Bull. Org. mond. Sante 1974, 50, 187-193Bull. Wld Hitha Org.f

Other pathological processes in malaria*BRIAN MAEGRAITH 1

Research since the World War 11 has confirmed that, apart from the production ofhaemozoin from haemoglobin, most ofthe pathologicalprocesses in the evolution ofmalariaare nonspecific. A few of these nonspecific host reactions are discussed, including theproduction of inflammatory stasis in certain areas (including the brain) where the vascukrendothelium is normally highly impermeable to heavy molecules. This production ofstasis isregarded as the basic phenomenon in local obstruction to bloodflow. So-called " plugging "ofsmall vessels with " sticky " infected erythrocytes is discussed in relation to stasis and todeep intravascular schizogony. Nonspecific vasomotor effects including shock and renal andhepatic failure are also discussed. Intravascular coagulation is not regarded as a potentiallyimportant host response despite demonstrable consumption coagulopathy. The diseasemalaria is regarded as an example of a chain reaction of physiological-pathologicalresponses in the host, which in the early stages are reversible.

The pathogenic processes in malaria have beenextensively reviewed elsewhere (1-4), and in thispaper I will refer to only a few points.

In the work we have done in Liverpool over thepast 25 years we have studied malaria as such and asa model to determine the reactions of the host toinfection. The simple fact has emerged that the hostbody can respond in only a limited number of ways,dependent on the structure and function of indi-vidual tissues and organs and on their interrelation.Superimposed on this general pattern there may becertain specific effects induced by the infecting agent.Examples are the specific effect of exotoxins, as indiphtheria, and the production of haemozoin fromhaemoglobin during the schizogony of the parasite inmalaria and its distribution in the tissues and uptakeby macrophages.

Otherwise, most of the host responses to plasmo-dial infection are nonspecific, although they may bemodified by the multiplication of the parasite in thehost erythrocyte-for example, the initial remittentfever of the first few days of overt infection withP. vivax followed by the periodic fever that developsas the schizogony of the parasites adjusts to regularintervals and the broods of parasites " get into step ".

Nevertheless, the plasmodium is undeniably theoriginating agent in malaria, even though the host

* Presented at the Symposium on Malaria Research,Rabat, Morocco, 1-5 April 1974.

1 Dean, Liverpool School of Tropical Medicine, Liver-pool 3, England.

reactions in the disease are similar to those of otherinfections. We are not yet sure how the pathologicalprocesses are initiated and how much the nonspecificeffects are modified or maintained by the presence ofthe multiplying parasite or by its metabolic pro-cesses, which may themselves be modified by thereacting host.

I will mention only a few of the nonspecificreactions and some of the factors that initiate andmaintain them.

THE CHAIN REACTION

From our studies of mammalian malaria hasevolved the concept of a chain reaction of physio-pathological processes that leads to the disease fol-lowing the infection. In malaria the pathogenicprocesses must be initiated by the parasite. Unfor-tunately, the links between the parasite and the hosthave not yet been clearly determined. One link seemsto be the soluble cytotoxic factor or factors capableof inhibiting mitochondrial respiration and phos-phorylation described by Maegraith and his col-leagues (2, 5) but this is probably only one of severalagents acting at various strategic points in the hostand influencing its biochemical and physiologicalbalance. The situation may be modified further byexternal factors, such as the nutritional status of thehost and changes in the parasite metabolism inducedby its presence in the diseased host.

In the later stages of simian malaria the visceral

3178 - 1874

B. MAEGRAITH

sympathetic nervous system becomes hyperstimu-lated. This affects the dynamics of the circulation ofthe blood in many organs including the liver, thekidney, and the adrenal glands, with resultant meta-bolic deviations and upsets in endocrine balance.Pharmacologically active substances including kininsand kininogenases are set free to exert their effects onthe permeability of membranes and their dynamicactions on the smaller blood vessels. Protein andwater escape through the damaged endothelium. Inareas where the vessels are normally highly imper-meable (e.g., the brain), inflammatory stasis results,sometimes with complete obstruction to the bloodflow. In this way a physiological chain reaction is setup leading to local and general disturbances that areat first reversible but, with time, become irreversibleand lead to characteristic pathological patterns in thetissues and finally to the dissolution of the host. Asnoted above, an important point is the nonspecificityof many of these reactions.As it develops, the chain reaction causes certain

changes in function and structure of the tissues andorgans that, when they become irreversible, deter-mine the pathological patterns seen macroscopicallyand histologically at autopsy.

