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REVIEW ARTICLE Cerebral malaria in children R. E. PHILLIPS malaria is a rapidly progressive encephalopathy with up to 50% mortality. A cardinal feature is the massing of red cells containing mature Plasmodium falciparum within the cerebral capillaries. Adhesion of these parasitised red cells to endothelium, an event which may initiate cerebral malaria, is being studied at the molecular level. However, the relevance of these studies to the pathophysiology and treatment of human cerebral malaria is uncertain. Although chloroquine is still widely used to treat falciparum malaria, resistance has spread to most of the endemic zone. Quinine is emerging as the only effective treatment for cerebral malaria, though resistance to this drug threatens to become a problem. Alternative drugs are urgently needed.

Cerebral

Introduction Over the past 30 years there has been a gradual realisation that malaria cannot be eradicated. Thus, it is essential that we improve understanding of this disease and so reduce its appalling toll. Nervous system involvement, often rather loosely diagnosed as cerebral malaria with anaemia, is the most prominent clinical feature in children who die of the infection. We review recent clinical and laboratory work on cerebral malaria with the aim of stimulating further research. Severe manifestations of malaria in children have been relatively neglected by investigators, yet in much of the world it is precisely this age group who are most likely to die from the disease.

Clinical features

Traditionally, cerebral malaria is diagnosed in patients with impaired consciousness when parasites are detected in blood. Convulsions alone are insufficient for the diagnosis, although they may herald cerebral malaria in up to 82% of children.1 Any neurological symptom or sign must alert doctors to the possibility of rapidly progressive, fatal malaria, although other causes of encephalopathy, such as neurotropic viruses and meningitis, must be excluded. At the bedside it is impossible to distinguish convulsions caused by cerebral malaria from those triggered by fever or hypoglycaemia.2 A strict defmition of cerebral malaria, which includes persistent coma as a criterion, helps describe a more clear-cut syndrome for research purposes.’ Tropical paediatricians are familiar with the problem of children who present in coma but do not have parasites

TOM SOLOMON detectable in their peripheral blood. Although the phenomenon has been attributed to infections which are wholly sequestered at the time of blood sampling, more mundane explanations such as misdiagnosis, partial treatment (particularly with chloroquine in Africa), or inadequate parasitology are more likely. However, any child with suspected cerebral malaria should be treated without delay, regardless of blood slide results. In endemic areas, the disease typically presents in children of less than 5 years oldusually with fever (which may be intermittent), headache, malaise, anorexia, and vomiting. Diarrhoea and cough are common, but are equally frequent in patients admitted to hospital with and without malarial parasitaemia.4 Deterioration can be rapid—eg, in a rural Gambian village 23 of 25 deaths

attributable

to

malaria occurred

at

home before

treatment

3

was sought. Neurological signs in children are those of a diffuse encephalopathy with symmetrical upper motor neuron signs and brainstem disturbances, including dysconjugate gaze palsies, stertorous breathing, hypertonicity, opisthotonus, upgoing plantar responses, absent abdominal reflexes, and retinal haemorrhages.1 Many clinical features of cerebral malaria, including decerebrate and decorticate posturing, can also be caused by hypoglycaemia,5 and without blood glucose measurements the two cannot be distinguished.6 Some signs (used in prognostic calculations1), however, predict poor outcome: deep coma, decerebration, absent corneal reflexes, convulsions on admission, and age less than 3 years are characteristic of those who develop sequelae or who die.1,7 In Thai adults, the coma of cerebral malaria is more prolonged than in African children, and there is a higher incidence of acute renal failure, jaundice, and pulmonary oedema.8,9 Unexplained differences such as these should make us wary of extrapolating observations made in adults to children. How dangerous is this syndrome? In The Gambia, malaria causes an estimated 25 % of deaths in children aged 1 to 4 years, and mortality attributable to malaria in children under 5 years is 10 per 1000 per year. In most children, outcome (life or death) is apparent within 48 h of loss of consciousness. Mortality rates for childhood cerebral malaria defined in various ways range from 6 to 50%.1,10,11 Since these studies did not use the same definition of cerebral malaria, useful comparisons cannot be made. There

ADDRESS: Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK (R E. Phillips, FRACP, T. Solomon, BM).

1356

is, however, general agreement that untreated cerebral malaria is almost invariably fatal." It is common dogma that most survivors of cerebral malaria make a full neurological recovery despite profound and sometimes prolonged coma.13 However, careful prospective studies report sequelae, such as hemiparesis, psychosis, epilepsy, and cortical blindness, with an incidence of 6 to I2%.1,3,10,14,1s A puzzling feature of falciparum malaria is that only a small minority of individuals in an endemic area develop severe manifestations. There is evidence from studies with neurosyphilis patients that parasites may differ in virulence.16 Some red cell abnormalities are protective, and studies of HLA polymorphisms in African children should answer the important question of whether particular alleles protect against severe malaria.

