PRESENTATION 3.3. MICROSCOPIC APPEARANCES .....5 OF CEREBRAL MALARIA IN 3.3.1. VASCULAR CONGESTION ....5 AFRICAN CHILDREN . .18 3.3.2. RING HAEMORRHAGES 6.2.4. NEUROLOGICAL AND GRANULOMA SEQUELAE . .19 FORMATION ...........5 6.3. METABOLIC ABNORMALITIES IN 3.3.3. CELLULAR ELEMENTS ......6 SEVERE MALARIA ......... 23 3.3.4. PIGMENT ............6 6.4. SEVERE MALARIAL ANAEMIA, 3.4. RELATIONSHIP BETWEEN JAUNDICE, AND HAEMOLYSIS ... 24 SEQUESTRATION AND CEREBRAL 6.5. THE COMMONEST MODES OF DISEASE .................6 PRESENTATION OF SEVERE 4. PATHOGENESIS—HOST FACTORS ......7 MALARIA IN CHILDREN ...... 24 4.1. MECHANICAL HYPOTHESIS .......7 6.6. MODERATE MALARIA ....... 25 4.2. TOXIN HYPOTHESIS ...........8 7. PATHOPHYSIOLOGY ........... 25 4.3. CYTOKINE HYPOTHESIS ........8 7.1. FEVER ............... 25 4.4. OTHER CYTOKINES AND MARKERS OF 7.2. COMA ............... 25 ENDOTHELIAL CELL ACTIVATION ...9 7.3. SEIZURES ............. 26 4.5. NITRIC OXIDE ..............9 7.4. RAISED INTRACRANIAL 4.6. REACTIVE OXYGEN SPECIES ..... 10 PRESSURE ............. 26 4.7. THE PERMEABILITY HYPOTHESIS ... 11 7.5. CAUSES OF NEUROLOGICAL 4.7.1. EXPERIMENTAL EVIDENCE .. 11 SEQUELAE ............. 27 4.7.2. BLOOD-BRAIN BARRIER 7.5.1. ISCHAEMIA . .27 IN HUMANS .......... 11 7.5.2. REACTIVE OXYGEN 4.8. THE IMMUNOLOGICAL SPECIES . .27 HYPOTHESIS .............. 12 7.5.3. EXCITOTOXINS . .27 4.8.1. EXPERIMENTAL EVIDENCE .. 12 7.5.4. APOPTOSIS . .28 4.8.2. CLINICAL STUDIES ...... 12 7.5.5. HEMIPARESIS . .28 5. PATHOGENESIS—PARASITE FACTORS .. 12 7.5.6. VISUAL IMPAIRMENT . .28 5.1. CYTOADHERENCE ........... 12 7.6. HYPOGLYCAEMIA ......... 29 5.2. ROSETTING .............. 13 7.7. LACTIC ACIDOSIS ......... 30 5.3. RHEOLOGY .............. 14 7.8. ANAEMIA AND THROMBOCYTOPAENIA ...... 31 7.9. ELECTROLYTE ABNORMALITIES AND FLUID BALANCE ....... 32 ‡ Corresponding authors. 7.10. RENAL IMPAIRMENT AND 2 C. R. J. C. Newton and S. Krishna BLACKWATER FEVER ....... 33 9.5. ACIDOSIS ............. 38 7.11. SECONDARY INFECTIONS ..... 33 9.6. ANAEMIA AND EXCHANGE 8. ANTIMALARIAL TREATMENT ...... 33 TRANSFUSION ........... 39 8.1. INTRODUCTION .......... 33 9.7. DESFERRIOXAMINE ........ 39 8.2. CINCHONA ALKALOIDS ...... 34 9.8. ANTI-INFLAMMATORY AGENTS .. 40 8.3. 4-AMINOQUINOLINES ....... 35 9.8.1. CORTICOSTEROIDS . .40 8.4. ARTEMISININ DERIVATIVES ... 35 9.9. AGENTS THAT IMPROVE 9. ADJUNCTIVE MEASURES ........ 35 MICROCIRCULATORY FLOW .... 40 9.1. ANTIPYRETICS .......... 35 9.9.1. PENTOXIFYLLINE . .40 9.2. ANTICONVULSANTS ....... 36 9.9.2. MISCELLANEOUS AGENTS .40 9.3. MEASURES TO REDUCE RAISED 9.10. OTHER AGENTS .......... 40 INTRACRANIAL PRESSURE .... 37 10. DISCUSSION AND FUTURE STUDIES ... 40 9.4. CORRECTION OF ACKNOWLEDGEMENTS ............. 41 HYPOGLYCAEMIA.......... 37 REFERENCES .................. 41 ABBREVIATIONS. BBB, blood-brain barrier; BCS, Blantyre coma score; CM, cerebral malaria; CPP, cerebral perfusion pressure; CSF, cerebrospinal fluid; CT, computerised tomography; CVP, central venous pressure; DAT, direct antiglobulin test; DCA, dichloroacetate; E-selectin, endothelial selectin; ICAM-1, intercellular adhesion molecule-1; ICP, intracranial pressure; Ig, immunoglobulin; IH, intracranial hypertension; IL, interleukin; iNOS, inducible nitric oxide synthase; NCM, non-cerebral malaria; NO, nitric oxide; NPRBC, nonparasitised red blood cell; Pfemp-1, Plasmodium falciparum erythrocyte membrane protein-1; PRBC, parasitised red blood cell; ROS, reactive oxygen species; TNF, tumour necrosis factor; TPI, triose phosphate isomerase; VCAM-1, vascular cell adhesion molecule-1; WHO, World Health Organisation. 