INFLAMMATORY REACTIONS IN MALARIA

Vascular membranes

In vessels that are normally relatively imper-meable, inflammation may allow the escape acrossthe endothelial membrane of large molecules, espe-cially protein, with accompanying escape of water.The final picture is one of impedance of the circula-tion or " stasis " in small vessels with tightly packederythrocytes. In vessels so affected there may also besome diapedesis of erythrocytes and escape of leuco-cytes into the surrounding tissue. In its early stages,stasis is reversible.The blood vessels of an organ are specific to it and

their function at a given time depends on theirdynamic responses and on the permeability of theendothelium, which differs from organ to organ. Forexample, the vessels in the brain are permeable onlyto small carbohydrate molecules; those in the liverare permeable to practically everything that circu-lates in the plasma. Agents that increase the per-meability of the endothelial membrane thus havemore pronounced effects in the brain than in the liver.

In the brains of patients dead from so-called"cerebral malaria " (falciparum) the usual picture

described is one of small blood vessels apparently" plugged " with parasitized erythrocytes in whichthe parasites were usually in the late stages ofschizogony. For many years it was considered thatsuch " plugging " of the vascular lumen arose fromthe parasitized erythrocytes "sticking" to them-selves and to the endothelial lining and interruptingthe blood flow.

It has now been demonstrated that in Plasmodiumknowlesi and P. berghei infections the obstruction ofcerebral circulation occurs before the " packing"with parasitized erythrocytes takes place and thepicture seen at autopsy is primarily post hoc ratherthan propter hoc. The processes involved in slowingthe circulation are primarily dependent not on theparasitized erythrocytes but on the presence of phar-macologically active substances that lead to inflam-matory stasis.The failure of the circulation in the brain in

malaria thus arises from endothelial dysfunction.The parasitization of the erythrocytes constituting

the " plug " in the cerebral vessel is a late develop-ment following rather than causing the obstruction.The parasites are nearly always in the same late stageof schizogony. Where haemorrhages have occurrednear the vessels apparently " plugged" by erythro-cytes containing schizonts, the erythrocytes in thetissues around the damaged vessels are not heavilyparasitized and those that are contain parasites inany phase of development.Recent work in Liverpool on P. knowlesi and

P. berghei infections has shown that excessive move-ment of both protein and water occurs across theendothelium of the brain vessels and of the bloodbrain barrier as a whole (3, 6). The net movement ofiodine-tagged albumin from the blood to the cere-brospinal fluid (CSF) is greatly increased, indicatinga change in the permeability of the membranes. Themovement from the CSF to the blood is also in-creased. The relatively small increase in protein inthe CSF noted in malaria by many authors thusarises from the fact that the protein moves freelyboth out into the CSF and back into the blood.

In P. knowlesi infection in Macaca mulatta theexcessive escape of protein across the brain mem-branes can be rapidly inhibited by chloroquine,mepacrine, and cortisone, all of which are powerfulanti-inflammatory drugs (3, 6, 7).The speedy clinical recovery from coma following

the administration of antimalarial drugs indicatesthat the clinical response to the drugs is muchquicker than could be accounted for by antiparasitic

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activity and can be explained only on an anti-inflammatory basis. The action of anti-inflammatorydrugs has recently been tested in the field by Tra-nakchit Harinasuta in cases of chloroquine-resistantfalciparum malaria treated by sulfonamides, whichhave a rapid effect on the parasites but promote aslow clinical response (3). When anti-inflammatorydrugs are given contemporaneously with the sulfona-mides, the clinical response becomes as rapid as andsometimes more rapid than the response of theparasites. This applies to chloroquine itself, evenwhen the relevant parasites are resistant to it!