Pathophysiology Soon after the plasmodium parasite was discovered, pathological studies on Italian victims of malaria showed that the cerebral capillaries were packed with parasitised cells.17 British pathologists in Salonika and Africa described the salient abnormality as a "temporary partial stasis of the blood in the capillaries", but did not attribute this to thrombosis since there was no coagulum of fibrin or

leucocytes.18,19 This interpretation of the cerebral pathology was revived by Edington2O to describe changes seen in West African children who died of malaria. It is in general agreement with the current belief that sequestration of parasitised red blood cells (PRBC) in the cerebral capillary bed initiates cerebral malaria.21 However, correlation of pathological changes with the clinical state has proved difficult. Blood-brain barrier In the 1950s Maegraith and colleagues developed a new of the pathology of cerebral malaria which has influenced the field ever since.13,22 They argued that the primary abnormality was a breakdown in the blood-brain barrier which allowed plasma to leak into the brain causing it to swell.22 The apparent concentration of PRBC in the cerebral vessels was interpreted as a consequence of the efflux of plasma. Local factors, possibly kinins, were thought to be responsible for increased permeability by causing inflammation in cerebral vessels. This work, based on a model using rhesus monkeys infected with Plasmodium knowlesi, was accepted uncritically, and inspired enthusiastic, but unsubstantiated, advocacy for the use of steroids and other anti-inflammatory drugs in cerebral malaria.23,25 Work in humans has repudiated the "permeability hypothesis" and shown that the rhesus monkey is an inadequate mode1.14,25 Although cerebral oedema has been seen occasionally at necropsy in adults26 and children,27 computed axial tomography of Thai patients with cerebral malaria did not consistently detect signs of oedema during life.28 In over 160 patients (chiefly adults), cerebrospinal fluid (CSF) opening pressures were usually normal and papilloedema was seen only once.29 Isotope studies of the blood-CSF barrier, designed to evaluate Maegraith’s ideas in man, showed no evidence of increased permeability in Thai adults with cerebral malaria.25 In the same patients, needle samples of brain taken immediately after death and examined by electronmicroscopy showed no inflammation, immune complexes, fibrin deposition, or oedema.21 The predominant finding was the tight packing of PRBC within cerebral capillaries. PRBC appeared to be in contact with endothelial pseudopodia via knobs on their surface membranes.21 These and other ultrastructural pictures of PRBC interacting with endothelial cells30 have encouraged further study of this process.

interpretation

Adherence of PRBC to endothelium Specific binding of PRBC to cultured human endothelial cells31 and an amelanotic melanoma cell line was demonstrated 10 years ago. Binding was inhibited by the monoclonal antibody OKM5, which binds to the membrane surface molecule CD36.32 Recent studies showed that monkey cells in culture acquired the capacity to bind PRBC when transfected with cDNA encoding CD36.33,34 There is evidence that intercellular adhesion molecule 1 (ICAM-1) is a receptor in the same transient expression system,32,33 but these results have yet to be confirmed with wild parasite isolates.34 Thrombospondin, a third candidate endothelial receptor, bound PRBC when stuck to plastic dishes, but relevance to in vivo sequestration is uncertain.35 Demonstration of cytoadherence in vitro relies on repeated selection of adherent "clones" from long-standing, culture-adapted parasite lines.34 Under these intense selection pressures, parasite lines completely lacking the red cell membrane knobs thought necessary for cytoadherence in human cerebral malaria nonetheless adhere to C32 melanoma cells.36 Furthermore, human brain capillary endothelium appears to lack CD36, the chief candidate receptor predicted by in vitro studies. Thus, the relevance of these laboratory studies to human cerebral malaria is uncertain. In vitro, unparasitised red cells appear to stick to red cells containing parasites derived from cultured lines.38 The "rosettes" formed in this way have been postulated as another mechanism of vascular obstruction in malaria. Although there is preliminary evidence that this phenomenon occurs in human malaria, results were ambiguous ;39 thus, it is premature to propose treatment with "receptor-blocking antibodies" to reverse rosetting.1 Attempts to correlate the cytoadherence properties of wild parasite isolates with the clinical condition of patients have been generally unsuccessful. 41

cytoadherence cause cerebral malaria? There is agreement that in fatal malaria large numbers of

