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·MALARIA
WITH SPECIAL REFERENCE TO
THE AFRICAN FORMS
by
W. K. BLACKTE
MD, PhD., FR C.P (E4) DTM&H.
Honorary Consulting Physielan
Salisbury Hospital Southern Rhodesia
Formerly Rhodesian Research Fellow
London School of Hygiene and Tropical Medicine
Published for the
POST-GRADUATE PRESS
by THE AFRICAN BOOKMAN
TOWN

·M
AB
M
PRINTED IN THE UNION OF SOUTH AFRICA FOR
THE AFRICAN BOOKMAN PO BOX 3115 - CAPE TOWN
BY THE PENINSULA PRESS

·FOREWORD There is something very satisfying in the practice of tropical medi cime Apart from the fascinating life cycles of so many of the parasites wfuch infect human beings, a large number of tropical diseases make nicely rounded-off studies There are hiatuses of course but the etiology is usually known, clinical features have been closely studied, the diagnosis is capable of definite proof by easy means there are a number of ercellent remedies and a great deal is known of prophylaxis These aspects are all thoroughly exemplified in malaria, the most important of all tropical diseases There is, however, also a difficult side to the case It used to be said of syphilis that if you knew it you knew the whole of medicine Malaria comes near to deserving the same description Its clinical manifestations are protean It may simulate a vast number of other clinical conditions To confound matters even more it is frequently found together with other diseases in the same person at the same time (an important aspect of tropical medical practice) Moreover, when another disease manifests itself chnically, a malarial infection, otherwise latent, tends to become active It is not only in tropical parts that the medical man needs to be ever alert for the occurrence of malana If the patient has been where he could have become infected malana must always be seriously considered no matter in what guise the disease presents itself Outside of malanous areas there is a tendency to think of malaria only when there are typical paroxysms that is often but to give a dare to what is practically self-evident It is against this general background that Dr Blackie with his extensive expenence, has dealt with the subject clearly, concisely and accurately This monograph on malaria is a well balanced and practical presentation of the subject F FORMAN, MD, FRCP, Professor of Clinical Medicine, University of Cape Town

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·CONTENTS
Foreword
PAGE
1 Historical review
V
2 Parasitology
3 Pathology and morbid anatomy
9
4 Cubical features
23
5 Diagnosis
37
6 Differential diagnosis
56
7 Prognosis and treatment
66
8 Prevention
71
Index
99
102

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·CHAPTER ONE HISTORICAL REVIEW Io the geographical zone that lies between the Tropic of Cancer and the Tropic of Capricorn, malaria is almost universally present as an epdemic disease of varying latensity. It is seldom found over 6,000 feet, and in certain desert areas where the mosquito vector cannot breed, so that even in the Tropics non-malarious areas exist. Pl falciparum constitutes the prevailing species throughout the tropical belt, but is also found wherever the seasons are characterised by a sub-tropical summer and a mild winter Consequently Pl. falciparum is found extending into Northern Afnca and across the Mediterranean to Southea Europe Pl vivar covers an even more extensive gcographical zope ro that it is distributed sporadically throughout the Tropics and sub-tropics and is found in the Temperate Zone as far north as 60° N in the vicinity of Lake Ladoga in Russia and Southern Sweden, while in the Southern Hemisphere st extends as far south as South Queens. land (20° S), Northern Argentina and Natal (30° S) Pl malariae has a very much more restricted distribution, and although it may constitute the prevailing species in localısed areas of tropical Africa, Ceylon and the Malay States, it occurs sporadic. ally throughout Central and West Africa It is found in Central Europe, eg, Macedonsa, and in the countries of the Near East, such as Syria, Palestine and Iraq In the Far East st has been found in the Andaman Islands, India, Central and South China, while in the New World it occurs as a rare infection in the West Indies, Brazil, Panama, Central America, Mexico and ia the Southern United States Like pl malariae, Pl osale appears to be confined to a limited area, being found especially in East and Southern Africa, but infections have also been reported from the Philippines, New Guinca, Russia, Persia, Palestine, India, China, Mauritius and South America ·2 MALARIA The distribution of malaria and the various plasmodial species 15 mainly a question of atmospheric temperature and humidity, but additional factors such as soil chemistry, altitude, racial im munity and local economics all contribute to the incidence of the disease both as a seasonal and as an endemic malady in any given locauty Wherever malana prevails in a highly endemic form, the tendency is for the indigenous inhabitants to build up a considerable measure of immunity to the disease, so that the acute paroxysms of infancy and early childhood gradually give way to a smouldering infection virtually devoid of clinical expression That is to say, a state of premudity prevails and is maintained only so long as the infection persists in the tissues of the host For this reason acute malana is seldom encountered amongst the adult population of an endemic area where re infection is taking place continuously Only in the presence of hyperinfection or of some debilitating illness are acute symptoms likely to appear, and even then are readily eliminated therapeutically Furthermore, the comparative freedom of the adult section of, for example the African native from the acute manifestations of malaria is all the more remarkable when it is borne in mind that he is being simultaneously assailed by the debilitating influences inherent in polyparasitism and avitaminosis The intrusion of the non immune European into the malanous zones of the Tropics has, however, brought the clinical features and after effects of acute malaria into sharp relief Not only are the immediate consequences of infection more damaging and more dramatic, but recurrent infection leads to progressive deterioration in the patient's general health, and in the case of young children may gravely retard development of mind and body It follows, therefore, that in the case of Europeans, neglected malaria not only exacts a high toll of life, but may engender a state of physical and psychological deterioration and thereby exerts an adverse influence on the economic efficiency and moral standards of those upon whom the ultimate success of all colonisation schemes must depend From the clinician's viewpoint, however, malaria has two great redeeming features Firstly, accurate diagnosis is possible in the great majority of malarial cases This is particularly so ia acute ·HISTORICAL REVIEW 3 malana, but even the chronic forms present many characteristic features Secondly, we bare a series of powerful plasmocidal drugs which caable the clinician to bring the acute forms of an attack under rapid control, provided a diagaosis has been arrived at expeditiously Finally, with the latroduction of new and potent insecticides, the hygienist 15 DOW 19 a position to intensify bus attack on the insect vector and so restrict the spread of the disease The outlook for the future is thus full of promise, but it may be well to pause at this point and pass in review the labours and in spirations of those men who have made possible the recent advances in the fight agarast malar13 Before the doctrine of the mosquito-transmission of malarial infection was postulated, malana was associated in the minds of men with swamps and marshes, even though the discrepancies that cxisted between "marsh fever" and marshy areas was fully appreclated It was long believed that the miasmata nisiog from tropical swamps constituted the immediate source of the fever, although as time went on there was considerable speculation concerning the precise nature of the fever producing components of these telluric emanations About the middle of the 19th century Hensioger, Mitchell and others endeavoured to cianfy the position by postulating a parasitic ause for malana This suggestion led Massy of Ceylon to claim that a microscopic fungus could be recovered from the atmosphere wherever malaria was prevalent, and later Holden made a special study of a malarial outbreak on shipboard, and not unnaturally isolated Thaliophyta from infected store rooms, He believed that Thallophyta were only capable of causing the disease in combination with His from the stagnant water of the holds la due course Algae were postulated first by Van den Corpat and later by Balestra as the pnmary cause of malariai fever Thus Scott quotes Balestra as saying that he took ſever twice after drawing deep breates over a vessel containing water from the Ponunt marshes of the Roman Campagna, in which algae were present " Then in 1879 Klebs and Tomması Crudel described rods and oval motile spores which "when isolated and cultivated produced the most marked malanal sickness in the animals which received them" From their description of the morbid anatomy of their experimental ·+ MALARIA animals, it is probable that these investigators were dealing with B anthracis They named their organism Schizometes bacıllaris, and claimed to be able to isolate it from the soil of the Roman Campagna They then built up an ingenious theory to the effect that for physical reasons these microbes lay like a ground fog over and around the marshes, and would therefore be inhaled by anyone walking in the vicinity Thus until 1880, malaria was regarded as a disease that followed exposure to the miasmata that rose from marshes, lakes or rivers What the "malarious substance" might be was uncertain, but was probably some lowly form of life, either algal, fungal or bacteria in character Then came one of the most momentous discoveries in the history of malaria—the discovery of the causal parasite by Alphonse Laveran on the 6th November, 1880 This was followed in 1881 by a detailed description of "certain parasitic elements," which he had succeeded in demonstrating in the peripheral blood of his malaria patients He regarded the parasite as a species of Oscillaria, and named it Oscillaria malariae After some controversy Laveran's findings were finally confirmed and extended by Richard in North Africa, Marchiafava in Italy, and in due course by workers in other parts of the world As morphological and clinical details accumulated, it became apparent that more than one species of parasite was concerned in human malaria, and eventually four distinct species came to be accepted But in spite of the wealth of parasitological detail that was being amassed, the whole question of transmission remained unsolved, and as yet nothing had occurred to upset the inhalation theory But it may be said that the first step towards solving the riddle was taken when the phenomenon of ex flagellation of the microgametocytes was observed While the Italan observers Bignamı and Grassi regarded ex flagellation as evidence of dissolution, Manson was convinced that it constituted an integral part of the plasmodial life cycle Maason's views were eventually confirmed JD 1897 by W G MacCallum of Johns Hopkins University, who was able to demonstrate impregnation of the female malarial gametocytes by the flagella extruded by the male forms Meanwhile, attention was being attracted to the possibility of malaria being an insect- ·HISTORICAL REVIEW 3 (ransmited disease It does not appear possible to say where of with whom the idea arose Io the first place it was already known tka's cettato plant and anunal diseases were transmuired by boting Iosects, and for several centuries before the discovery of the plassnodi3, the indigenous inhabitants of talansous regions had vaguely associated marsh fevers with mosqwtoes Then, in 1819, the 385ect transmission of human disease became an estadushed fact when Mapson demonstrated the transmission of Wuchererja bancofu by the Culex mosquito While the wider 19plcations of this important discovery were not immediately appreciated, it undoubtedly conststuted the foundation of Ross's work on the mosquito $aasmission of malarsa Bearly 20 years later It is not proposed to give in detasl the inspiring story of Ross's work in India during 28e years 1895 to 1898 which fulminated 18 the discovery of the mosquito transmission of the avian plasmodium The story is fully expounded by Sse Harold Scott a kis scholarly Hotory of Tropical Medicine Horever, U is of salerest to glance Ancfly at the steady growth of the conviction that malan3 was a mosquito-borne disease long before the experimental proof besame avslagle In 1883 King in America por forward the view, based on 19 points, that mosques constituted the tectors of mafana, hut just how tr985 tisson occurred as a master of surmise and controversy Bota Manson and Layecan held the view that matas could be acquired by drinking water in which mosquitoes had died after feeding on a malarious patseat or by intalng dust from dned-up mosquito-haunted pools So obsessed was Manson with the association of malara and stagnant water that he administered to human volunteers a concoction of malassal blood and sterilized marga Hater after a swiadle period of incubation--a procedure sugmatized by Darw as a fool experimenti Maasont had already shown that the sect transmission of a human parasite (w bancrofa) occurred as true biological (as opposed 10 a "mechanical'') phenomenon in hich a vital phase of parasiuc development took place in the sues of the instct host and in connection with the malsua parasite was convinced that the phenomenon of ex flagellation constituted ence of a lfe cycle outside the human body > by 3 process of inductive reasoning Klanson formulated the ·6 MALARIA mosquito-malaria hypothesis He himself was prevented by circumstances from working out his idea, so that it fell to Sir Ronald Ross, to whom Manson communicated his views, to carry through the long series of experiments which in 1898 established the truth of Maason's theories Ross began his "historic quest"in India in 1895, and soon showed that the phenomenon of ex-flagellation took place in the stomach of a dapple-winged (anopheline) mosquito, and later on found that the flagella soon disappeared, or at least could no longer be recog. nised in the mosquito's stomach Then at Secunderabad in 1897 he saw pigmented cysts (oocysts) in the stomach wall of laboratorybred mosquitoes, of the spotted-wing variety which had fed on malarious patients, so that now he was reasonably certain he had found the species concerned in malaria transmission He saw, too, the rupture of the oocyst, whereby the sporozoites were released into the body cavity of the mosquito with some eventually reaching the tissues of the salivary glands At this juncture Ross's investigations were temporarily suspended by reason of bis transfer to a non-malarious district in Rajputana, but on his return to Calcutta he was urged by Manson to follow McCallum's lead and utilise avian malana in his final experiments This he did, and in 1898 succeeded in tracing the developmental cycle of the avian plasmodium through all its phases, and finally succeeded 10 establishing the truth of Manson's hypothesis by carrying out a series of transmission experiments by the bite of infected anopheline mosquitoes All that now remained to be done was to verify these findings in relation to human malaria, but an all-fated transfer to Assam on a new problem denied to Ross the final discovery Instead the problem was taken up and carried to finality by the Italian