1. INTRODUCTION cesses in the 1960s, insecticides have failed to curb trans- Malaria is one of the most common and important parasitic mission by anopheline mosquitoes (World Health Organi- diseases worldwide. About 40% of the world’s population sation, 1993). Insecticide-impregnated bednets have reduced lives in malaria-endemic areas (Sturchler, 1990), and malaria mortality and morbidity in malarious areas (Nevill et al., is responsible for up to 500 million episodes of clinical infec- 1996; D’Alessandro et al., 1995c), but their efficacy may tion and 2.7 million deaths every year (World Health Organ- not be sustainable (D’Alessandro et al., 1995b; Greenwood, isation, 1996). Plasmodium falciparum is the principal cause 1997). Results of recent trials with the current generation of of severe disease, since the other species of malaria rarely malaria vaccines have been unimpressive (D’Alessandro et cause death or persistent sequelae. P. falciparum may infect al., 1995a; Alonso et al., 1994), although newer prototypes humans at any time from conception to adulthood. Malarial are under continuous investigation (Stoute et al., 1997; Tar- infection probably results in 3.5 million low birth-weight gett, 1995). Therefore, it probably will require a concerted infants every year (Steketee et al., 1996), since an estimated combination of measures, including antimalarials, vaccines, 24 million pregnant women live in malaria-endemic areas. and vector control, before a reduction in infection and mortal- Children living in sub-Saharan Africa bear the brunt of the ity can be maintained. Furthermore, reducing the transmission disease, as they are exposed to malaria frequently after birth, of malaria in an endemic area runs the concomitant risk of and either die from complications or experience clinical epi- reducing the development of antimalarial immunity in the sodes of infection for many years until the slow and capricious population. This reduction in “herd immunity” eventually development of antimalarial immunity (Edington, 1967). may result in the rapid spread of severe infection if control This balance between acquisition of immunity and develop- measures fail, so that longer-term study of preventive inter- ment of severe disease has continued for thousands of years. ventions will be crucial to assessment of their true and sus- Since the first description of malarial parasites in a suf- tainable worth. The goal of effective prevention is not yet ferer by Laveran in Constantine, Algeria in 1880, there achievable, and consequently, we will still need to manage have been considerable advances in the understanding of cases of severe malaria in the foreseeable future. disease mechanisms in malaria (Laveran, 1880; White and The early effective treatment of falciparum infection is Ho, 1992). These advances have resulted from detailed critical in preventing the progression to severe, life-threat- studies in patients, animal models of infection, biochemi- ening disease. Falciparum malaria has become increasingly cal, cellular, and molecular investigations. These studies refractory to chloroquine, the cheapest and most widely have illuminated our understanding of disease processes, al- available antimalarial (Krishna and White, 1996; Zucker et though none have succeeded so far in reducing mortality al., 1996). In Southeast Asia, multidrug resistance is rapidly from severe infection. Mortality from treated severe malaria spreading (Pukrittayakamee et al., 1994a; White, 1992), in- in children is between 5 and 15% (Waller et al., 1995; creasing the likelihood of severe disease. In Africa, wide- Marsh et al., 1995), and the current management of severe spread chloroquine resistance has increased the incidence malaria has changed surprisingly little, in spite of rapid sci- of some complications such as anaemia (because of inability entific advances in malariology. to cure infections) (Lackritz et al., 1992), and other related Measures to eradicate malaria have been ineffective problems are anticipated to worsen as higher-grade resis- (World Health Organisation,