Does

PRBC accumulate in cerebral capillaries,14,21,26,27 but the same vascular changes have been seen in patients who died without developing cerebral malaria.21,42 Needle necropsy specimens examined blindly for quantitative differences in the degree of parasitisation and packing of PRBC in cerebral capillaries, showed that patients who had been unrousably comatose some time before death tended to have more vascular changes.21 However, there is still no adequate pathological explanation for cerebral malaria. Local hypoxia, metabolic derangements, and the action of endogenous mediators have all been proposed as possible factors, but there is little evidence for any of these mechanisms. Concentrations of lactate in CSF were high in adults and children with cerebral malaria, but this cannot be construed as definite evidence of cerebral hypoxia. 1,43 Plasma concentrations of lactate were also high in these patients and in Molyneux and colleagues’ study in children! there was a highly significant correlation between CSF and plasma lactate concentration, suggesting that sources other than the brain (eg, the parasites themselves and poorly perfused viscera) might contribute to the lactate load. Although cerebral oxygen consumption was reduced in 12 Thai adults with cerebral malaria, the significance of this finding is uncertain since the values remained low after recovery from coma.44 If packing of PRBC in cerebral

1357

was widespread, total cerebral blood should be In reduced. Thai adults there was no clear evidence of this, although a combination of low flow in some areas and compensatory high perfusion elsewhere was not ruled out.44 In any case, widespread brain circulatory standstill is most unlikely because most survivors recover without serious

capillaries

neurological damage.

Hypoglycaemia clear that hypoglycaemia causes impaired consciousness, convulsions and decerebrate signs in some patients with malaria. In Thailand, hypoglycaemia was detected in 8% of adults with unrousable coma and malaria.46 In most of these patients hypoglycaemia was considered a complication of cerebral malaria since correction of the blood glucose did not reverse all neurological signs. Studies in The Gambia2 and Malawi45 found that 26-32% of children with severe infections were hypoglycaemic. It is surprising that such a treatable abnormality has gone undetected for so long. Only 1 of 19 hypoglycaemic children in Malawi responded to intravenous dextrose, suggesting that underlying cerebral malaria was also present.45 In the rural tropics this distinction will be difficult or impossible to make. Prolonged hypoglycaemia alone may cause sufficient brain damage to explain persistent coma and other signs, since permanent neurological sequelae following malaria often develop in those who are hypoglycaemic.15,45 Convulsions were also more common in hypoglycaemic children; thus, there is no doubt that this neglected complication contributes to the morbidity and mortality of falciparum malaria.2,6,45 The metabolic disturbances engendered by the massing of parasites within vascular beds are not known. Even if systemic glucose concentrations are maintained, it is possible that local demand for glucose could exceed supply, and so have important consequences for functions such as membrane transport. Children are more prone to hypoglycaemia, probably because of limited hepatic glycogen reserves.4’ During childhood illness reduced intake of food will increase the risk of hypoglycaemia, but in severe falciparum malaria malabsorption is also present. Thai adults with severe malaria had greatly reduced absorptive capacity for sugars transported actively and passively;48 hepatic blood flow was also low in the acute illness, suggesting that reduction in splanchnic blood flow could be responsible for malabsorption. Unlike adults treated with quinine, African children are usually hypoglycaemic before antimalarials are started.2,45 Plasma insulin concentrations are appropriately low, there is adequate counter-regulatory response, while plasma alanine and lactate concentrations are high.2,45 A similar pattern was found in Bangladeshi children who were hypoglycaemic during enteric infections including shigellosis (the neurological signs of hypoglycaemia in this condition used to be attributed to the infection itself).49 Since inhibition of gluconeogenesis is the most likely mechanism it is possible that a toxic factor might cause malarial hypoglycaemia.5o It is

now

Malarial toxins and tumour necrosis factor "Toxins" have long been used to explain the severe manifestations of malaria.16 They were evoked by Rigdon5l to explain shock in "algid malaria", and, as kinins, formed part