workers Grassi and Bignami, who confirmed Ross's work and established the mosquito transmission of human malana In the years that have followed these brillant discoveries, a wealth of biological detail has been accumulated round the vectors of malaria in all parts of the world, so that present day control measures are based on accurate knowledge of the bionomics of the mosquito host Again, a keener appreciation of the natural history of malaria ·HISTORICAL REVIEW 7 in man has led to greater precision in its therapeutics, while quinine, which has long held pnde of place as the drug of choice in malana, 18 now being nvalled and to some extent replaced by a senes of synthetic plasmocidal drugs The first of these was prepared at Elberfeld in 1924 and tested against avian malaria in 1926 It was onginally termed biprochın, but later became known as plasmoquine Plasmoquine is a synthetic quinoline derivate which destroys the schizonts and gametocytes of Plasmodium virax, Pl osale, P/ malariae and the gametocytes but not the schizonts of Pl falciparum except when combined with quinine in the form of plasmoquine compound Further investigations led in 1930 to the production of Enon or Plasmoquine E, a synthetic acndine derivative which was later termed Atebrin Since the drug is now manufactured in several parts of the world, it is variously known as mepactine, quinacrine, haffkinine and crinodora Its plasmocidal action is analagous, to quinide in that it destroys all forms of Pl vivax, Pl ovale and PI malariae In the case of PI falciparum infections it destroys the schizonts but not the gametocytes Finally, the latest synthetic plasmocidal drug to appear was prepared in England by the Imperial Chemical Industries under the name of Paludane, and the preliminary trials show a high order of therapeutic efficiency This brief historical review brings us back to the malaria problem of the present day The disease continues to be widespread throughout the length and breadth of the Tropics and beyond, and in consequence is rest ponsible for a heavy toll of life, both amongst the indigenous inhabı tants and amongst European settlers In addition it is responsible for much in the way of chronic ill health and invalidism But recent advances in chemo-therapy have provided the clinician with new and powerful drugs for the more efficient treatment of the disease in all its phases, and at the same time refinements in laboratory technique have enhanced the accuracy of laboratory diagnosis Again, in the sphere of preventive medicine, the hygienist is now in possession of highly potent insecticides by means of which he can strike at the very heart of the malaria problem--the mosquito vector None the less, the scientific control and climination of malaria ·8 MALARIA will long remain a task of the first magnitude but the balance is now more definitely weighted in favour of those who are grappling with this elusive biological challenge to human life and enterprise ·CHAPTER TWO PARASITOLOGY Human malaria is conditioned by an infection with protozoa which belong to the class Sporozoa, suborder Haemospondia, genus Plasmodia The various members of this genus exhibit a biphasic life cycle whereby one developmental phase occurs within the tissues of an invertebrate host-the female anopheline mosquito, and the other takes place within the endothelial and the red blood cells of the human host The mosquito phase represents the sexual cycle or sporogony which is initiated by fusion of the sexual forms of the plasmodium within the mosquito's stomach and is followed by gradual evolution of an oocyst in which develop vast numbers of sporozoites These are subsequently transmitted to the human host by the bite of the mosquito From the biological view point, the mosquito constitutes the definitive host of the plasmodium with man the intermediate host The human or corporeal phase of the cycle follows upon the inoculation of the human host with sporozoites from an infected mosquito On entering the red blood cells an asexual developmental process known as schizogony occurs This process, which is confined to the red blood cells, results in the formation of a number of daughter spores or merozoites, the sudden release of which into the blood stream precipitates the febrile paroxysms which constitute the classical presenting clinical feature of acute malaria These pyrogenic forms, however, are incapable of infecting the mosquito host, and are therefore valueless from the point of view of propagating the plasmodial species Hence, an additional developmental phenomenon can be observed during the corporeal phase, and consists in the cyolution of sexual forms or gametocytes which, though without influence on the febrile parotysms, render the blood infective to the carrier mosquito The term gametogony is applied to this process, and by this means a ·10 MALARIA biological link is forged between the human and mosquito cycles Thus the full life cycle of the malarial parasite is made up as follows 1 Sporogony which takes place in the female anopheline mosquto and from the view point of human malani represents the extracorporeal phase of the cycle 2 Schuzogony and gametogony, both of which occur within the red cells of the human host, the former precipitating acute febrile paroxysms and the latter rendering man infective to the mosquito THE HUMAN PLASMODIAL SPECIES There are at least four plasmodial species encountered in human malaria These are 1 Plasmodium vivax (Grassi and Feletti, 1890) 2 Plasmodium ovale (Stephens, 1922) 3 Plasmodium malariae (Laveran, 2881) 4 Plasmodium falciparum (Welch, 1897) These four species of malaria parasite can be differentiated morphologically throughout their developmental cycle in the human host, and in view of the clinical implications inherent in the species differentiation a systematic description of the plasmodia will be given later Meanwhile a more detailed picture of the biology of the life cycle common to all four species will be described THE PLASMODIAL LIFE CYCLE As already stated, the life cycle of the malaria parasite is biphasic in character, consisting of (a) the Human Phase (sometimes referred to as the corporeal, endogenous or asexual phase or the phase of schizogony), and (b) the Mosquito Phase (or the extra-corporeal, exogenous or sexual phase or the phase of sporogony) THE HUMAN PHASE SCHIZOGONY The human host is infected through the bite of a female anopheline mosquito when sporozoites are injected into the subcutaneous tissues The immediate fate of the sporozoites is still sub judice, but there ts increasing support for the view that they gain access to the cells of the reticulo-endothelial system, in which they undergo a prelimin. ary stage of development before entering the red blood cells This ·PARASITOLOGY 11 phase, which is vanously referred to as the 'X'cycle, the first tissue stage or the exo-erythrocytic cycle, has been amply demonstrated in the case of certain avan plasmodia, eg, Pl relictum, Pl gallinaceum, Pl lophurae, while similar claims have been made in connection with the human plasmodia In the case of avan plasmodia the cro-erythrocytic forms appear as non pigmented bodies within the cytoplasm of macrophage cells in the liver, spleen, bone marrow, and eventually in the endothelium of blood vessels in various parts of the body. They appear to undergo a form of division with the formation of daughter spores or merozoites which on escaping from the parasitised cell not only enter cells of a similar class, but also invade the red blood corpuscles This remarkable phenomenon not only provides a clue to the vagaries of chemoprophylaxıs, but may also constitute the basis of clinical relapses in the therapeutics of malaria Eventually, however, the parasite appears in the red cells as a thin, crescentic ning of cytoplasm surrounding a central vacuole with a small chromatin dot or dots lying on the crescent at its most tenuous part This growing form is known as a trophozoite The number of trophozoites in a given red cell may vary from one to several, depending to some extent on the intensity of the infection, but more especially on the species of the infecting plasmodia As will be seen later, multiple parasitism of the red cells is a common cvent in heavy infections with Pl falciparum As the trophozoite matures it assumes an irregular, amoeboid outline with fine fila mentous strands of protoplasm extending out into the substance of the red cell It is possible, of course, that the plasmodium lives on the surface of the red cell rather than within its substance, but It is not necessary to delay over this controversial point which does not affect the developmental pattern Since the growth of the parasite takes place at the expense of the red cell, modifications occur in its staining reactions, to an extent which may be utilised in species diagnosis In addition to the chroma tic changes which in the presence of an appropriate staining technique can be shown to consist in either stippling or decolounsation the red cell may be demonstrably colarged of may appear more compact and solid than usual lo one variety of stippling, the red cell is covered with fine, pink spots known as Schuſſner s dots This type ·12 MALARIA of stippling is seen in infections with Pl mar and Pl orale Another variety consists in the formation of coarse red dots with a coccold, cuneiform or irregular outline They are never more than a few to a red cell, and are known as Stephen's and Christopher's or Maurer's dots It does not appear that young red cells (reticulocytes) are infected with greater frequency than the more mature forms, even though some workers claim to have shown that in Pl snar infections particularly the plasmodia exhibited a predilection for the reticulocytes As the parasite develops, yellowish brown granules known as malarial pigment appear within the cytoplasm, representing a special degradation product of haemoglobin, and therefore an excretory product of the plasmodial metabolism The quality and quantity of the malarial pigment varies as between one plasmodial species and another As the parasite gradually fills the red cell, amitotic division of the chromatin dot occurs and continues until from eight to 32 subdivisions have formed As division of the cytoplasm occurs simultaneously, each daughter nucleus comes to be contained in a small fragment of cytoplasm, thereby giving origin to a group of new spores or merozoites which lie enclosed within the red cell envelope The merozoites tend to be disposed round the central mass of pigment and residual cytoplasm after the manner of a rosette In due course the red cell membrane gives way, and the merozoites are scattered into the plasma, but they rapidly become attached to a new senes of red cells and eventually penetrate the cell membranc to initiate a further developmental cycle The pigment released by the rupture of the red cells is taken up by the cells of the reticulo-endothelial system in the spleen, liver and elsewhere THE HUMAN PHASE GAMETOGONY From the biological view point schizogony is a stenle phenomenon which would lead automatically to the extraction of the plasmodial species, but in order to maintain continuity with the definitive host a morphological variant appears from amongst the merozoites, sometimes quite early on in the malarial attack, or it may be after a delay of several days These variants are destined to become the ·PARASITOLOGY 13 sexual forms of the plasmodium, and are designated gametocytes lastially they appear as globular structures which develop within and gradually fill or even distend the red blood cell During development they exhibit little or no amoeboid activity, and when suitably stained have a more compact appearance than the developing schizoots, while it is usually possible to distinguish between the male and the female forms Thus the cytoplasm of the male gametocyte (or microgametocyte) stains a faint blue, the nucleus is composed of fine chromatin granules centrally situated but loosely dispersed over a fairly wide area, while the pigment consists of a finc granular deposit, In the case of the female gametocyte (or macrogametocyte) the cytoplasm stains a deep blue, the nucleus is deeply stained and compact with the pigment a coarse yellow-brown colour The detailed morphology of the gametocytes varies with the plasmodial species but is globular in all the recognised species with the single exception of Pl falciparum in which crescentic forms appear The process of gametogony ends with the fully grown parasite occupying the red cell where it remains in a dormant phase until taken up and reactivated by the appropriate anopheline mosquito THE MOSQUITO PHASE SPOROGONY The sexual phase of the life cycle (or sporogony) is initiated within the stomach of the mosquito where the gametocytes escape from the red cell envelope to form a spherical body, whatever its original shape By means of reduction division a process of maturation follows, during which portions of nuclear substance are probably extruded as polar bodies The nucleus of the male gametocyte breaks up to form from four to eight divisions, each of which acquires a thin filament of cytoplasm, and by a process of vigorous flagellation succeeds in breaking away from the parent cell This new body is now termed a microgamete The female gametocyte undergoes a similar process of maturation, but apart from extruding two chromatin fragments or polar bodies the nucleus remains intact and the cell globular The cell thus modi fied is now the macrogamete, and as such is capable of being fer. tilised Fertilisation is effected by the actively motile microgameto ·MALARIA which penetrates the cytoplasm of the macrogamete, whereupon fusion of the nuclear elements of the cells ensues The fertilised macrogamete is now referred to as the zygote, which rapidly changes to become an actively motile body termed the travelling vermicule or ookinete It penetrates the gastric epithelium and finally comes to rest immediately beneath the delicate outer membrane of the mosquito's stomach, where it rounds up to form a minute transparent structure or oocyst which at this stage measures 6 to 12p in diameter, and consists of a single vesicular nucleus enclosed in cytoplasm As the oocyst matures it increases in size, the cytoplasm becomes vacuolated and the nucleus subdivided with the production of a series of chromatin granules which are distributed on the protoplasmic strands In due course each granule becomes the centre of an acicular cytoplasmic structure or sporozoite arranged in radial fashion within the oocyst When fully matured each oocyst measures from 40p to 60ps in diameter and contains thousands of sporozoites An infected mosquito will carry an average load of some 20 oocysts, but counts as high as 500 have been recorded On attaining full maturity thc oocyst ruptures and the sporozoites escape into the body cavity of the mosquito, and by virtue of their motility they migrate anteriorly to the salivary glands where they eventually appear in heavy concentration, although most other parts of the insect's body become infiltrated to a greater or less extent The sporozoites measure 14 to 154 in length and carry either one or more nucle: The mosquito 15 now infective to man, and in the act of biting, the sporozoites are carried down in the salivary secretion and thus gain access to the human host NOMENCLATURE AND DESCRIPTION OF THE MALARIA PARASITES PLASMODIUM VIVAX (Grassi and Feletti, 1890) Synonyms Haemamoeba malariae rar tertianae (Cell and Sanfelici, 1891), Haemamoeba malariae sar magna (Laveran (in part), 1900), Except where otherwise stated the morphology of the malana parasite will be described as it appears in smear preparations stained either by Leishman's or Giemsa's technique ·☺. 