Peptides

Tella & Maegraith (8, 9) demonstrated that on thefourth to fifth day of infection with P. knowlesiin M. mulatta there was a dramatic fall in thekininogen and kallidinogen content of the serum.From this period until death the level remainedextremely low. There was a concurrent increase inthe blood kinin level and in the output of kinins in theurine (10, 8), which Goodwin & Richards in 1960 (11)had reported in rats infected with P. berghei. Therewas also a considerable increase in circulatingkininases. Thus the kininogens are rapidly brokendown to kinins and these in turn are converted intoinactive peptides. This indicates a quick turnover ofactive peptides in the blood. Unfortunately, at pre-sent it is not possible to say what is happening atthe tissue face where the changes in endothelialpermeability are occurring.

It is interesting to speculate on whether the kininproduced from the kininogen by the kininogenaseremains long enough in the peripheral circulation toexert its pharmacological effects before being de-stroyed by the kininases. It is possible that kinin maybe active in such circumstances even though its half-life may be very short. This introduces a concept ofvery fast intermediate pharmacological reactions,perhaps series of reactions, which is helpful in tryingto translate the more static situation in the serum(the only one we can at present measure) into what ishappening at the tissue face.The kininogenases are also considerably increased

in the late stages. They are as pharmacologicallyactive as the kinins (even in the presence of kinino-genase inhibitors) in increasing endothelial perme-ability and, in certain circumstances, causing vasodi-lation or vasoconstriction. Kallikrein obtained fromblood protein fractions in infected animals on injec-tion into normal animals also causes leakage ofprotein and water from capillaries similar to that

demonstrated in P. knowlesi and P. berghei infec-tions (3, 12).

It would appear therefore that both kinin andkallikrein act as nonspecific inflammatory agents inP. knowlesi malaria, causing endothelial membranesthat are normally impermeable (e.g., in the brain) tobecome permeable.The kinin complex is probably only one of many

systems operating. Desowitz & Pavanand (13) de-scribed an uncategorized " permeability factor " inthe serum of gibbons infected with P. coatneyi. Thismay be related to the peptides under discussion butclearly, from the method of extraction, could nothave been kinin. Other substances concerned withmembrane permeability include histamine, which isalso a powerful vasodilator and which is sometimesliberated by antigen antibody reactions. An increasein histamine concentration occurs in the blood ofM. inulatta in the late stages of P. knowlesi infection.Nothing is known about histaminase activity in theinfection. Adenosine, which has strong vasomotoractivity, has been demonstrated in blood returningfrom ischaemic tissue; it is also increased in lateP. knowlesi infection (3, 14).

Vasomotor effectsThe vasomotor reactions that occur in acute ma-

laria also have been shown to resemble those ofgeneral inflammation. Medical shock is a commonend point in acute P. falciparum infection in the non-immune subject (1-3). The shock is nonspecific andsimilar to the shock that may occur in many otheracute infections and physiological states.

I have pointed out (15, 1) that one of the factorsinvolved in producing hepatic lesions in acute falci-parum malaria and blackwater fever is local circula-tory failure associated with centrilobular cellulardamage similar to that occurring in other conditions,especially where shock is involved (16). Both thecirculatory changes and the cellular damage can beproduced artificially in the perfused liver (17).The hepatic circulation in P. knowlesi infection in

M. mulatta has recently been examined by X-rayangiography. In the severe stages of this infection,obstruction to intrahepatic flow can be demon-strated, accompanied by intense constriction of thesmall branches of the portal veins. This constrictioncan be relieved by 1,1'-oxybisbenzene (" phenoxy-benzene ") and other blocking agents. Similar vascu-lar changes develop in shock following manipulationof the gut and can also be controlled by blockingagents (2, 3, 18).