of

Maegraith’s permeability hypothesis. 52 The

fashionable mediator in malaria necrosis factor

(TNF).53

at

present is

tumour

When pharmacological doses of TNF are injected, symptoms such as nausea, vomiting, fever, headache, and myalgia are sufficiently reminiscent of malaria to raise the question of whether TNF has any role in the infection. Lipopolysaccharide was the first recognised trigger for TNF release, 54 but malarial parasites have been shown to release TNF from macrophages.ss Injection of mice with recombinant TNF reproduced changes seen in terminal P vinckei infection: animals with subclinical malaria required thirty times less TNF than normal mice to produce the same degree of change. 56 When TNF was infused into cancer patients some developed focal neurological deficits, expressive aphasia and fatigue; thus, it has been suggested that TNF could be responsible for cerebral malaria. 56 These in vivo models bear no more than a superficial resemblance to human cerebral malaria. Symptoms elicited by large doses of TNF are either nonspecific or dissimilar from the prototype disease. In a study of Malawian children with severe malaria, 57 TNF concentrations were high on admission, and there was evidence that they were higher in those who died compared with survivors. It has been suggested that TNF might promote cytoadherence in man38 because it can increase expression of surface molecules such as ICAM-1 in vitro. Any theory linking circulating TNF with cerebral malaria must account for low TNF levels in some comatose patients, high levels in some well individuals5g and those with benign malaria,5"0 and innate differences in the capacity of healthy individuals to produce TNF which have been linked to HLA class II alleles and gender 61 These important constraints mean that inferences drawn from single TNF measurements in serum or in vitro are unlikely to reflect the pathophysiological processes operating at a cellular level 61 In an animal model and in the hypothesis promoted for man, TNF is thought to act as an inflammatory mediator,59 despite there being no sign of inflammation in human cerebral malaria.21,5O More clinical measurements are unlikely to reconcile these problems; a trial of anti-TNF antibody should settle the argument.

Treatment In childhood malaria death can occur within hours of the of illness .1,3,14 Because antimalarial drugs are the only specific therapy known to arrest the infection, children suspected of having cerebral malaria must be given the best available antimalarial via a parenteral route in appropriate doses (adjusted for weight) as quickly as possible. In comatose febrile children, blood smears should be examined urgently for parasites, but specific therapy should never be delayed if cerebral malaria is suspected and cannot be ruled out.

onset

Antimalarial drugs Most authorities advocate the exclusive use of parenteral quinine for treatment of severe falciparum malaria, because chloroquine-resistant parasites have become prevalent in virtually the entire endemic zone.13 However, there is dissent from this view:62a Gambian study63 showed that chloroquine was not toxic when used in novel regimens, and was at least as active as quinine against chloroquine-sensitive falciparum malaria. When treatment for patients with falciparum infections of uncertain sensitivity to chloroquine must be decided without delay, quinine (or quinidine) should be given. The chloroquine sensitivity of P falciparum can be guaranteed in fewer and fewer parts of the world. An initial loading dose of quinine has been widely advocated for treatment of cerebral malaria (table) since

1358

studies in Thai adults showed that conventional regimens might take 48 h to achieve desirable plasma concentrations.66.67 Although the loading dose regimen produced quinine concentrations during the first infusion presumed to be parasiticidal, the optimal dosage of quinine for children was still uncertain.66.68 Since 1983, children in Malawi,45 The Gambia,63 and the USA69,7O have been treated with various "loading dose" regimens of quinine and quinidine without serious toxicity. There has been speculation71 that African strains of P falciparum might be more sensitive to quinine than those found in Asia; however, in a recent clinical trial, Kenyan children responded better to a "high" dose regimen of quinine (G. Pasvol, personal communication) (table). Recent studies have confirmed the safety and efficacy of intramuscular quinine in African children with severe malaria; the loading dose produced satisfactory drug concentrations without toxicity.72.73 Reports of quinine-induced hyperinsulinaemia in Zairean children74 were not confirmed in Malawi,45 although in both the latter study and in a report from The Gambia 63 hypoglycaemia occurred in children after treatment with quinine was started. ANTIMALARIAL DRUGS FOR CEREBRAL MALARIA

Chloroquine-resistant falciparum malaria or malaria of unknown origin* Quinine dihydrochloride: 20 mg salt (16-7 mg base) per kg body weightt by intravenous (IV) infusion over 4 h (loading dose),t followed by 10 mg salt (8-3 mg base) per kg IV infusion over 4 h repeated every 12 h until the patient can swallow. Complete a 7-day course.§ Or

Quinidine gluconate: 24 mg salt (15 mg base) per kgt by IV infusion over 4 h (loading dose),t followed by 12 mg salt (7-5 mg base) per kg IV infusion over 4 h repeated every 8 h. Complete a 7-day course.§ Chloroquine-sensitive falciparum malaria65 Chloroquine: 10 mg base per kg body weight by IV infusion followed by 15 mg base per kg over the next 24 h.