2 Plasmodium vivax 10 11 16 18 12 Plasmodium malariae 19 20 ) 21 22 23 Plasmodiu o ale 27 30 31 32 33 34 35 28 29 36 37 Plasmodium falciparum AR 40 19 Plasmod tin testire (To face page 14) ·KEY TO MALARIA PARASITES 111 Pla mod in war Smallest ring (about one third d ameter of cell) Accole form Smilar forms occur in all the spe les but are not shown R 3 s u 9 10 . 12 20 P maluriae 12 Smallest ring (about one third diameter of cell) 13 Ring form showing a pigment grain 14 Ribbon form IS IT 16 / 17 18 19 20 21 26 P ovale 21 Smalkst ring (about one third diameter of cell) 22 Partially grown schizont showing lobose form as in quartan st ppl ng is not shown but should be present of spa imen were properly sta ned 13 Same showing appearance not uncommonly seen stippling should normally be present in well stained preparation 24 Partially groun schizont with stippling showa compare Fig 4 ( Plar in wh ch amoeboid processes are very evident at this stage) 25 Maturing schizont 26 Mature schizont 27 38 Pfalciparum Smallest ring (about one sixth d ameter of cell) 28 Ring with double chromatin mass 29 Same with fine hair like cytoplasm 30 Commencing amoeboid changes compare size of ring in Fig 3 (P star) 31 Largest ring form showing Maurer s stippling 37 Most advanced stage usually seen in peripheral circulat on (Maurer s די 33 31 35 36 37 38 39 44 39 30 41 P tenue Smallest ring (about one sixth d ameter of cell) 43 44 irger and more commonly seen Maurer s stippin, as in Fig 42 would normally be present in well sta ned films Form similar to Fig 33 but commonly present in peripheral blood (Colour pla e reproduced by perms n of But erwo b and Co rom the 8n1 sh Encyclopicd a of Meu cal Practice > ·PARASITOLOGY la terzis reach the red blood cells the form a ner ke bac's whxh mesures about?. demeter or froumate we had the inter of the red corpuscle. The had stands to plusa is furty abundent and is an arestuallı rounds cole exth Stade regarded as a food zeucle. The naceus 2ppears 29 2 brett red paremal dot of chromata Exch paysozetimes be stated Cere: the centre of the nog As development proceeds, the tag parance is mustained but the cytoplasta 258 wamem sed the chromatus det enlarge Gradually, konever, the perve assumes an irregular shape, and aben cummed in the fresh state during this phase of development It exhibits a lively amoeboid acuity 25 revealed by the vivorous extension and retraction of the peripheral pseudopodu. In stained Preparatons the amobord activity is reflected in the irregular out Tine of the projecting pseudopoduz. As the parasite merges from the res to the amorbord stage, fige Figment gradules appear within its cytoplasm, and in fresh preparations these shon active Browtuan movemect. When stained they appear either as brows or black granules. With the approach of ouclear segmentation, amoebord movements become more slugask, the vacuole vaishes and the plasmodi im dot appears as a compact rounded body which fills the greater part of the enlarging red cell Nuclear derision sets in from 36 to 48 hours after invasion of the red cells, and leads to the formation of approximately 16 new chromatin particles, althoush the actual number vares from 12-24 Division of the cytoplasm then follows, so that ach chromatin fragment acquires part of the ongnal cytoplasm In this way & number of young forms or merozoites are evolved and are temporarily clustered within the red cell after the manner of a rosette or mulberry Thus the fully matured schuzont is composed of some 16 meron 1 or other side They rapidly pererate or attach themselves to fresh red cells where the asexual forms reappear as nors to initate a con Schizogony cycle The cycle lasts approumately 45 hours and trio ·16 MALARIA place within the red cells of the peripheral circulation The Parasitised Red Blood Cells in Pl vivax Infections Infection of the red blood corpuscles by Pl inax initiates a series of characteristic changes in the parasitised cell, whether the infection be caused by the sexual or asexual forms of the parasite Within a few hours of infection the red corpuscle begins to increase in size and simultaneously becomes paler in colour With the steady growth of the parasite a number of fine red dots of uniform size appear, and in due course stipple the entire red cell in a regular pattern These dots are termed Schuffner's dots--after their discoverer-and are never found apart from infections with Pl wax and Pl ovale They enlarge slightly and become more defined as the plasmodium develops, and are regarded by Schaudınn and others as representing a fine precipitate in the substance of the red cell brought about by the colloidal disintegration which accompanies plasmodial absorption of the more readily digested components of the red cell structure It is important to bear in mind that the stippling affects the red cell, not the parasite, and furthermore that it can only be demonstrated when the blood films are stained in a medium of suitable alkalinity Gametocytes The factors governing the onset of gametogony are not definitely known, but gametocytes are not usually demonstrable in the peripheral blood until after the completion of several schizogony cycles, although it must be admitted that young sexual forms have been observed in the course of the first febrile paroxysm Young tertian gametocytes appear as small globular bodies staining blue with a chromatin particle situated either centrally or to one side Stained preparations may show a zone of pennuclear pallor, but vacuolation does not occur As growth continues the differential characters of the male and female gametocytes become more defined, that when fully matured differentiation in stained preparations becomes relatively easy The Lively amoeboid activity of the schizont is never observed in the developing gametocyte which therefore remains round or ovoid throughout the intracorpuscular phase Full matunty is attained in six days The female gametocyte fills the enlarged red cell and measures from 9u to 10p in diameter The cytoplasm stains a dark blue and ·PARASITOLOGY 17 is densely infiltrated with a coarse yellow brown or brownishblack pigment The chromatin is concentrated to form a compact nucleus situated peripherally, and as already observed in the young forms, frequently shows a pale or colourless perinuclear zone-the **zone of caryolymph " The male gametocyte remains smaller than the fernale, so that it never quite fills the enlarged red cell. For this reason Schuffoer's dots may be demonstrable It bas an ovoid shape and measures from 71 to 8g in its longest diameter The cytoplasm stains a faint blue or slate grey and contains abundant pigment in the form of fine rodiets or granules The nucleus consists in a loose reticular aggregation of chromatin granules distributed over a fairly wide area in the centre zone of the parasite It should be noted that the rich pigment content of the gametocytes renders their recognition possible in unstained preparations when the active Brownian movement of the granules can be seen to best advantage by means of dark ground illumination PLASMODIUM OVALE (Stephens, 1922) PI ovale bears a general resemblance to PI malariae except that the infected red cell is often elongated or oval in outline with a ragged margin, while the trophozoites are either round or oval In stained preparations the ring forms of Pl ovale stain a deep blue with a prominent chromatın dot while even in this early phase numerous Schuflaer's dots can be demonstrated in the infected ted cell From the ring stage the parasite matures without exhibiting any of the lively amoeboid activity of the P/ war The schizont develops as a compact rounded or oval body which stains a deep blue and exhibits a tendency to assume band forms When nuclear division occurs the chromatin which stains a decp red or violet is distnbuted irregularly throughout the cytoplasm together with fine grains of light brown pigment When segmentation is complete the schizont contains from six to ten merozoites-usualy eight The schizogony cycle occupies 48 hours and takes place within the penpberal circulation A charactenstic feature of the parasitised red cell in Pl orale ·18 MALARIA infections is the early appearance of prominent Schuſſner's dots These dots appear much earlier than in Pl war infections where they are seldom observed at the "ring" stage At the same time the red cell enlarges slightly, becomes progressively decolourised and assumes an oval shape with a ragged margin at one pole The gametocytes of PI ovale are compact rounded bodies beanog a close resemblance to Pl malariae, but occupying an oval shaped red cell in which Schuffner's dots are readily demonstrable. Differentiation from Pl wax, however, is not always easy PLASMODIUM MALARIAE (Laveran, 1881) Synonyms Haemamoeba laseranı var quartana (Labbe, 1894) Pl golgı (Sambon, 1902) The young ring forms occupy about one third of the diameter of a normal red cell, and measure from 24 to 2 544 in diameter Intra corpuscular growth is relatively slow and at the same time there is At all stages of development the parasite shows a tendency to assume the form of a band which crosses the full extent of the red cell, but does not necessarily lie in the long axis of the smear In these band forms the chromatin usually lies dear one margin The schizont slowly enlarges and may for a short time contain a vacuole, but whatever shape the plasmodium assumes, the nucleus is invariably situated near the edge Pigment gradually develops in the form of a fine golden yellow granular material which accumulates on the margin directly opposite the nucleus, more especially in the case of the band forms The schizont has a characteristically compact appearance, and when mature fills or practically fills the red cell which is neither decolourised nor enlarged. Before the onset of nuclear division, the pigment, which by now has accumulated in considerable quantity, is distributed more diffusely throughout the cytoplasm as well as in the marginal zone Nuclear division leads to the formation of eight to 12 merozoites ·19 PARASITOLOGY symmetrically arranged around a loose mass of centrally placed Pigment granules The asexual cycle occupies 72 hours with schizogony occurring in the peripheral circulation The Parasitised Red Blood Cells in Pi malanae Infections The red corpuscles are neither enlarged nor decolourised but may even appear smaller than neighbourng nob-parasitised cells Very rarely and only after intensive staining a form of stippling known as "Ziemann's stuppling" can be demonstrated in the form of scattered dots which, though resembling Schuffner's dots, are usually finer and fainter Since the stippling is not seen in the course of routine staiping, the red cells in Pl malariae infections may be said to contain no diagnostic stigmata Gametocytes The sexual forms are rounded in appearance with a large chromatin mass situated centrally The fully developed macrogametocyte fills the red cell and shows a compact darkly staining nucleus situated peripherally in a cytoplasm which stains dark blue and in which basophilic granules appear The cytoplasm also contains aggregates of a light coloured Pigment The microgametocytes are usually present in low concentration in the peripheral blood Apart from being slightly smaller they stain more lightly than the female gametocytes, due to the fact that the chromatın is less concentrated and is frequently distributed in the form of an equatorial band The pigment, though plentiful, is of a finer texture than in the female parasite The gametocytes grow slowly, and in the absence of nuclear division, may be difficult to distinguish from developing schizonts PLASMODIUM FALCIPARUM (Welch, 1897) Synonyms The main synonyms include Oscillaria malariae (Laveran, 1881, pro parte) Haemamoeba praecox (Grassi and Feletu, 1890) Haemamoeba immaculatum (Grassi and Feletti, 1890) Laverania malariae (Grassi and Fclitu, 1890) Haemamoeba malariae praecox (Grassi and Feletti, 1892) ·20 MALARIA Plasmodium malariae praecox (Labbe, 1899) Plasmodium praecox (Blanchard, 1900) The earliest asexual forms demonstrable in the peripheral blood take the form of minute rings measuring about I 5u in diameter or about one sixth the diameter of a red cell or even less They are the smallest and finest of all the ring forms, and are easily distorted Ia smear preparations The nucleus consists of a single circular granule of chromatin situated on or within the rim of cytoplasm which encloses the vacuole Sometimes the granule appears to be situated within the vacuole With the rapid onset of nuclear changes the chromatın takes the form of a straight or slightly curved structure, or it may appear in the form of twin granules placed either contiguously or at opposite poles This binuclear appearance is a frequent finding in all infections with Pl falciparum Another highly characteristic feature of Pl falciparum infections is the occurrence of multiple infections of the red cells together with the tendency for the parasite to be silhouetted against the cell margin (appliqué or accolé forms) The delicate rings gradually increase in size and give rise to what is sometimes referred to as the signet ring appearance These forms measure up to 4p in diameter and are richer in cytoplasm with a well defined chromatin granule (or granules) which may project beyond the cell margin or may be within its substance In addition to the signet ring appearance, more amoeboid forms may be encountered in which traces of pigment may be demonstrable But some 18 to 24 hours after their appearance the rings disappear from the peripheral blood and only under conditions of exceptional gravity are the more mature developing stages encountered in the peripheral circulation On leaving the peripheral circulation the parasites become solid, non vacuolated bodies with the pigment aggregated into a single round mass, while the chromatın is loosely distributed in contra distinction to the single compact chromatin granule of the other plasmodial species during early schizogony The parasite continues to grow until it occupies about two thirds of the un enlarged red cell, when nuclear division recurs with the formation of from eight to 32 merozoites The whole process of schizogony, which begins in the penpheral ·PARASITOLOGY 21 circulation and is completed within the capillanes of the internal organs, occupies about 48 hours The Parasitised Red Blood Cells in P1 falciparum Infections, The red cells do not enfarge, but 10 Giemsa stained preparations they frequently acquire a purplish tinge, and when deeply stained showa coarse stippling This stippling takes the form of a few coarse, irregularly shaped red dots, rings or loops, or may appear as a chromatın-coloured ning enclosing the parasite or demarcating the red cell margin These intracorpuscular deposits are known as Maurer's or Stephen's and Christopher's dots, and in view of their extreme rarity in quartan infections they are regarded as characteristic of infections with Pl falciparum The phenomenon of auto-agglutination is frequently observed in infected red cells, and there is also a tendency for these cells to adhere to the capillary endothelium of the internal organs This latter observation is believed to offer at least partial explanation of the occurrence of schizogony within the capillary system of the internal organs As will be seen below, the gametocytes assume an elongated crescent shape, and in so doing stretch the red corpuscle in such a way that it may appear as a dark red capsule surrounding the parasite, or at other times as a delicate bow-shaped line curving across the concavity of the crescent In such circumstances extensive decolourisation of the red cell has taken place Gametocytes The gametocytes of Pl