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B. MAEGRAITH

Critical reduction of cortical or total renal bloodflow with consequent failure of secretion of urineacross the glomeruli and resorption in the tubuleswas first suggested as a cause of renal failure inblackwater fever patients in West Africa (15, 19).Constriction of these vessels has been demonstratedin the later stages of P. knowlesi infection in M. mu-latta by means of the angiography technique. Thiscan also be overcome by blocking agents. InP. knowlesi infection therefore the pattern of acuterenal dysfunction follows reduced renal circulation.This is a phenomenon common to many othermedical states, and is nonspecific (20); it may re-spond to haemodialysis or peritoneal dialysis (3).

Vasoconstriction of the intestinal arterioles hasrecently also been demonstrated in experiments onintestinal absorption of amino acids and xylose insimian and human malaria (3).The general picture of the visceral circulatory

changes and shock fits in well with the concept ofhyperexcitation of the sympathetic nervous systemsuggested by Skirrow et al. (18) in P. knowlesimalaria.Ray & Sharma (21) also indicated the significance

of sympathetic stimulation as a factor in the produc-tion of hepatic centrilobular lesions in P. knowlesiinfection in M. mulatta by performing thoracicsympathectomy before infecting the monkeys. Thecentrilobular lesions that constantly appeared innormal monkeys after infection were absent in thesympathectomized animals.

"Stickiness " and deep schizogonyThe pattern of cerebral vessels " plugged " with

erythrocytes bearing late-stage parasites that is com-monly reported in falciparum malaria is usually afeature of parasite species in which there is deepintravascular schizogony. Studies of the latter phe-nomenon in P. coatneyi and P. falciparum in manand Aotus monkeys have demonstrated a regionaldistribution of plugged vessels, which are usuallyfound in organs in which the vascular endothelium isnormally relatively impermeable but is not uniformlydistributed anatomically (e.g., the heart, the brain,and the adipose tissue).

In P. coatneyi infection and in P. falciparuminfection in man and in Aotus monkeys the " plug-ging " in some organs occurs not only in the terminalstages but also locally in various visceral organsduring deep schizogony.

In these infections thickenings and irregularitieshave been described in or immediately below the

membranes of the erythrocytes containing late-stageparasites and it has been argued that these areprobably responsible for " stickiness ", which causesthe parasitized cells to become temporarily attachedto the endothelium of the small vessels. This idea isnot altogether in keeping with the fact that inP. knowlesi infection, in which final schizogonyoccurs in the deep tissues, late stages of parasites arecommonly seen in the peripheral blood in the finaldevelopment of the disease and the electron micro-scope does not reveal any unusual changes in thesurface of the erythrocytes containing schizonts,although these cells also appear to be " sticky " andadhere to the endothelium of the blood ves-sels (22-25).To this mechanical concept of " plugging " Miller

and colleagues (26) have recently added a " rheologi-cal" hypothesis. They have suggested that the" plugging " of small vessels arises because the in-fected cells are nonmalleable and their changes inshape lead to shear resistance to the flow. I find thishypothesis (which is based on in vitro experiment infixed-bore channels) difficult to accept as being ofmajor significance. It would be interesting to test thetheory in other plasmodial infections, in particular inP. vivax malaria in which there is neither deepintravascular schizogony nor " plugging " of smallvessels (i.e. no "stickiness "), although the para-sitized cells are considerably enlarged and containmuch larger and sturdier parasites than P. falci-parum.