over

8

h,

Or

Chloroquine: 5 mg base per kg by IV infusion over 6 h to a total dose of 25 mg base per kg over 30 h. *If there is any doubt about the ortgm of P falciparum infections reqmnng parenteral therapy, quinine (or quinidine) should be used. tChildren must be weighed and all doses carefully calculated #The loading dose should not be used If the patient has had quinine, quinidine or mefloqulne in the previous 24 h glf IV infusion is not possible, initial doses can be given by intramuscular (30 or 60 ml mg/ml) solutions of quinine at neutral pH may be

InJection;67.72.73 irntating. dilute less

Other measures Phenobarbitone 3-5 mg/kg reduced the incidence of convulsions in adults with cerebral malaria.71 Until the results of trials in children are known, there is a strong case for giving this drug to all children with severe malaria. Careful nursing, including cooling with sponging and fans, of unconscious febrile patients, and the prompt treatment of secondary bacterial infections such as pneumonia and septicaemia (which may be wrongly dismissed as "algid malaria") are mandatory. Most large series of severe malaria

patients who also have bacterial or fungal meningitis.14 Unless lumbar puncture is done routinely in ill, febrile children, irrespective of the presence of malarial parasites, treatable meningitis will be missed with disastrous consequences. Some children with malaria have bulging fontanelles and, sometimes, raised CSF pressure, so spinal taps should only remove enough fluid for diagnosis. Anaemia is a prominent feature in childhood cerebral malaria, and severely reduced haematocrit may be a direct threat to life. There is no consensus, but a rapid fall in haematocrit to 15% or below in a patient who still has high include

parasitaemia is an indication for transfusion.16 If anaemia is chronic and there is no parasitaemia, blood may be withheld unless heart failure develops. The possibility of HIV infection has made transfusion much more hazardous, although even in areas of high prevalence elderly relatives sources of blood. 16 Numerous supplementary drugs have been used in severe malaria with no rational basis. Anti-inflammatory agents, particularly dexamethasone, were widely recommended with the idea that they reduced the cerebral oedema predicted by "the permeability hypothesis".23 Double-blind trials from Thailand 14 and Irian J aya76 provided no support for low or high dose dexamethasone. In Thai adults, steroid treatment prolonged coma, and was associated with increased complications.14 Although controlled trials of exchange transfusion for malaria have not been published, reports suggest that parasitaemia greater than 20% is reduced more rapidly by exchange than by antimalarial drugs alone.77 In children with high parasitaemia and no complications the prognosis can be excellent; the role, if any, for this technique in hyperendemic areas has not been determined.

may be safe

Conclusions

Despite decades of research we know very little about the underlying causes of cerebral malaria. In endemic areas most individuals survive exposure to falciparum malaria while a small susceptible group succumb rapidly. Recent laboratory studies provide real hope that we will eventually understand the molecular processes which cause severe malaria. We should, however, be wary of extrapolating from the test tube to the clinic. Most of the studies reviewed here emphasise how much we rely on antimalarial drugs; none of the ancillary agents has withstood the test of controlled trials. Derivatives of the Chinese herbal drug Qinghaosu kill malarial parasites faster than quinine,78 and offer the prospect of better treatment. These agents are currently under trial, but in many places quinine is the only effective drug for severe chloroquine-resistant falciparum malaria. If quinine resistance advances as it threatens to, we face the very real prospect of untreatable falciparum malaria.

Many colleagues in the UK, Thailand, and Mozambique have made important contributions to ideas summarised in this review. We particularly acknowledge Prof David Warrell, Dr Nicholas White, Dr Somchai Looareesuwan, Dr Mary Warrell, Dr Shapira, and all our clinical collaborators. We thank Diane Large for preparing the manuscript. Some recent work reviewed here was supported by the Wellcome Trust as part of the Wellcome-Mahidol University, Oxford Topical Medicine Research Programme.

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S, Warrell DA, White NJ, et al. Retinal hemorrhage, a sign of prognostic significance in cerebral malaria. Am J Trop Med Hyg 1983; 32: 911-15. 10. Schmutzhard E, Gerstenbrand F. Cerebral malaria in Tanzania: its epidemiology, clinical symptoms and neurological long term sequelae in the light of 66 cases. Trans R Soc Trop Med Hyg 1984; 78: 351-53. 11. Stace J, Bilton P, Coates K, Stace N. Cerebral malaria in children: a retrospective study of admissions to Madang hospital, 1980. Papua New Guinea Med J 1982; 25: 230-34. 12. Gelfand M. Neurological complications of parasitic disease. In: Spillane JD, ed. Tropical neurology. London: Oxford University Press, 1973: 9. Looareesuwan common