falciparum assume a characteristic crescentic shape and are commonly referred to as crescents Initially they appear in the peripheral circulation as small, compact non vacuolated bodies which gradually elongate and take on mately 124 by 2 to 3 Morphological variants are frequently encountered, such as straight forms with tapering extremities or short stumpy forms The female gametocytes are characteristically crescentic in outline with a cytoplasm which stains a dark blue The chromatın is collected into a centrally placed mass and is closely invested by the coarse Pigment granules ·22 MALARIA The male gametocytes have a stumpy or oval appearance and the cytoplasm stains more lightly The chromatin is distnbuted over a wider area while the dark brown pigment is scattered throughout the cytoplasm in the form of coarse granules or rodlets It should be noted that during the collection of blood samples the gametocytes may assume a globular shape This morphological change has never been observed as an intravascular phenomenon ·CHAPTER THREE PATHOLOGY AND MORBID ANATOMY CLINICAL PATHOLOGY HAEMATOLOGICAL FINDINGS THE RED BLOOD CELLS The intracorpuscular distribution of the plasmodium leads to des truction of the infected red cells at the termination of schizogony, and at the same time cells that have been damaged by the malatia toxins are removed from the circulation by the phagocytic activity of the reticulo-endothelial system In this way an anaemia of the baemolytic type is induced The degree of anaenua will be determined by a variety of factors such as the severity of the plasmodial infec. fron, the actual species parasite concerned in the attack, the pre-existing state of the blood, the resources of the erythropoietic marrow, and so on For these several reasons a wide range in haematological values is encountered both in acute and in chronic malaria The lowest counts are usually found in Association with subtertian infections, but in spite of this it may be stated that severe anaema is not a feature of acute malaria in previously healthy Europeans the red cell count may fall to between 4 5 and 4 million cells per cubic millimetre following an acute attack of malaria, but it is certainly not common to find a count of less than 3 million The observation has also been made that the red cell count may begin to fall before the onset of the clinical paroxysmas There is an associated fall in the hacdioglobin values, so that a colour Index of 0 9 may be regarded as an average finding ch 20 - Teu Cu Iudy be seen in the more chronic types of plasmodial infec tion giant semulunarshadow cells (the "corps en demilune" of the Sergents) are frequently seen as pale crescent shaped shadows 43 ·24 MALARIA They take ongin in the decolourised red cells which become enlarged and vacuolated, and subsequently break up to form semilunar shadows when blood smears are being prepared Cabot's rings and Jolly bodies are also frequently seen and may give rise to diag nostic errors if the possibility of their existence is overlooked Punctate basophilia occurs to a variable extent and is characterised by the presence of fine uniform basophilic granules which are difficult of recognition in over stained preparations When severe grades of anaemia are induced by massive or re current plasmodial infections, it is not uncommon to encounter Qucleated red cells (normoblasts) in the peripheral blood On rare occasions the resultant anaemia conforms to the megalocytic type, but compared with pernicious anaemia, megalocytes are relatively few in the peripheral blood, hence it is doubtful if a widespread megaloblastic reaction occurs in the marrow The presence of polychromatic cells in the blood has already been mentioned, and in vitally stained preparations the polychromatic cell has been identified with the reticulocyte The behaviour of the reticulocyte in malanal infections has been closely studied, and it is now generally accepted that a slight but persistent increase in the reticulocytes occurs in the presence of a chronic plasmodial infection More significant, however, is the steady rise in the reticulocyte counts which attends the employment of plasmocidal drugs This rise is directly proportional to the degrec of anaemia existing immediately prior to treatment, and attains maximal values between the sixth and tenth days following the onset of treatment It follows, therefore, that in these special circumstances a study of the reticulocyte count may supply indirect evidence of a chronic malarial infection The actual counts obtained during the treatment course may range from 3% to 30% THE WHITE BLOOD CELLS The white cells in malaria vary with the phase of the attack and the chronicity of the infection so that variable and apparently divergent figures are frequently quoted both for the total and for the differential whute cell counts At the outset of a malarial paroxysm a rise occurs in the total count, but as the attack develops and passes through its various ·25 PATHOLOGY AND MORBID ANATOMY phases the count falls to normal and subnormal values during the apyretic interval During the febrile phase the neutrophile percentage may remain within the normality range or a definite increase may be found Dunng the afebrile phase, however, the haemogram shows a charactcristic reduction in neutrophiles with an associated screase in lymphocytes and monocytes When the monocytes are studied throughout a series of malarial parorysms it can be shown that their percentage varies inversely as the temperature that is to say the monocyte percentage rises as the temperature falls The monocyte in malaria appears as a large non granular cell rich in cytoplasmı which may contain a few vacuoles and which stains a pale greyish blue The nucleus is situated eccentrically, is oval or round in outline, and stains a pale violet colour The chromatın is arranged in strands which are characteristically thickened at the points of intersection Occasionally a very large form of monocyte is encountered in whick the bucleus is banded, lobulated or horse shoe shaped Such forms are frequently referred to as the transitional cells of Ehrlich In healthy normal blood the monocytes constitute from 4 %to 8% of the total white count, whereas in chronic or latent malaria the percentage may increase to between 15% and 30% or over Where a monocytosis of this order is encountered in association with an appropriate clinical picture, it undoubtedly affords valuable presumptive evidence of malaria in those cases in which for one reason or another the plasmodium cannot be demonstrated in the peripheral blood On the other hand, it is important to bear in mind that there may be a complete absence of monocytosis in those who have been repeatedly exposed to plasmodial infections over a long period of time, as in the case of Afacans in an endemic area Again, monocytosis may arise in conditions Other than malaria such as kala azar, amoebiasis glandular fever, nickettsiosis, and so on, hence the importance of assessing the differential white cell count in conjunction with clinical data However, a study of the white cell count in malaria supports the view that a tecurring febrle illness characterised by splenomegaly, leucopenia and a relative monocytosis of 10% or over may be ·26 MALARIA regarded as presumptive evidence of a plasmodial infection and justifies a course of anti malarial therapy THE PIGMENTED LEUCOCYTE A highly characteristic but relatively infrequent finding in blood smears prepared from malarial patients is the pigmented leucocyte The leucocyte is usually a monocyte containing small clumps of malarial pigment within its cytoplasm Less commonly the pigment containing cell is a neutrophile polymorph The presence of these pigment-containing cells implies that the patient is suffering from or has recently suffered from an acute attack of malaria THROMBOCYTES The chief significance of the thrombocytes in relation to malarial diagnosis lies in the possibility of their being mistaken for plas modia When stained by Glemsa's method they appear as small reddish violet bodies which may be round or oval 10 outline, so that when overlying a red cell they may simulate the malaria parasite but closer study will usually reveal the absence of a chromatin particle and of vacuolation in the cytoplasm During an acute malarial paroxysm the thrombocytes are reduced in number, but usually increase during the afebrile phase in conjunction with a leucopenic state of the white cell count BIOCHEMISTRY OF THE BLOOD IN MALARIA HAEMOGLOBINAEMIA The demonstration of haemoglobinaemia in plasmodial infections presents many technical difficulties and so far no significant increase in the haemoglobin content of the plasma has been demonstrated even in the presence of massive infections On the other hand Schumm s test for methaemalbumin is usually positive, thereby providing indirect evidence of intravascular haemolysis The absence of haemoglobinaemia can probably be explained by the steady absorption or conversion of haemoglobin by the plas modium during schizogony, together with the swift phagocytosis of all infected or damaged red corpuscles by the cells of the reticulo ·PATHOLOGY AND MORBIDANATOMY 27 endothelial system In this way haemoglobin released during sporuta tion must necessarily elude detection by current analytical methods BILIRUBIN CONTENT OF THE PLASMA The occurrence of excessive blood destruction in acute malaria leads to a demonstrable measure of hyperbilirubinaemia in most but not in all cases of the disease In terms of van den Bergh units (taking 1 0 as the upper limit of normality) haematogenous bilirubin may range from 30 to 60 units with an average finding of 1 45 to 1 75 units These unit figures bear no direct relationship to the degree of anaemia prevailing in any given case but are determined essentially by the rate of blood destruction The direct or biphasic van den Bergh reaction is not obtained in malaria except in the presence of some complicating factor such as cholelithiasis Thus yn conformity with the intravascular haemolysis conditioned by plasmodial infection the qualitative van den Bergh test is positive in the indirect phase only ALKALI RESERVE Conflicting data have been obtained in acute malarial attacks but when the CO2- combining power of the plasma is determined by the van Slyke technique no significant decrease in the alkalı reserve can be demonstrated in uncomplicated cases of acute malaria BLOOD UREA Any slight rise in the urea content of the plasma in acute malana is of a temporary nature and merely reflects the state of enhanced katabolism that normally accompanies any acute febrile condition Permanent mitrogen retention would be consistent with permanent renal damage which rarely occurs in plasmodial infections except in quartan infections BLOOD CHOLESTEROL If the normality values for tropical patients be accepted as ranging between 120 and 200 mg per 100 cc then it will usually be found that hypocholesterolaemia predomipates in acutc malana The fall in the cholesterol values coincides with the appearance of the ·28 MALARIA plasmodium in the peripheral circulations and persists until specific therapy is well established It is of interest to note that the rise in cholesterol values parallels the rise in the reticulocytes BLOOD SUGAR Most observers record a normal blood sugar range in acute malaria, although there have been occasions in which a rise has occurred SERUM PROTEIN FRACTIONS There is a general reduction in the total serum protein, largely on account of a fall in serum albumin Euglobulin is increased to twice the normal values and pseudoglobulin is reduced Lloyd and Paul have demonstrated a rise in the serum globulin. albumin ratio from the normal index of 0 66 to just below unity SEDIMENTATION RATE This is usually increased in acute malaria (Landeiro) THE URINE The urine is usually concentrated and highly coloured during the febrile paroxysm There is a characteristic increase in urobiln and urobilinogen (which is gradually converted to urobilin on standing) A trace of albumin is commonly found, but clears up in the presence of efficient antı malarial treatment On the other hand, a heavy albuminuria may develop and may constitute evidence of an acute parenchymatous nephntis In such cases the aetiological factor is almost invariably an untreated quartan infection, and it will usually be found that resolution of the renal lesion follows upon the elimination of the plasmodial infection Very occasionally a transient glycosuria is noted in acute malaria IMMUNITY IN MALARIA The complex subject of immunity in malaria has been materially advanced by the study of the disease in the treatment of neurosyphilis and by the detailed immunological studies of Taliaferro and of Sinton on avian and simjan malaria ·PATHOLOGY AND MORBID ANATOMY 29 It is now evident that immunity in malaria may be either patural or acquired NATURAL IMMUNITY The existence of a natural immunity to malaria is frequently encountered in groups of neuro syphilitics undergoing malana therapy In these circumstances the patient may prove refractory to infection or, if infected, the resultant febrile paroxysms are extremely mild In the same way clinical practice affords instances of a natural resistance to malarial infections amongst non immune groups Apart from variations in the severity of the febrile paroxysms, the incubation period may be protracted up to as much as six months Again, the existence of a natural immunity may be revealed by the presence of an occasional plasmodium in the peripheral blood with an entirely negative clinical picture When this occurs in the absence of any history of clinical malaria, it is logical to explain the phenomenon in terms of natural immunity This immunity, however, may be restricted to one plasmodial species or even to one plasmodal strain ACQUIRED IMMUNITY Acquired immunity is met within areas of endemic malaria where it develops in response to repeated plasmodial infection In these circumstances recurrent pyrexia together with splenomegaly persists for a period of two or three years, and in due course a high degree of immunity is built up and will continue at a high level so long as the individual remains in the hyper-endemic area A high infantile mortality rate is exacted as the price of this immunity in any given community The usual measure of its existence is the spleen rate which remains more or less constant in any community with a high rate of tolerance, but the labile nature of the immunity is shown by the fact that any interruption in the active transmission of infection may at some later datc be followed by a major epidemic and a high mortality rate The building up of a defence mechanism against na is a two fold phenomenon based on a proliferation and heightened activity of the macrophages or reticulo-endothelial elements together with the elaboration of specific anubodies which are probably of the nature of opsonins ·30 MALARIA The cellular changes occur mainly in the spleen, liver and bone marrow where the circulation is comparatively sluggish, thereby facilitating phagocytosis Consequently it can be shown that in the presence of recurrent malaria the macrophage content of these organs is enormously increased whilst the phagocytic activity of the cells is heightened to an amazing degree The source of the macro phages is still uncertain, but it is probable that they are derived from cells of the lymphocyte series It may be argued that if immunity to malaria were based on the cellular responses already described, a general resistance to hetero logous plasmodial species and strains would result, but it has been shown that unmodified infections may develop in the presence of an hypertrophed macrophage system that is to say, a highly