It is possible that membrane changes in the in-fected erythrocytes and the inflexibility of shape ofthe erythrocyte containing the late stages of theparasite may ultimately play some part in diminish-ing the flow through the small vessels but only afterthe flow has already slowed.The movement of solid erythrocytes through a

small vessel, often with a resting bore smaller indiameter than the cell itself, must ultimately dependon four factors-the head of the flow, the dynamicstate of the vessel (which is capable of constrictionand dilatation), the mechanical resistance offered bythe passing cell, and the state of the endotheliumalong which it is passing.The fixation of attention on the changed erythro-

cyte as described above ignores the other factors. InLiverpool we have tried to keep this in mind andhave examined changes in the total circulation, in thedynamic state of the vessels, in their lining endothe-lium. We have demonstrated, on balance, that mostsignificant changes in malaria occur in the latter, and

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OTHER PATHOLOGICAL PROCESSES IN MALARIA 191

the response, in terms of what happens to theinfected cell within the small vessel, varies in differentanatomical areas depending on the original degree ofimpermeability of the local vascular membranes andthe damage and increase in permeability induced inthem during the infection.The local changes in blood flow are part of a

general picture, shared by many infections other thanplasmodial ones and by physiological situations suchas shock.

Intravascular coagulationThe situation is still not clear, since it is difficult to

determine whether the fibrin that is occasionallypresent in lesions, as in the brain in P. falciparuminfections, has been developed as a primary reactionor is secondary to inflammatory stasis.

If intravascular coagulation were a factor of majorimportance in the pathogenesis of the tissue lesionsin malaria, evidence of clotting should be regularlyvisible. Instant microclotting countered by instantfibrinolysis, which has been suggested as a patho-genic factor in shock (27) is difficult to credit in thecircumstances and could hardly be involved in ob-struction to circulating blood in the small vessels. Itseems that intravascular coagulation is probably nota major pathogenic process in malaria and that theoccasional clot observed is secondary and resultsfrom a failing circulation and does not cause it. Someauthors have demonstrated a few fibrin strands andoccasional clotting in cerebral malaria but extensiveintravascular clotting, such as would be needed topromote impedance of circulation, has not beendemonstrated at autopsy in falciparum malaria or inmammalian malaria in the laboratory (28).Devakul et al. (29) injected fibrinogen labelled

with radioactive iodine intravenously into Thaipatients infected with local chloroquine-resistantP. falciparum. In two severely ill patients with highparasitaemia, but not in three moderately ill patientswith high parasite counts, the fibrinogen was rapidlyremoved from the circulation. It was suggested thatthe rapid loss of fibrinogen in the severely ill patientsmight indicate widely disseminated intravascularcoagulation but, unfortunately, in these experi-ments fibrinogen degradation products were notmeasured.

Dennis and others (30, 31) claimed that heparinwas of some value in the treatment of complicatedfalciparum malaria and demonstrated coagulationdefects in P. knowlesi infection in M. mulatta and inP. falciparum infection in man in South Viet-Nam.

The conclusion drawn was that some degree ofconsumption coagulopathy existed in these infec-tions.Jaroonvesama (32) recently studied coagulation in

P. berghei infection in mice and found a smallincrease in fibrinogen breakdown products and aslight increase in plasminogen, indicating that fibri-nolysis was active and intrinsic and probably second-ary to whatever coagulation there was. The smallincrease in fibrinogen degradation products indicatedthat clotting had occurred in the past, not necessarilythat it was current. There was a normal range offibrinogen values in infected animals, suggestingcontinuing synthesis despite increased use-that is, agreater turnover. This increased turnover asso-ciated with a shortened half-life of tagged fibrinogenhas also been noted in P. coatneyi and P. knowlesiinfections by Areekul et al. (33) and Pramualmal &Reid (34). On the whole, the picture observed byJaroonvesama was one of low grade consumptioncoagulopathy, which in fact represented a currentrelative inability of the circulating blood to clot.

Knisely's " sludge " (1, 3) is a late phenomenon. Ithas been suggested that the erythrocytes in the" sludge " mass are cemented together by strands offibrin. If this is the case, it might account for some ofthe increase in fibrinogen degradation productsfound in the late stages of human, simian, and rodentmalaria.

Reid & Sucharit (35) in 1972 further examinedthe importance of intravascular coagulation in sim-ian malaria by treating infected animals with heparin,the antifibrinolytic drug EACA,a and the defibrinat-ing drug ancrod.b None of these drugs materi-ally affected the process of the parasitaemia orof the clinical features. The authors consider thatthese findings virtually exclude an important patho-physiological role for fibrin, as such, in simianmalaria.