247-51. 13. WHO Malaria Action Programme. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1986; 80: 1-50. 14. Warrell DA, Looareesuwan S, Warrell MJ, et al. Dexamethasone proves deleterious in cerebral malaria: a double blind trial in 100 comatose patients. N Engl J Med 1982; 306: 313-19. 15. Brewster DR, Kwiatkowski D, White NJ. Neurological sequelae of cerebral malaria in children. Lancet 1990; 336: 1039-43. 16. WHO Malaria Action Programme. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990; 84 (suppl 2): 1-65. 17. Marchiafava E, Bignami A. On summer-autumn malaria fevers (translated from the first Italian edition by J. H. Thompson). London: New Sydenham Society, 1894. 18. Dudgeon LS, Clarke CA. An investigation on fatal cases of pernicious malaria caused by Plasmodium falciparum in Macedonia. QJ Med 1918; 12: 372-90. 19. Daniels CW, Newnham HB. Laboratory studies in tropical medicine. London: Bale, Sons and Danielsson, 1923: 137. 20. Edington GM. Pathology of malaria in West Africa. Br Med J 1967; i: 715-18. 21. McPherson GG, Warrell MJ, White NJ, et al. Human cerebral malaria: a quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol 1985; 119: 385-401. 22. Maegraith BG, Fletcher A. The pathogenesis of mammalian malaria. Adv Parasitol 1972; 10: 49-75. 23. Woodruff AW, Dickinson CJ. Use of dexamethasone in cerebral malaria. Br Med J 1968; iii: 31-32. 24. Smistskamp H, Wofthius FH. New concepts in treatment of malignant tertian malaria with cerebral involvement. Br Med J 1971; i: 714-16. 25. Warrell DA, Looareesuwan S, Phillips RE, et al. Function of the blood cerebro-spinal fluid barrier in human cerebral malaria; rejection of the permeability hypothesis. Am J Trop Med Hyg 1986; 35: 882-89. 26. Spitz S. The pathology of acute falciparum malaria. Military Surgeon 1946; 99: 555-72. 27. Edington GM. Cerebral malaria in the African Gold Coast: four autopsy reports. Ann Trop Med Parasitol 1954; 48: 300-06. 28. Looareesuwan S, Warrell DA, White NJ, et al. Do patients with cerebral malaria have oedema? A computed tomography study. Lancet 1983; i: 434-37. 29. Warrell DA. Cerebral malaria. QJ Med 1989; 265: 369-71. 30. Luse SA, Miller LH. P falciparum malaria ultrastructure of parasitized erythrocytes in cardiac vessels. Am J Trop Med Hyg 1971; 20: 655-60. 31. Udeinya IJ, Schmidt JA, Aikawa M, et al. Falciparum malaria infected erythrocytes specifically bind to cultured human endothelial cells. Science 1981; 213: 555-57. 32. Bamwell JW, Ockenhouse CF, Knowles DM. Monoclonal antibody OKM5 inhibits the in-vitro binding of Plasmodium falciparum infected erythrocytes to monocytes, endothelial and C32 melanoma cells. J Immunol 1985; 135: 3494-97. 33. Oquendo P, Handt E, Lawler J, Seed B. CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes. Cell 1989; 58: 95-101. 34. Berendt AR, Simmons DL, Tansey J, et al. Intercellular adhesion molecule 1 is an endothelial cell adhesion receptor for Plasmodium falciparum. Nature 1989; 341: 57-59. 35. Roberts DD, Sherwood JA. Spitalnik S, et al. Thrombospondin binds falciparum malaria parasitized erythrocytes and may mediate cytoadherence. Nature 1985; 318: 64-66. 36. Biggs BA, Gooze L, Wycherley K, et al. Knob independent cytoadherence of Plasmodium falciparum to the leucocyte differentiation antigen CD36. J Exp Med 1990; 171: 1883-92. 37. Aikawa M. Human cerebral malaria. Am J Trop Med Hyg 1988; 39: 3-9. 38. Berendt AR, Ferguson DJP, Newbold C. Sequestration in Plasmodium falciparum malaria: sticky cells and sticky problems. Parasitol Today 1990; 6: 247-54. 39. Carlson J, Helmby H, Hill AVS, Brewster D, Greenwood BM, Wahlgren M. Human cerebral malaria: association with erythrocyte rosetting and lack of anti-rosetting antibodies. Lancet (in press). 40. Howard RJ, Gilladoga AD. Molecular studies related to the pathogenesis of cerebral malaria. Blood 1989; 74: 2603-18.