hyper trophied macrophage system is a relatively ineffective defence against malana in the absence of specific sensitization of the macrophages It becomes evident, therefore, that immunity to malaria is of a highly specific character which must necessarily be conditioned by specific antibodies, probably of the nature of opsonins It is believed that these antibodies are elaborated in organs such as the liver and spleen and for this reason their presence in the per pheral blood has never been successfully demonstrated PATHOLOGY The pathological changes encountered in both acute and chronic malaria are largely conditioned by the destruction of the red blood cells on the one hand, and by a vigorous proliferation of the macro phages (reticulo-endothelial cells) on the other The reduction in the red cell content of the blood that accom panies all plasmodial infections leads in time to a compensatory hypertrophy of the red bone marrow, whilst the proliferation of the macror ges is reflected in various organs but more especially in the spleen and placenta At the same time the pigmentary deposits which accompany the intracorpuscular development of the plasmodium constitute a characteristic feature of the histopathology of those organs in which active phagocytosis predominates, whilst various pon specific changes are brought about by the intense malarial toxaemia ·PATHOLOGY AND MORBID ANATOMY 31 THE SPLEEV In acute malaria the spleen is moderately enlarged, is soft in consistency and is usually a slaty grey or black colour The distended state of the organ is reflected in the tense capsule which encloses a soſt, almost diffluent, dark pulp, and is easily torn at post mortem examination Histologically the splenic pulp is diffusely congested and oedematous and shows scattered foci of haemorrhage in the case of subtertian infections the splenic sinuses commonly contain vast numbers of sporulating plasmodia Malarial pigment (haemozon) is readily demonstrated in the form of small compact deposits which have been taken up by the splenic macrophages It will usually be noted that if pigmentation of the malpighian corpuscles occurs at all it does so to a very limited extent A somewhat different picture is presented by the spleen in recurrent malaria It is usually considerably enlarged, and in some cases may occupy the whole of the left hypochondrium On the other hand, in long standing chronic malaria with stabilisation of the fibrotic changes within the splenic substance, only moderate degrees of splenomegaly are observed The organ is firm and hyperplastic while the capsule is usually thickened and at the same time shows patches of chronic perisplenitis and areas of perisplenic adhesions The pigmentary content of the spleen in such circumstances is variable, but is always densest after a recently imposed acute attack Consequently the colour of the spleen may vary from a slate grey to black On section, the splenic pulp is seen to be traversed by prominent white trabeculae, and on histological examination a significant hyperplasia of the macrophage cells is usually evident The mal pighian corpuscles are usually small and atrophied In this state the spleen is easily ruptured THE LIVER In acute malaria the liver is moderately enlarged and deeply congested The colour, however, will be determined by the extent of the pig mentary deposits and the associated degenerative changes in the hepauc parenchyma, but is commonly plum-coloured when first exposed ·32 MALARIA In subtertian infections the sinusoids are distended with heavy concentrations of parasitized red cells together with actively phago cytic macrophages In these circumstances the pressure may be such as to set up atrophic changes in the adjoining trabeculae In this way small foci of parenchymatous degeneration are brought about Alternatively thrombotic reactions in the radicles of the portal vein in the presence of massive infections may cause areas of necrosis Focal haemorrhages, fatty degeneration and other toxic changes may all be demonstrated in acute infections malarial pigment appears within the macrophages of the hepatic sinusoids when not contained in the parasitised red cells, whereas in chronic infections the pigment is usually distributed throughout the fibrous tissue of the portal tracts It is never found within the parenchymatous cells of the liver While a fine intercellular fibrosis may possibly be ascnbed to chronic malaria it is unlikely that gross hepatic cirrhosis ever occurs THE BONE MARROW The continued blood destruction in malaria leads to a compensatory hyperplasia of the red bone marrow which gradually encroaches and may to a variable extent replace the yellow marrow of the long bones The new erythroblastic tissue is essentially normoblastic in type although excessive stimulation may lead to a relative increase in megaloblasts The extent of the normoblastic hypertrophy is directly related to the duration and severity of blood destruction, hence the degree of reticulation that follows elimination of the plasmodial infection constitutes a measure of erythroblastic hypertrophy A striking feature of all marrow preparations in malaria is the great increase that takes place in the concentration of macrophages and the vigour and scope of their phagocytic activities They can readily be demonstrated containing plasmodia, pigment, parasitised and non parasitised cells and sometimes even leucocytes In this way the bone marrow constitutes an important defence mechanism in malaria THE KIDNEYS A certain amount of transient renal damage occurs in the WAYSC of an acute malarial paroxysm as in any other acute febrile condition ·PATHOLOGY AND MORBID ANATOMY 33 In some instances, however, more especially in subtertian and in quartan infections, lesions of a more permanent nature may be produced In severe subtertian infections the renal capillanes may be blocked with masses of parasitised red cells, thereby giving rise to small renal infarcts At the same time glomerular congestion, oedema of the interstitial tissue, desquamation of the tabular epithelium with focal haemorrhages and areas of necrosis may all occur in varying degrees of intensity Pigment granules appear within the vascular endothelium and in the interstitial tissue In rare instances an acute haemorrhagic nephritis has been pre cipitated by an acute subtertian infection Nephrosis is especially common in relation to foci of quartan malaria, where it frequently becomes a feature of long standing chronic infections Although Gigliol considers that a condition analogous to chromic Bright's disease may be conditioned by chronic quartan infection, it appears to be more usual for the albuminuria to clear up after elimination of the plasmodial infection THE SUPRARENAL GLANDS Microscopically there is an evident loss of the normal yellow colour due to the disappearance of the fat and lipoid content of the gland Histologically a relative or complete absence of cell chromaffin occurs in many cases whilst other changes met with include focal haemorrhages, capillary thrombosis and focal tissue necrosis These acute lesions arc especially associated with subtertian infections, where it is believed they give rise to a state of vasomotor asthenia THE PANCREAS A condition of acute haemorrhagic pancreatitis has been described in relation to acute subtertuan malaria, but the more usual changes consist in the concentration of plasmodi3 within the pancreatic capillaries with the production of focal haemorrhages or thromboses In rare instances lesions of the islet tissue haic been described and have been held responsible for the occurrence of a diabetic syndrome in malaria Normally, however, the degree of pancreatic involvement in plasmodial infections is insufficient to give rise to any regional clinical features ·34 MALARIA THE GASTRO-INTESTINAL TRACT A state of diffuse gastritis is usually demonstrable in acute malana, together with focal haemorrhages or capillary thrombosis Thesc changes are especially common in acute subtertian infections when local tissue anoxia occurs as a sequel to the overcrowding of the gastro-intestinal capillaries by masses of sporulating plasmodia When similar lesions develop in the large bowel, an acute diarrhoeic or dysenteric state may arise with blood and mucus in the stools In such circumstances, however, the more usual bacterial or parasitic causes of dysentery must be carefully eliminated Finally, a pigmented atrophy of the small bowel has been described by Rogers, in which the bowel mucosa assumes a dark colour while fibrous tissue replacement of the normal bowel structure occurs THE HEART Severe myocardial changes are infrequent in all save severe subtertian infections either in the acute or chronic phase When widespread sporulation occurs within the cardiac capillaries, a state of diffuse fatty change is induced which renders the myocardium pale and flabby In the same way thrombosis of the capil laries may arise with the formation of foci of cardiac ischaemia Punctate haemorrhages, either subpericardial or subendocardial, are readily demonstrable in severe acute malaria, when they are usually associated with focal haemorrhages in the substance of the myocardium These myocardial changes in acute malana are reflected in a state of arterial hypotension with a tendency to acute myocardial failure in the presence of massive infections THE LUNGS Pulmonary changes are usually restricted to an acute congestion of the alveolar capillaries together with a variable degree of congestion of the bronchial mucosa In some instances small intra alveolar haemorrhages may occur, usually in the lower lobes posteriorly where small areas of oedema or alveolar collapse may be found There is no convincing evidence, however, that plasmodial infections bring about extensive poeumonic ·PATHOLOGY AND MORBID ANATOMY 35 consolidation of the fung, even though plasmodla tay sometimes be noted within the alveolar capillanes THE BRAIN AND MENINGES Demonstrable changes in the central nervous system are mainly confined to subtertian infections of great seventy which clinical evidence of cerebral involvement has been observed While a true malarial meningitis has been described (Laveran), the usual meningeal change consists in diffuse congestion and ocdema induced by a massive plasmodial infection of the meningeal capıllaries The cerebral lesions, on the other hand, are the product of two primary factors 1 Mechanical blocking of the cerebral capillaries by masses of parasitised red cells, leading to (a) thrombosis, and (6) haemorrhage, and 2 Malarial toxaemia The blockage of the cerebral capillanes may constitute the origin of the so-called 'matarial granulomata' which are distributed mainly in the subcortical zones Interference with the capillary Circulation leads to the formation of a small necrotic area around which small haemorrhages develop, and in due course the disintegrated cerebral substance is replaced by neuroglial elements which constitute the histological basis of a 'malarial granuloma" Cerebral granulomata have also been observed in the general paralytics treated by means of induced malana In these circum Stances the lesions consist in a focalised proliferation of the regional macrophage cells Ia the presence of severe toxaemia, the tissue changes encountered are non specific in character, and for the most part consist in numerous punctate haemorrhages scattered throughout the brain substance in conjunction with degenerative changes in the nerve cells THE PLACENTA A histological study of the placenta in malanta reveals two character- Istic features 1 A heavy concentration of plasmodia in the intervillous spaces 2 A remarkable accumulation of actively phagocytic macrophages ·34 MALARIA THE GASTRO-INTESTINAL TRACT A state of diffuse gastritis is usually demonstrable in acute malaria, together with focal haemorrhages or capillary thrombosis These changes are especially common in acute subtertian infections when local tissue anoxia occurs as a sequel to the overcrowding of the gastro intestinal capillaries by masses of sporulating plasmodia When similar lesions develop in the large bowel, an acute diarrhoeic or dysenteric state may arise with blood and mucus in the stools In such circumstances, however, the more usual bacterial or parasitic causes of dysentery must be carefully eliminated Finally, a pigmented atrophy of the small bowel has been described by Rogers, in which the bowel mucosa assumes a dark colour while fibrous tissue replacement of the normal bowel structure occurs THE HEART Severe myocardial changes are infrequent in all save severe subtertian infections either in the acute or chronic phase When widespread sporulation occurs within the cardiac capillaries, a state of diffuse fatty change is induced which renders the myocardium pale and flabby In the same way thrombosis of the capillaries may arise with the formation of foci of cardiac ischaemia Punctate haemorrhages, either subpericardial or subendocardial, are readily demonstrable in severe acute malaria, when they are usually associated with focal haemorrhages in the substance of the myocardium These myocardial changes in acute malaria are reflected in a state of arterial hypotension with a tendency to acute myocardial failure in the presence of massive infections THE LUNGS Pulmonary changes are usually restricted to an acute congestion the alveolar capıllaries together with a variable degree of congestion of the bronchial mucosa In some instances small satra-alveolar haemorrhages may occur, usually in the lower lobes posteriorly where small areas of oedema or alveolar collapse may be found There is to conmong evidence, however, that plasmodial infections bring about extensive pneumonic ·PATHOLOGY AND MORBID ANATOMY 35 consolidation of the lung, esen though plasmodua may sometimes be noted within the alveolar capıllanes THE BRAN AND MENINGES Demonstrable changes in the central nervous system are mainly confined to subtertian infections of great seventy in which clinical evidence of cerebral involvement has been observed. While a true malarial meningitis has been described (Laveran), the usual meningeal change consists in diffuse congestion and oedema induced by a masse plasmodial infection of the meningeal capillaries The cerebral lesions, on the other hand, are the product of two primary factors 1 Mechanical blocking of the cerebral capillaries by masses of parasitised red cells, leading to (a) thrombosis, and (b) haemorrhage, and 2 Malarial toraemia The blockage of the cerebral capillaries may constitute the origin of the so-called "malarial granulomata " which are distributed mainly in the subcortical zones Interference with the capillary circu- Iation leads to the formation of a small necrotic area around wbich small haemorrhages develop, and in due course the disintegrated cerebral substance is replaced by neurogital elements which constitute the histological basis of a "malanal granuloma" Cerebral granulomata have also been observed in the general paralytics treated by means of induced malaria In thesc circumstances the lesions consist in a localised probferation of the regional macrophage cells In the presence of severe toxacmia, the tissue changes encountered are non specific in character, and for the most part consist in oumer. ous punctate haercorrhages scattered throughout the brain substance 10 conjuncuon with degenerative changes in the serve cells THE PLACENTA A histological study of the placenta in malaria reveals two characteristic features ! A heavy concentration of plasmodia in the intervillous spaces. 