It is nevertheless possible that regional intravas-cular coagulation may be important occasionally andthat the measurement of fibrinogen degradationproducts could give a lead to the situation in a givenpatient in terms of whether the use of a fibrinolyticdrug such as streptokinase might be rational.The significance of intravascular coagulation in

malaria is open to further discussion. The pathwaysof the clotting mechanism may be changed in malaria

a Acronym for " epsilon amino-caproic acid "-i.e.,6-aminohexanoic acid.

b Arvin, derived from Agkistrodon rhodostoma venom(Twyford Ltd).

192 B. MAEGRAITH

so that the demonstrated increase in fibrinogendegradation products may represent a breakdown ofthe protein along some pathway not directly con-nected with coagulation. The possibility is pharma-

cologically interesting in view of the close similarityof the peptide: peptidase reactions occurring in thekinin complex and the peptidase reactions involvedin coagulation.

R1nSUMI2

AUTRES PROCESSUS PATHOLOGIQUES DANS LE PALUDISME

Les processus pathologiques, au cours du paludisme,sont pour la plupart non specifiques et analogues aceux observes chez l'h6te en reponse a un grand nombred'autres infections et agressions. Le present article exposebrievement la succession des reactions physiopatholo-giques provoqu&es par l'infection paludeenne.

Les reactions de nature inflammatoire modifient lapermeabilite et les proprietes vasomotrices des vaisseauxlocalement et dans tout l'organisme et ont des repercus-sions sur la circulation. Des substances du groupe deskinines interviennent pour declencher et entretenir cesreactions qui peuvent entrainer la perte d'eau et de pro-teines a travers la paroi endommagee de vaisseaux nor-malement impermeables et la stase circulatoire. Ce pheno-mene est 'a l'origine de l'obstruction des vaisseaux cer&braux par les erythrocytes parasites dans le paludismea Plasmodium falciparum. L'<adh&rence> de crs erythro-cytes ne semble jouer qu'un r6le mineur dans le pro-

cessus d'obstruction au cours de la schizogonie profonde.Une autre hypothese attribue l'obstruction des vaisseauxa l'augmentation de volume et au manque de malleabilitedes erythrocytes parasites. Quant a la coagulation intra-vasculaire, elle ne represente pas, apparemment, un fac-teur physiopathologique important au cours de l'evolu-tion du paludisme.Les reactions vasomotrices au niveau du foie et des

reins sont examinees en relation avec le dysfonctionne-ment et la defaillance de ces organes, en particulier dansle paludisme humain a P. falciparum.

I1 importe de reconnaitre le caractere non specifiquede certaines reactions de l'h6te dans l'infection palu-deenne, susceptibles de regresser sous l'effet du traitementdurant les premiers stades de la maladie, afin de pouvoirevaluer 1'efficacit6 antiinflammatoire des medicamentsantipaludiques independamment de leur activite purementantiparasitaire.

REFERENCES

1. MAEGRAITH, B. G. Pathological processes in black-water fever and malaria. Oxford, Blackwell, 1948.

2. MAEGRAITH, B. G. Pathogenic processes in malaria.In: The pathology of parasitic diseases. 4th Sympo-sium, British Society of Parasitology. Oxford, Black-well, 1966, pp. 15-32.