41. Marsh K, Marsh VM, Brown J, Whittle HC, Greenwood BM. Plasmodium falciparum: the behaviour of clinical isolates in an in vitro model of infected red blood cell sequestration. Exp Parasitol 1988; 65: 202-08. 42. Kean BH, Smith JA. Death due to estivo-autumnal malaria: a resume of one hundred autopsy cases, 1925-1942. Am J Trop Med 1944; 24: 317-22. 43. White NJ, Warrell DA, Looareesuwan S, et al. Pathophysiological and prognostic significance of cerebrospinal-fluid lactate in cerebral malaria. Lancet 1985; i: 776-78. 44. Warrell DA, White NJ, Veall N, et al. Cerebral anaerobic glycolysis and reduced cerebral oxygen transport in human cerebral malaria. Lancet 1988; ii: 534-38. 45. Taylor TE, Molyneux ME, Wirima JJ, et al. Blood glucose levels in Malawian children before and during the administration of intravenous quinine for severe falciparum malaria. N Engl J Med 1988; 319: 1040-47. 46. White NJ, Warrell DA, Chanthavanich P, et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 1983; 309: 61-66. 47. Pagliara AS, Kavel IE, Haymond M, et al. Hypoglycemia in infancy and childhood. J Pediatr 1973; 82: 558-77. 48. Molyneux ME, Looareesuwan S, Menzies IS, et al. Reduced hepatic blood flow and intestinal malabsorption in severe falciparum malaria. Am J Trop Med Hyg 1989; 40: 470-76. 49. Bennish ML, Azad AK, Rahman D, Phillips RE. Hypoglycemia during diarrhea in childhood: prevalence, patho-physiology and outcome. N Engl J Med 1990; 322: 1357-63. 50. Phillips RE, Warrell DA. The pathophysiology of severe falciparum malaria. Parasitol Today 1986; 2: 271-82. 51. Rigdon RH, Stratman-Thomas WK. A study of the pathological lesions in P knowlesi infection in M rhesus monkeys. Am J Trop Med 1942; 22: 329-39. 52. Maegraith BG. Clinical tropical diseases (8th ed). Oxford: Blackwell Scientific, 1984. 53. Clarke IA. Possible roles of tumour necrosis factor in the pathology of cerebral malaria. Am J Pathol 1987; 129: 192-99. 54. Carswell EA, Old LJ, Kaddel RL, et al. An endotoxin induced serum factor that causes necrosis of tumours. Proc Natl Acad Sci USA 1975; 72: 3666-70. 55. Bate CAW, Taverne J, Playfair JHL. Malarial parasites induce TNF production by macrophages. Immunology 1988; 64: 277-31. 56. Clarke IA, Chaudri G, Cowden WB. Roles of tumour necrosis factor in the illness and pathology of malaria. Trans R Soc Trop Med Hyg 1989; 83: 436-40. 57. Grau GE, Taylor TE, Molyneux ME, et al. TNF and disease severity in children with falciparum malaria. N Engl J Med 1989; 320: 1586-91. 58. McLaughlin PJ, Davies HM, Aikawa A. Tumour-necrosis factor in normal plasma. Lancet 1990; 336: 1014-15. 59. Kwiatkowski D, Hill AVS, Sambou I, et al. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodiumfalciparum malaria. Lancet 1990; 336: 1201-04. 60. Butcher GA, Garland T, Ajdukiewicz AB, Clark IA. Serum tumour necrosis factor associated with malaria in patients in the Solomon Islands. Trans R Soc Trop Med Hyg 1990; 84: 658-61. 61. Jacob CO, Franck Z, Lewis GD, Koo M, Hansen JA, McDevitt HO. Heritable major histocompatibility complex class II-associated differences in production of tumour necrosis factor alpha: relevance to genetic predisposition of systemic lupus erythematosus. Proc Natl Acad Sci USA 1990; 87: 1233-37. 62. White NJ. Drug treatment and prevention of malaria. Eur J Clin Pharmacol 1988; 34: 1-14. 63. White NJ, Krishna S, Waller D, et al. Open comparison of intramuscular chloroquine and quinine in children with severe chloroquine-sensitive falciparum malaria. Lancet 1989; ii: 1313-16. 64. Phillips RE, Warrell DA, White NJ, et al. Intravenous quinidine for the treatment of severe falciparum malaria. N Engl J Med 1985; 312: 1273-78. 65. White NJ, Miller KD, Churchill FC, et al. Chloroquine treatment of severe malaria in children. N Engl J Med 1988; 319: 1493-1500. 66. White NJ, Looreesuwan S, Warrell DA, et al. Quinine loading dose in cerebral malaria. Am J Trop Med Hyg 1983; 32: 1-5. 67. Wattanagoon Y, Phillips RE, Warrell DA, et al. Intramuscular quinine loading dose for falciparum malaria: pharmacokinetics and toxicity. Br Med J 1986; 293: 11-13. 68. Greenberg AE, Nguyen-Dinh P, Davachi F, et al. Intravenous quinine therapy of hospitalised children with Plasmodiumfalciparum malaria in Kinshasa, Zaire. Am J Trop Med Hyg 1989; 40: 360-04. 69. Rudnitsky G, Miller KD, Padua T, Stull TL. Continuous infusion quinidine gluconate for treating children with severe Plasmodium falciparum malaria. J Infect Dis 1987; 155: 1040-43.