2 A remarkable accumulation of actively phagocytic macrophages ·36 MALARIA The features are seen to best advantage 1a infections with Pl falcıparum The intervıllous spaces are crowded with compact trophozoites and maturing schizonts, many of the red corpuscles show multiple infections, but ring forms are scanty and gametocytes are rarely or never found The heavy concentration of parasites in this situation is probably due to the sluggish circulation in the sinuses where reproduction by schizogony goes on steadily with only a small percentage of parasites reaching the general maternal circulation For this reason plasmodia will always be more readily demonstrated in placental smears than in blood films prepared from the peripheral blood The macrophage response to plasmodial infections is also strikingly seen in relation to the intervallous spaces, which in normal circumstances contain nothing but blood In established or relapsing malaria many of these spaces are virtually obliterated by masses of macrophage cells and in some cases they may be so numerous as to jeopard use the foetal circulation It has even been suggested that abortions 10 malaria may sometimes be due to physical rather than to toxaemic causes The vigorous phagocytosis that takes place in the placenta is largely the monopoly of the macrophages, although there are other cells that may play a minor role Histologically, therefore, the placenta clearly shares in the defence against malaria, and it is thought that in hyperendemic areas it may be indirectly responsible for the low parasite rate in infants up to two months ·CHAPTER FOUR CLINICAL FEATURES When acute malaria is regarded from the strictly clinical view point, it tends to fall into two categories In the one, the paroxysms are sharp and severe but grave complications are rarely or never en countered, whereas in the other, not only is the febrile paroxysm severe, but there is an ever present risk of serious complications acising Hence on clinical grounds acute malaria may be grouped as (1) acute benign malaria, and (2) acute malignant malaria From the parasitological view point the benign forms are due mainly to P/ wax, PI ovale and Pl malariae, while the malignant forms are associated with infections with Pl falciparum The clinical features of malaria may be still further modified (a) in terms of a frequently recurring attack, and (b) in terms of racial immunity In both circumstances a state of chronic malaria is induced which, however, varies as between the European and zodigenous races The following clinical classification will be adopted in the present discussion Malana in the European 1 Acute benign malaria 2 Acute malignant malaria 3 Chronic maları3 Mfalaria in the African 1 Acute malaria 2 Chronic malari3 MALARIA IN THE EUROPEAN 1 ACUTE BENGN MALARIA This variety of acute malana constitutes the clinical expression of infection with Pl war, Pl orale or Pl malariae The febrile paroxysos, though severe enough in themselves, are seldom accompanied ST ·38 MALARIA by the onset of pernicious symptoms Exceptions to this rule on doubtedly occur, as, for example in the case of the cerebral attacks induced by Pl war infections in Macedonia during the last war, but such exceptions are rare Again while renal complications may arise in the course of an uncontrolled quartan infection, the tendency for the senal lesions to resolve in the presence of adequate anti plasmodial therapy renders it unnecessary to regard this as a "malignant" complication Finally, in Pl ovale infections the febrile paroxysms are usually shorter and milder than in the other forms, so that far reaching con stitutional disorders are relatively infrequent in this type of infection INCUBATION PERIOD The average incubation period in pl max and Pl orale infections varies from 10 to 20 days and represents the interval that elapses between the snoculation of the sporozoites by the mosquito and the first febrile paroxysm This period may be very materially modified either by quinine or mepacrine prophylaxis or by some measure of natural immunity For these various reasons the incubation period, or perhaps more strictly the period of latency, may last for several months or even extend over a year This phenomenon is especially common in Plinar malaria in temperate zones where infections acquired in the summer or autumn months may not become cinically apparent until the following spring In Pl malariae infections the average incubation period ranges from 12 to 21 days, but it is especially noteworthy that the parasite may remain dormant for years PRODROMAL SYMPTOMS The actual malarial paroxysm is sometimes preceded by certain premonitory symptoms which include a feeling of tiredness in association with recurrent chilly sensations, headache, anoreua, pains in the bones, stiffness in the neck muscles and fugitive fluctuations in temperature THE FEBRILE PAROXYSM The actual febrile paroxysm sets up abruptly with a violent rigor and the subjective sensation of intense cold This marks the beginning ·CLINICAL FEATURES 39 of the cold or shivering stage which may last from 30 minutes up to about two hours The patient looks pinched and cold and the whole body shivers violently and uncontrollably, so that his teeth chatter audibly, his speech becomes jerky and uncertain and he vainly attempts to get warm by piling on blankets and surrounding himself with hot water bottles, even though the weather be sweltering hot Even at this stage of the attack the temperature has begun to risc and may soon reach 100° to 102° F Frontal headache sets in early in the attack and may be severe Sometimes it culminates in and 18 partially relieved by a sharp epistaus Nausea and vomiting are common and in some cases the paroxysm may be ioitiated by violent vomiting The pulse is rapid and usually of low tension Then in due course the clinical picture changes abruptly as the cold stage merges rapidly into the hot or febrile stage During the transition stage the patient may experience a fleeting sense of well being, but soon becomes so hot and uncomfortable that he rapidly casts aside his bed clothes The skin is now hot and dry the face flushed and the headache increases in intensity as the temperature rises to about 105° F Myalgic pains develop all over the body, but arc especially acute in the lumbar region The vomiting becomes more urgent as the pyreval phase develops, the respirations quicken and the pulse is now full and bounding The tongue becomes dry and ſurred and the conjunctivae congested Meanwhile the patient feels and looks acutely ill, and there is frequently a tendency to delirium at the height of the pyreval phase After a period of from one to six hours the dry burning pyreu, gives way to the stage of sweating The break in the pyreuia is heralded by the appearance of a few beads of sweat on the forehead near the hair margin, and then very soon the whole body is drenched in a soaking sweat which continues to pour from the body for the next two to four hours The temperature falls by Crisis with the onset of profuse sweating, and a feeling of relief and comfort replaces the misery and distress of the dry pyreria As the sneating passes off, the patient rapidly recovers his sense of well being and may cither doze off into a restful sleep or may enjoy a light meal ·38 MALARIA by the onset of pernicious symptoms Exceptions to this rule uodoubtedly occur, as, for example, in the case of the cerebral attacks induced by Pl mar infections in Macedonia during the last war, but such exceptions are rare Again, while renal complications may arise in the course of an uncontrolled quartan infection, the tendency for the renal lesions to resolve in the presence of adequate anti plasmodial therapy renders It unnecessary to regard this as a "malignant" complication Finally, in Pl osale infections the febrile paroxysms are usually shorter and milder than in the other forms, so that far reaching constitutional disorders are relatively infrequent in this type of infection INCUBATION PERIOD The average incubation period in Pl war and Pl osale infections vanes from 10 to 20 days and represents the interval that elapses between the inoculation of the sporozoites by the mosquito and the first febrile paroxysm This period may be very materially modified either by quinine or mepacrine prophylaxis or by some measure of natural immunity For these various reasons the incubation penod, or perhaps more strictly the period of latency, may last for several months or even extend over a year This phenomenon is especially common in PP max malarsa 10 temperate zones, where infections acquired in the summer or autumn months may not become clinically apparent until the following spring la Pl malariae infections the average incubation period ranges from 12 to 21 days, but it is especially noteworthy that the parasite may remain dormant for years PRODRONAL SYMPTONS The actual malarial paroxysm is sometimes preceded by certain premonitory symptoms which include a feeling of tiredness in association with recurrent chilly sensations, headache, anoreua, pains in the bones, stiffness in the neck muscles and fugtc fluctuations in temperature THE FEBRILE PAROXYSM The actual febrile paroxysm sets in abruptly with a violent ngor and the subjective sensation of intense cold This marks the beginning ·CLINICAL FEATURES 39 of the cold or shiveriog stage which may last from 30 minutes up to about two hours The patient looks pinched and cold and the whole body shuyers violently and uncontrollably, so that his teeth chatter audibly, his speech becomes jerky and uncertain and he vainly attempts to get warm by piling on blankets and surrounding himself with hot water bottles, even though the weather be sweltening hot Even at this stage of the attack the temperature has begun to nise and may soon reach 100° to 102° F Frontal beadache sets in early in the attack and may be severe Sometimes it culminates in and is partially relieved by a sharp epista vis Nausea and vomiting are common and in some cases the paroxysm may be initiated by violent vomiting The pulse is rapid and usually of low tension Then in due course the clinical picture changes abruptly as the cold stage merges rapidly into the hot or febrile stage During the transition stage the patient may experience a fleeting sense of wellbeing, but soon becomes so hat and uncomfortable that he rapidly casts aside his bed clothes The skin is now hot and dry, the face flushed, and the headache increases in intensity as the temperature rises to about 105° F Myalgic pains develop all over the body, but are especially acute 10 the lumbar region The vomiting becomes more urgent as the pyrcual phase develops, the respirations quicken and the pulse is now full and bounding The tongue becomes dry and furred and the conjunctivac congested Meanwhile the patient feels and looks acutely ill, and there is frequently a tendency to delirium at the height of the pyrexial phase After a period of from one to six hours the dry burning pyrexia gives way to the stage of sweating The break in the pytcva 15 heralded by the appearance of a few beads of sweat on the forehead near the hair margin, and then very soon the whole body is drenched in a soaking sweat shich continues to pour from the body for the nert two to four hours The temperature falls by crisis with the onset of profuse sweating, and a feeling of relief and comfort replaces the misery and distress of the dry pyrex13 As the sweating passes off, the patient rapidly recovers his sense of well being and may either dozc off into a restful slecp or may enjoy a light meal ·40 MALARIA The whole attack will have occupied from six to ten hours Physical signs during the paroxysm During the initial stage of shivering the skin remains cold and blue," but with the onset of the hot stage it becomes hot, dry and flushed, and continues thus until the pyrexia breaks, when it rapidly cools in the presence of the profuse perspiration Very occasionally an erythematous rash develops during the hot stage, when it most commonly appears as a roseolar eruption As the attack develops, a slight ictenc tinge appears in the skin and conjunctivae, but is more apparent in recurrent malarial attacks than in a primary paroxysm The eyes are usually bright and alert even though conjunctival congestion pre vails The pulse is rapid and of low tension initially, but becomes full and bounding as the fever stage develops The blood pressure may fall to low levels at the beginning of an attack, but in the ordinary sthenic type of malarial paroxysoi it approximates to normal values during the hot stage Signs of a mild bronchitis are frequently apparent, although the persistent dry cough may be the result of a mild tracheitis, in which case no particular chest signs will be noted The tongue soon becomes coated and the bowels may either be loose or constipated The spleen undergoes progressive enlargement during an attack but may not be palpable until after a series of paroxysms have occurred, nevertheless, some degree of splenic tendemess can practically always be elicited on deep and steady palpation in the left hypochondrum, even in the absence of demonstrable splenomegaly A moderate degree of hepatomegaly frequently occurs, but even though this feature may not be particularly noticeable, hepatic tenderness is almost invariably present Labial herpes commonly develop early in an attack of acute benign malana, but the mouth, face and cars may also be involved During the cold stage the urine is pale in colour and of low specific gravity, but with the onset of the hot phase it becomes concentrated and highly pigmented by reason of the high urobilin content Febnle albuminuria is the rule, while in quartan infections a true malarial nephritis may supervene The cytological and chemical changes that take place in the blood during an acute attack of malaria have already been described ·CLINICAL FEATURES COURSE OF THE DISEASE THE TEMPERATURE CHARTS The "classical" temperature chart in acute benign malaria is characterised by a recurring series of pyrexial paroxysms consisting of an abrupt nise, a sharp peak reaching 1040 10 1059 F, a steep fall and a narrow base In the case of Pl mar and Pl orale infections, the febrle paroxysm recurs every third day, and in the case of Pl malanae infections every fourth day Between the paroxysms the temperatust remains at normal or subnormal levels, and in the absence of treatment a sharp recurring pyrexial reaction will persist with either a tcrtian or a quartan penodicity over a period varying from a few days to onc or two months The "classical" temperature is not always observed in benign malana Thus a quotidian type of fever may be encountered during the first few days of the attack, to be followed later by a true tertan or quartan periodicity Sometimes the opposite state of affairs obtains The explanation lies in the existence of two generations of plasmodia developing in series and so precipitating a quoudian ſever The disappearance of one generation in the course of an attack or its tendency to assert itself later in the attack wll be the determining factor in the timing of a true teruan or quartan penodicity The pyrcual paroxysm tends to occur with greatest frequency between midnight and noon except in inſections with P1 orale, when the nse of temperature takes place in the late afternoon or at night UNTRLATED BENIGN MALARIA and is apparently maintained at an effective level so long as the plasmodium persists as a subclincal infection There is, however, an ever present tendency to relapse, especially in the presence of some debilitating factor such as chull, fatigue, intercurrent disease and so on On the other hand, a relapse may occur in the absence of any demonstrable precipitating cause Clinically a relapse consists in a sharp febrile paroxysm which presents all the features of a primary atrach, although usually in lesser degree The penodicity, either tertian or quartan, 13 main.