3. MAEGRAITH, B. & FLETCHER, A. Advances in parasito-logy, 10: 49-75 (1972).

4. PETERS, W. Chemotherapy and drug resistance inmalaria. London and New York, Academic Press,1970.

5. FLETCHER, A. & MAEGRAITH, B. Advances in parasito-logy, 10: 31-48 (1972).

6. MIGASENA, P. & MAEGRAITH, B. G. Transactions ofthe Royal Society of Tropical Medicine and Hygiene,61:6 (1967).

7. MAEGRAITH, B. G. Journal of protozoology, 2: 65(1967).

8. TELLA, A. & MAEGRAITH, B. G. Transactions of theRoyal Society of Tropical Medicine and Hygiene, 5: 1(1963).

9. TELLA, A. & MAEGRAITH, B. G. Annals of tropicalmedicine andparasitology, 60: 304 (1966).

10. ONABANJO, A. 0. & MAEGRAITH, B. G. Transactionsof the Royal Society of Tropical Medicine and Hy-giene, 65: 5 (1971).

11. GOODWIN, L. G. & RicHARDs, W. H. G. Britishjournal ofpharmacology and chemotherapy, 15: 152(1960).

12. ONABANJO, A. 0. & MAEGRAiTH, B. G. Annals oftropical medicine andparasitology, 64: 227 (1970).

13. DESOWITZ, R. S. & PAVANAND, K. Annals of tropicalmedicine and parasitology, 61: 128 (1967).

14. BILLINGS, F. T. & MAEGRAITH, B. G. Quarterlyjournal of experimental physiology, 27: 249 (1938).

15. MAEGRAITH, B. G. Transactions of the Royal Societyof Tropical Medicine and Hygiene, 38; 1 (1944).

16. MAEGRAirH, B. G. ET AL. Lancet, 2: 781 (1947).17. ANDREws, W. H. H. British medical bulletin, 13: 82

(1957).18. SKIRRow, M. B. ET AL. Annals of tropical medicine

and parasitology, 48: 502 (1964).

OTHER PATHOLOGICAL PROCESSES IN MALARIA 193

19. MAEGRAiTH, B. G. & FINDLAY, G. M. Lancet, 2: 403(1944).

20. MAEGRAr1H, B. G. Er AL. Lancet, 2: 293 (1945).21. RAY, A. P. & SHARMA, G. K. Indian journal of

medical research, 46: 367 (1958).22. LUSE, S. A. & MILLER, L. H. American journal of

tropical medicine and hygiene, 20: 655 (1971).23. RuDzINsKA, M. A. & TRAGER, W. Journal ofproto-

zoology, 15: 73 (1968).24. MILLER, L. H. Transactions of the Royal Society of

Tropical Medicine and Hygiene, 66: 459 (1972).25. SMITH, D. H. ET AL. Annals of tropical medicine and

parasitology, 63: 433 (1969).26. MILLER, L. H. ET AL. American journal of tropical

medicine and hygiene, 21: 133 (192).

27. HARDAWAY, R. M. Syndromes of disseminated intra-vascular coagulation with special reference to shockand haemorrhage. Springfield, Ill., Thomas, 1966.

28. EDINGTON, G. M. & GELLES, H. M. Pathology in theTropics. London, Arnold, 1969.

29. DEVAKUL, K. Er AL. Lancet, 2: 886 (1966).30. DENNis, L. H. ET AL. Blood, 29: 713 (1967).31. DENNIs, L. H. ET AL. Lancet, 1: 769 (1968).32. JAROONVESAMA, N. PhD thesis, University of Liver-

pool (1969).33. AREEKUL ET AL. Southeast Asian journal of tropical

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DISCUSSION

COHEN: 1 question the evidence for the existence ofso-called antitoxic immunity in malaria.

McGREGOR: I think it originally referred to theability of young children in hyperendemic areas tocarry relatively dense parasitaemias with few clinicalsigns or symptoms. Evidence of antitoxic immunityhas also been shown in mice, in which, despiteconsiderable blood destruction, toxicity is minimal.

BRAY: Max Miller, working in Liberia, has shownthat the threshold parasitaemias for symptoms are

approximately 12 000 per mm3 for children and 2 500per mm3 for adults with P. falciparum and 1 200per mm3 with P. malariae.

VAN DER KAAY: If we accept the hypothesis thatintracapillary plugging occurs secondarily to in-creased permeability of the endothelial lining of thesmall capillaries, then treatment of cerebral malariashould include, in addition to intravenous quinineand corticosteroids, 4-aminoquinolines, which arepowerful anti-inflammatory drugs.