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CLINICAL PRACTICE Angiotensin-converting-enzyme inhibitors and anaphylactoid reactions to high-flux membrane dialysis

In

retrospective study, 9 of 236 haemodialysis patients treated with high-flux polyacrylonitrile a

’AN 69’ membranes

were

found to have had

with reactions. Treatment anaphylactoid angiotensin-converting-enzyme (ACE) inhibitors had been recently started in all 9 affected patients; only 5 of 227 unaffected patients had been treated with ACE inhibitors, and anaphylactoid reactions disappeared after discontinuation of ACE inhibitors.

Introduction

High-flux haemodialysis membranes are increasingly used because they more efficiently remove circulating &bgr;2-microglobulin,1 which is involved in the occurrence of dialysis amyloidosis/,3 than do standard membranes. Since the introduction of the high-flux membrane ’AN 69’ (Hospal, Brussels, Belgium) we observed anaphylactoid reactions that could not be attributed to heparin or ethylene-oxide hypersensitivity. These reactions were similar to those described in patients in whom severe microbial contamination of the bicarbonate dialysate occurred during dialysis with high-flux membranes.4-6 However, microbial contamination was most unlikely to be a major factor in our patients because of the use of high osmolarity acetate concentrate-which largely prevents bacterial growth-and because the episodes repeatedly occurred in only 9 patients, whereas 227 others dialysed under identical conditions remained symptom-free. In a retrospective study of all 236 patients who underwent haemodialysis we tried to identify possible associations with these anaphylactoid reactions. Patients and methods From April 7,1986, to February 1,1990, 236 patients who required chronic haemodialysis were treated with a high-flux parallel-plate dialyser (AN 69) and with a dialysis solution that contained acetate.

Over the same period another 55 patients were treated with haemofiltration with a high-flux hollow-fibre dialyser (AN 69) and a substitution fluid that contained acetate. The clinical records of both groups were retrospectively analysed. The parallel-plate dialysers were reprocessed with 0-45% (62-5 mmol/1) sodium hypochlorite, and the hollow-fibre dialysers with ’Renalin’ (Renal Systems, Minneapolis, USA), a commercially available mixture of peracetic acid, acetic acid, and hydrogen peroxide. Neither type of dialyser was reused more than 6 times in the same patient. The ’Bioprime’ rinse method (Hospal) is a novel filter rinsing procedure for dialysis with high-flux membranes, designed to prevent anaphylactoid reactions due to bacterial contamination of the dialysate.7 A sterile saline solution is used to rinse consecutively the blood and the dialysate compartment; after the rinse, blood circulates for 5 min through the blood compartment with the sterile saline solution in the dialysate compartment, and only after this procedure is the regular dialysis solution connected. Anaphylactoid reactions were defined as a combination of severe hypotension (fall of systolic blood pressure below 100 mm Hg with faintness and nausea), flushing, swelling of face and/or tongue, and dyspnoea within 5 min of the start of haemodialysis. In all patients with anaphylactoid reactions serum concentrations of IgE antibodies against ethylene oxide were measured, and filter use (first use or re-use) and method of priming were recorded. A detailed list of drugs taken by patients with anaphylactoid reactions was compared with the treatment of the other patients.

Results 9 of 236 haemodialysis patients had anaphylactoid reactions. These patients were taking one or more of the following drugs in the period during which they had anaphylactoid reactions: calcium carbonate (8 of 9), sodium bicarbonate

(7/9), metoprolol (4/9), nifedipine (2/9), ranitidine (2/9), (2/9), temazepam (1/9), simvastatin (1/9), azathioprine (1/9), and angiotensin-converting-enzyme (ACE) inhibitors (9/9:7 enalapril, 1 captopril, 1 lisinopril). corticosteroids

ADDRESS. Department of Nephrology, Universitair Ziekenhuis Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium (L. Verresen, MD, M. Waer, MD, Y Vanrenterghem, MD, Prof P. Michielsen, MD). Correspondence to Dr L Verresen.