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·CLINICAL FEATURES yalgic pains which attain their greatest intensity in the lumbar gion Vomiting sets in early in the attack and may be of such seventy s to give risc ta great prostration and exhaustion Delirium is common at the height of the attack The pyrexial phase is usually prolonged from 12 to 18 hours, but he subdivision of the attack into relatively short, sharply defined old, hot and sweating stages is rarely observed The patient remains a a state of hot, dry pyrexia throughout the attack and only obtains elief from his distress with the onset of sweaung As in the benign orms, the sweating is profuse and is an essential prelude to a brief pyretal period Physical Features of the Attack The skin remains hot, dry and vurning throughout the paroxysm, while the face looks flushed and he eyes congested The patient is very obviously acutely ill The Yrostration which is usually associated with acute malignant malana s always sharply accentuated by severe and persistent vomiting ience in such circumstances the blood pressure remains low and he pulse soft and rapid A flecting exanthem may be observed at the onset of the attack sually of the roscolar type, but in some very acute infections may assume a purpuric character tween midni and sclerae show a slight but easily recognised icteric e rise of tem in the attack, but this becomes more defined as the itinue The Pyrex 7 mc mca ad is appier also becomes swollen and tender The urine, which is Podsum pred sn volume, is highly coloured, heavily charged with jer presel and usually contains a trace of albumin butatio COURSE OF THE DISEASE TEMPERATURE 00 On Emonstrpcraturc cunes in Pl falciparum infection reveal an essen- Clinica luotidian periodicity in which the temperature rises less Esents ly than in the benign forms The stage of pyrex13 is more izlesser ted and is charactersed by the presence of remissions before 11 1 ·4+ MALARIA the final fall to normality In these circumstances a four hourly temperature chart shows several sharp peaks in the course of a single febrile paroxysm The apyrexial interval is brief However, it must be emphasised that a wide range of temperatures is encountered in acute malignant malaria In some cases the temperature rises in a step ladder fashion as in the opening phases of typhoid fever, at other times an approuimately tertian periodicity is observed, or the paroxysms may run into one another with the production of a remittent fever It is therefore wiser to be without any rigid concept of the pyrexial pattern in acute malignant malaria THE UNTREATED ATTACK OF MALIGNANT MALARIA A study of the natural history of untreated (or imperfectly treated) malignant malaria at once reveals its potentialities for grave and often rapidly fatal complications, and it is in this important respect that acute malignant malaria differs so fundamentally from the benign form The biological background to this differentiation is to be found in the sporulation of PI falciparum within the capillanes of the internal organs such as the brain, heart and adrenals, thereby inducing serious and even fatal structural or functional damage It follows, therefore, that in the absence of treatment a heavy infec tion with Pl falciparum will almost inevitably move rapidly to a fatal termination, probably within the space of 24 hours, certainly within a few days In less massive infections in which the body is given time to mobilise its cellular and humoral defences, the temperature gradually subsides after a week or two of daily paroxysms and an afebrile period lasting perhaps 10 to 14 days will ensue From now on relapses occur, and although they may be milder than the original attack it is always possible for the course of the disease to be abruptly interrupted by fatal involvement of a vital organ More often, however, the relapses grow less frequent and less severe until after about 12 to 18 months they may disappear altogether PERNICIOUS FORMS OF ACUJE MALJGNANT MALARIA It has already been mentioned that the intensive sporulation of Pl falciparum within the capillaries of the internal organs constitutes ·CLINICAL FEATURES 45 the main biological basis of the grave clinical variants encountered in acute malignant malaria. This phenomenon, peculiar to PI folciparum, leads to extensive capillary blockage which, together with the associated toxaemia must necessarily have serious clinical implications when vital organs such as the brain, heart or adrenals constitute the main focus of infection These grave or pernicious forms are encountered most frequently amongst Europeans and especially amongst non immunes such as newcomers or young children in an area of endemic or hyperendemic malaria in which Pl falciparum constitutes the dominant plasmodial species On the other hand Europeans who have already suffered from malignant malaria may succumb to one of the pernicious forms, either in the presence of a massive infection or by reason of inefficient therapy A state of general debility induced by precxisting disease or malnutrition and the absence of a spleen will still further pre-dispose the European patient to the grave forms of malignant malaria As will be seen later, pernicious forms are rarely encountered in the African, except in the case of African infants in whom cerebral malaria is a frequent cause of death The curical manifestations of the pernicious forms are many and varied, and on analysis it will usually be found that the clinical pattern in any given case is determined by two primary factors - 1 The anatomical site of the massive internal sporulation and 2 The profound toxacmia occurring in association with the developmental cycle Consequently, apart from exhibiting characteristic features, the patient is always acutely ill in the pernicious forms of acutc maligoant malaria It is undoubtedly the case that this typc of malaria may simulate almost any acute febrile disease, whether medical or surgical hence apart from being conversant with the common clinical variants of pernicious malaria, it is highly important to exclude the disease in any acute febrile allness in which the diagnosis may be in doubt This is especially important in surgical practice The pernicious forms of malignant malana fall into fairly well defined clinical types, the man varieties of which will be discussed in scries ·46 MALARIA ALGID FORMS The damataant chacal feature ia algid malaria is the overall state of collapse, and as this is the one form of malana in which there may be no rise of temperature, it must always be kept in mind if a serious diagnostic error is to be avoided The patient is pallid and collapsed with a thin thready pulse and a cold clammy skin The breathing is shallow and rapid and weakness is extreme, while nausea and vomiting with cramps in the leg muscles commonly occur The temperature of the body surface is always subnormal, but the rectal and oral temperature may be in the neigh bourhood of 990 or 100° F The clinical state is clearly a reflection of the intense vasomotor collapse which prevails and is thought to imply a massive infiltration of the adrenal glands by sporulating plasmodia A similar chacal picture results from a heavy invasion of the myocardium In these circumstances the temperature falls and rest lessness sets in Dull pain over the precordium is usually complained of, and on examination the heart sounds will be soft and remote while some variety of arrhythmia may set in The cardiovascular changes in algid malaria may be compared with those encountered in diphtheria in that the symptom complet may be conditioned by 1 Paresis of the peripheral vasomotor system, or 2 Direct involvement of the myocardium Whatever the precise pathological basis of the algid state in malaria may be, the situation is an extremely dangerous one with a tendency to terminate fatally unless recognised promptly and treated ex peditiously CEREBRAL FORMS (CEREBRAL MALARIA) Cerebral malaria constitutes one of the gravest forms of acute malignant malaria It occurs most frequently in infants and young children, both African and European, and in non-immune newcomers to any area in which Pl falciparum infections predominate An attack is precipitated by the sudden massing of sporulating plasmodia within the capillary vessels of the brain and meninges The pathological reactions that occur in these circumstances have already been described, and on the basis of these reactions ·47 CLINICAL FEATURES the clinical features of cerebral malaria may be grouped in two categones 1 The meningeal form in which the infection is concentrated in the meningeal vessels, and 2 The encephalitic forms in which sporulation occurs mainly within the brain substance, either in a focal or in a diffuse manner It must be appreciated, however, that cases presenting evidence of simultancous involvement of both the meninges and brain substance are also met with, but as a rule in any given case either the meningeal or the encephaltic element predominates MENINGEAL FORMS These forms are not encountered very frequently, but when they do occur they present all the clinical features of meningeal imtation with intense headache, pains in the back and legs, vomiting and stiffness of the neck muscles with some degree of head retraction The temperature is practically always continuously high, remain ing between 1040 and 105° F On lumbar puncture a considerable increase in the pressure of the cerebrospinal fluid will be found, but it is unusual to find any chemical or cytological abnormalities Very occasionally a mild pleocytosis may occur Since the meningeal reaction is of an acute nature accompanied by severe toxaemia, the tendency is for fatal coma to set in rapidly in the absence of speedy and effective therapy ENCEPHALITIC FORMS Cerebral malaria etpresses itself with greatest frequency in one of the encephalıtıc forms, but in view of the fortutous distnbution of the plasmodia within the brain substance a wide range of clinical lynes is encountered General Syndromes When the plasmodia are distributed diffusely throughout the brain substance or when a state of profound totaem13 prevails, a fairly well-defined symptom complet sets in consisting essentially of an ingravescent coma The patient becomes drowsy, apathetic and non-cooperative Ile resents being examined and usually lies with his eyes closed, either because of the drowsiness or on account of photophobia There is ·48 MALARIA a generalised slackness of the muscles with diminution or loss of reflexes The temperature rises to 101° or 105° F, but rarely exceeds 106°F As the attack develops a general restlessness sets 10 often accom panied by the onset of jerky movements of the limb and face muscles In children convulsions frequently occur at this stage, either as an isolated event or as a series of attacks Mental confusion is now apparent as the patient lapses into a state of semi-consciousness Finally, complete loss of consciousness follows, when the patient may be either delirious or in a deep coma Muscle twitchings frequently persist into this stage, with or without generalised convulsions, and in the event of a spread of the infection to the meninges, head retraction with spasm of the trunk muscles may be superimposed on the orginal clinical picture As the attack moves swiftly to its close, the twitchings and convulsions cease, and a state of deep coma prevails At this stage nothing can avert a fatal issue The march of symptoms may take place with alarming rapidity, so that a child taken ill in the morning may be dead by evening In fulminating cases of this type the attack sets in with a violent convulsion or series of convulsions to be fulminating cases of cerebral malana a delay of more than 12 hours from the onset of the attack to the start of treatment will seriously prejudice the patient's chances of recovery In other cases the encephalitic syndrome is dominated by a state of cerebral excitation The degree of excitement varies from excited, ceaseless talk to one of extreme restlessness and even mania A high temperature persists throughout the attack In the absence of specific therapy, excitement gives way to coma and death 2 Local Syndromes When plasmodial invasion of the brain substance evolves as a focal rather thap a diffuse lesion, a wide range of local neurological syndromes may be encountered These include demiplegia, monoplegias, aphasma, diplopua, signs of bulbar paralysis, Jacksoduan epilepsy and so on On rare occasions involvement of the spinal cord occurs with the production of para-

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·48 MALARIA a generalised slackness of the muscles with diminution or loss of reflexes The temperature rises to 104° or 1050 F, but rarely exceeds 106° F As the attack develops a general restlessness sets in, often accom panied by the onset of jerky movements of the limb and face muscles In children convulsions frequently occur at this stage, either as an isolated event or as a series of attacks Mental confusion is now apparent as the patient lapses into a state of semi-consciousness Finally, complete loss of consciousness follows, when the patient may be either delirious or in a deep coma Muscle twitchings frequently persist into this stage, with or without generalised convulsions, and in the event of a spread of the infection to the meninges, head retraction with spasm of the trunk muscles may be superimposed on the onginal clinical picture As the attack moves swiftly to its close, the twitchings and convulsions cease, and a state of deep coma prevails At thus stage nothing can avert a fatal issue The march of symptoms may take place with alarming rapidity, so that a child taken ill in the morning may be dead by evening In fulminating cases of this type the attack sets in with a violent convulsion or series of convulsions, to be followed almost immediately by the onset of a deep and fatal coma It is more usual, however, for the attack to evolve more gradually over a period of 24 to 48 hours, but even in what may be called non fulminating cases of cerebral malaria a delay of more than 12 hours from the onset of the attack to the start of treatment will seriously prejudice the patient's chances of recovery In other cases the encephalitic syndrome is dominated by a state of cerebral excitation The degree of excitement vanes from excited, ceaseless talk to one of extreme restlessness and even mania. A high temperature persists throughout the attack In the absence of specific therapy, excitement gives way to coma and death 2 Local Syndromes When plasmodial invasion of the brain substance evolves as a focal rather than a diffuse lesion, a wide range of local neurological syndromes may be encountered These include hemiplegia, monoplegias, aphasia, diplopia, signs of bulbar paralysis, Jacksonian epilepsy and so on On rare occasions involvement of the spinal cord occurs with the production of para- ·CLINICAL FEATURES 31 rashes are only found in the presence of a profound malarial tovacmia In some cases, and for the same reason, profuse bleeding takes place from the nose, mouth, gastro-intestinal tract, lungs or genitourinary tract 3 CHRONIC MALARIA In the presence of repeated or inadequately treated attacks of malaria a clinical state is gradually evolved, to which the term chronic malaria is applied The period of time required for the production of this chronic state is necessanly a variable quantity, but even in the presence of constant reinfection a period of about a twelve-month will usually clapse before chronicity may be said to have established itself The condition implies the persistence of the plasmodium in the tissues of the human host not in a state of commensalısm but as a truc pathogen, whose activities have been modified by virtue of prior activation of the immunity mechanism both in respect of its humoral and cellular components in this way the clinical responses to the plasmodial infection no longer assume the acute overtly febrile character of a primary infection, but are "damped down" to the extent of giving rise to a complex syndrome which may be said to represent the sum of a modified malaria toracmia and a progressive malanal anaemia While the syndrome of chronic malana may be summansed in terms of this apparently simple formula, its complexity is such that it has become a favourite clinical scrap-heap for conditions difficult of accurate identification The basic critena on which the diagnosis of chronic malana must depend are dealt with later in the section on diagnosis, meanwhile the main clinical features of the condition will be discussed The clinical pattern varies considerably in degrec, hence the following descnption may be said to represent the findings in a typical case of chronic malaria in the European, but it must be remembered that mild clinical variants erist and may prove more difficult of recognition CLINICAL FEATURES The salient feature of chronic malaria 15 a state of general debility which is characterised by persistent lassitude in both a physical ·S2 MALARIA and a psychological sense That is to say, the patient is always tired so that fus capacity for any sustained mental or physical effort is grievously impaired Consequently he shows an increasing tendency to shark the daily routine Then too the discovery that he can no longer concentrate nor remember things easily exercises a depressant effect on his general outlook and gives rise to a weariness of the spint and even a sense of hopeless frustration Anorexia is common and is frequently accompanied by feelings of nausea and even a tendency to vomit occasionally, especially immediately after a meal This feature is probably related to the state of chronic catarrhal gastritis which supervenes on the associated achlorhydna or hypochlorhydria The poor appetite leads in turn to loss of weight, so that is a well-established chronic malaria the patient is constantly underweight to the extent of emaciation in the more severe cases Constipation is usual, but a spunous diarrhoea may occur from time to time, either by reason of the defective gastric secretion or on account of recurrent infections of the vulnerable gastro-intestine Headache is a frequent complaint and is often of maximal inteasity ja the lower occipital region It may also show a tendency to develop at a more or less regular time each day, and is seldom relieved except to a limited extent by ordinary headache tablets, whereas antimalarial therapy is invariably effective In some cases the headache assumes the characteristics of a hemicrania A state of vasomotor asthenia is common and is characterised by arterial hypotension in association with poor myocardial tone, shortness of breath even on moderate exertion, and in some cases hypostatic oedema may be found Sweating with subjective shivering sensations occur from time to time, and may even show a rough periodicity Apart from general dulling of the mental processes already mentioned, certain psychotic disorders may arise in previously pormal individuals A bright, cheerful personality may give way to general apathy and depression, which merges eventually into a state of melancholia There may even be attacks of disorientation or clouding of consciousDess after which Ibe pabent may have no Tecollection of hes activities Alternatively curious aberrations of conduct may occur in which the patient becomes unexpectedly untable and unreliable ·CLINICAL FEATURES 33 During these phases he is often untruthful in a petty stupid way and may abandon any sense of responsibility in regard to the execution of his routine duties In some cases the presenting symptoms may be of a neurological character such as neunts of a cranial or a peripheral nerve, cg, the fifth cranial nerve or the sciatic nerve In such cases the neuntic symptoms tend to appear and disappear in an irregularly periodic manner Finally, the granulomatous and sclerotic lesions which follow in the wake of cerebral malaria may be responsible for a variety of chronic neurological syndromes ranging from disturbances of speech to spastic paraplegia PHYSICAL SIGNS In a well-established case of chronic malaria the patient looks tired and thin, and may even have a cachectic appearance The skin and sclerae show a distinct yellowish unge which accentuates still more his sickly appearance The spleen is usually palpable but the degree of enlargement varies from case to case The spleen is not usually tender, but a dragging pain or ache in the left hypochondrium is often enough complained of, and can probably be explained in terms of a chronic perisplenitis or chropic perisplenic adhesions The spleen in chronic malaria is always firm, even hard, and is easily traumatised A moderate degree of hepatomegaly usually develops but no textural changes occur The blood pressure tends to be low in conformity with the general vasomotor hypotension, whilst the cardiac tone is poor Penodic attacks of tachycardia are frequently encountered, and in the presence of severe anaemia hacmic murmurs are heard The haematological changes have alrcady been discussed, but may be summarised by saying anaemia of varying degree is encountered The urine is usually highly coloured, largely on account of an increase of urobilin ercretion, whilst traces of albumin are common When the temperature is talen systematically, a low continuous feser is the rule with periodic rises to 100° F or so, lasting only an hour or two at the most. These periodic febnle reactions are usually accompanied by sensations of cold or an attack of sucating, or by cracerbation of the presenting clinical feature ·54 MALARIA Finally, in the case of chronic malaria becoming established in a European child from an early age, a state of infantilism may be induced MALARIA IN THE AFRICAN From infancy onwards the African of the kraals is exposed to repeated plasmodial infection The mortality rate is necessarily high, but those who survive gradually build up a considerable measure of immunity despite such debilitating factors as malnutrition, polyparasitism and general poverty Except in very young children malania is therefore a relatively mild disease in the African, so that clinically it may be grouped as 1 Acute malaria, 2 Chronic malaria This grouping pplies, whatever the causal parasite, which in any given case can be determined by blood smear examination only Very occasionally, in the case of Pl falciparum infections, pernicious complications occur, either on account of a massive infection or as a sequel to depression of the premunity in the presence of general debility ACUTE MALARIA This is predominantly a disease of infants and young children in whom premunition has not yet been established Consequently the clinical features are essentially the same as those encountered in the non immune European and have already been described Furthermore, in the case of Pl falciparum infections, pernicious complications, including cerebral malaria, occur and account for a considerable proportion of deaths amongst African infants In older children and adults living in an endemic area, the gradual acquisition of a relative immunity to plasmodial infections becomes evident in the clinical features of the malarial attack The rise of temperature which heralds the onset of a paroxysm is seldom accompanied by shivering, and the actual rise of temperature is less and of shorter duration than in the European Headache and diffuse myalgic pains, though not severe, are common features of an attack, but both vomiting and sweating are usually absent A troublesome cough is not uncommon ·CLINICAL FEATURES 55 Complications are practically unknown in the immune African except in quartan malana, in which malarial nephrius not infrequently occurs Very rarely an acute malarial attack is complicated by the onset of cerebral malana, or even blackwater fever Finally, all cases, whether complicated or not, show a rapid response to quinine or mepactine therapy, although spontaneous recovery will usually take place in the absence of plasmocidal drugs CHROVIC MALARIA In the majority of cases chronic malaria exists in the African without giving nse to any significant features, even though plasmodia may be present in blood smears Thus the stigmata of ill health so well portrayed in the European in like circumstances are strikingly absent in the African Splenomegaly 13 almost always present in chronic malaria, but vanes ir degree In some cases the spleen extends almost to the umbilicus whilst in others it may be barely palpable It is hard but not tender, although the presence of arcas of perispicnitis is frequently associated with a dragging ache or pain in the left hypochondrium A low grade continuous pyrexa is sometimes observed, but us scidom sufficiently pronounced to interfere with the patient s daily routine Finally, in highly malarious areas, the blood deteriorates to a greater or less degree, so that anaemia, usually in the form of a moderate hypochromic type, becomes apparent Occasionally an anacmis of the macrocytic type is encountered, but it may be difficult to ascribe this to malaria alonc The anaemic state is usually associated with anorexia and loss of weight, although never to the sime extent as in the European

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·DIAGNOSIS 57 paroxysm, which may evolve through fairly sharply defined phases, terminating in a drenching sweat or, in the absence of such phases, headache, vomiting and backache constitute the presenting clinical features which, after some hours, are relieved by a heavy sweat These features, together with a tender and enlarging spleen, constitute presumptive evidence of an acute malarial attack, and in the absence of laboratory facilities, would justify a course of antimalarial therapy Wherever possible the diagnosis should be confirmed by direct examination of blood smears for plasmodia By this means not only is the diagnosis confirmed, but the species of the infecting plasmodia is identified, and if we accept the clinical classification of acute malaria into benign and malignant forms it is clear that species identification is of more than academic interest It may be said to afford information of considerable prognostic value both in an immediate and in a more remote sense THE EXAMINATION OF BLOOD SMEARS The preparation and examination of blood smears constitutes the basic procedure in the laboratory diagnosis of malaria, but it must never be forgotten that plasmodia will not always be demonstrable in every case of acute malaria Wherever sporulation is occurring freely in the peripheral blood no difficulty will be experienced in demonstrating the parasites, but in the presence of chemoprophylaxis with quinine or mepacrinc or when, as in the case of Pl falciparum infections, sporulation takes place within the capillary system of the internal organs, parasites may be extremely difficult to find in smcar preparations, even during a febrile paroxysm Consequently, to enhance the accuracy of smear diagnosis in malaria, & series of preparations should be made at regular intervals, say, cvery two or four hours With these limitations in mind the clinician should never be afraid to base his diagnosis of acute malaria on an accurate assess ment of the clinical findings and so avoid unnecessary and even dangerous delay in the application of vigorous therapeutic measures PREPARATION OF THE BLOOD SVEARS Blood for the preparation of smears is most conveniently obtained from the dorsal surface of the terminal phalant of the thumb just ·$8 MALARIA behind the nail The site is cleansed with spirit and after drying is pricked with a sharp triangular needle or with a thangular splinter of glass To prepare a thin smear, a blob of blood is expressed and a clean glass slide brought gently into contact with it so that a portion of the drop is transferred to one end of the slide This slide is then laid flat and held between the finger and thumb of the left hand A second or spreader slide is brought into contact with the drop of blood in such a way that the blood spreads rapidly along the junction between the two slides The spreader slide, held at an angle of about 20°, is then pushed steadily and rapidly over the surface of the first slide, thereby leaving behind a uniform layer of blood The blood film so formed is then dried in air A thun smear prepared in this way should be a single cell layer thick and should peather extend to the edges of the slide nor reach its distal end As soon as the smear has been prepared the patient's dame or initials should be written in the blood at one end of the film, which. if it cannot be stained immediately, must be suitably protected against flies, ants and cockroaches Thick films should always be prepared at the same time ezther on the same slide, but preferably on a separate one A large drop of blood is placed on the centre of the glass slide, and using a stout it tends to flake off the slide during drying so long as the hands of a watch can be seen through the drying drop the density of the preparation may be regarded as satisfactory It is then dried in air, preferably under a petri dish and duly labelled FLXATION AND STAINING OF BLOOD FILLES Thin Blood Films The Gremsa staining technique constitutes a re- Lable and satisfactory procedure in the examination of blood films for plasmodia The films are fixed for two or three minutes 10 methyl alcohol either by immersion in a specially constructed trough or by laying the glass slide film side upwards across two parallel glass ·DIAGNOSIS $9 rods (fixed on plasticine across a sink) and flooding it with the fixative Absolute or 96% alcohol may also be used, when a penod of 10 to 15 minutes must be allowed for fixation The fixative is drained off and the si de dried air. Thereafter at is flooded with Giemsa's solution which has been diluted in the ratio of one drop of the stain to 1 0 cc of buffer solution consisting of 1 G potassium dihydrogen phosphate and 2 G sodium phosphate (tribasıc) in 1,000 cc of distilled water Staining is allowed to continue for half to three-quarters of an hour, after which the slide is held horizontally and the stain floated off by flooding with tap water The stained film is then rapidly dried in air or by placing between clean blotting paper, and is then ready to be examined Where rapid examination of a blood film is necessary a more concentrated form of Giemsa s stain may be employed by mixing one part of Gıemsa's with five parts of water and staining from five to ten minutes The stain is washed off as described, and the film dried on clean blotting paper When Giemsa's stain is employed the nuclear chromatın of the plasmodium appears a bright red with the cytoplasm staining bloc or pink The nuclei of the white cells stain dark violet, the platelets a light violet red, with the red cells a salmon pink colour Thick Film Preparations Thick films are not fixed so that they may be stained and dehacmoglobinued simultaneously After drying, the slide is placed on its edge in a trough containing Gremsa's solution (diluted in the ratio of one drop of the stain to 1 0cc of buffer solution) and left standing for 30 minutes The watery nature of the staining solution rapidly releases the haemoglobin in the preparation The slide is then dipped in a beaker of tap water and gently moved to and fro to remove all traces of stain Tinally, it is dried in dir Vanous staining techniques have been cvolved with the object of obtaining better contrasts in the stained preparations with a minimum of distortion of leucocytes and protozoa The most successful of these techniques is undoubtedly Field s thick film method, the details of which are as follows Preparanon of the Stain ·60 MALARIA 500 cc Two isotonic solutions are employed with a pH adjusted to 66 Solution (1) Methylene blue 08G Azure blue OSG Disodium hydrogen phosphate (anhydrous) 50G Potassium dihydrogen phosphate (anhy drous) 6 25 G Distilled water 500 cc Solution (2) Eosin 106 Disodium hydrogen phosphate (anyhdrous) SOG Potassium dihydrogen phosphate (aphy drous) 6 25 G Distilled water These solutions are allowed to stand for 24 hours and are then filtered They keep for several weeks but may require filtering from time to time to remove any scum or any sediment that might inter fere with the staining results The appearance of a greenish tunge in the eosin solution is an indication that it should be discarded Technique and Staining (1) Dip the film in Solution (1) for one second (2) Rinse immediately in clear tap water until stain ceases to flow from the film (3) Dip in Solution (2) for one second (4) Rinse in clear water (5) Drain and dry by placing vertically against a staining rack Considerable experience is necessary for the accurate interpretation of thick smear preparations, whatever the staiping technique may be In the case of young trophozoites the ring stage is seldom preserved but the cytoplasm stains fairly deeply except in Pl falciparum infections when the cytoplasm of the young rings may be very difficult to discern The chromatın appears smaller and more faintly stained than in Giemsa stained thin film preparations Schizonts are deeply stained and therefore casily distingusbed although it is sometimes difficult to distinguish the larger forms from gametocytes except in Pl falciparum infections The chromatin ·DIAGNOSIS 61 is not well defined but the cytoplasm stains decply and the pigment is usually in evidence Species differentiation is therefore a matter of some difficulty, but a consideration of such features as the size and concentration of the parasites, the texture and arrangement of the pigment, the number of merozoites in the maturc schizonts and so on, will assist in species diagnosis It will usually be found more profitable to differentiate the species in thin rather than in thick smear preparations CHRONIC MALARIA From the clinical viewpoint malaria in the European both in its latent and chronic forms commonly appears as an obscure illness in which a state of general debility possibly accompanied by spleno megaly constitutes the presenting clinical feature In the case of the immune African a chronic or latent infection 13 usually devoid of clinical features although a palpable spicen may provide a clue to the malarial background While the patient's clinical history together with the knowledge that he resides in a known malarious area will provide presumptive evidence of chronic malaria, it is always desirable to obtain a modicum of laboratory support for the diagnosis otherwise there is a temptation to group all manner of chronic ills in this category Unfortunately the scarcity of plasmodia in the peripheral circulation renders it necessary to have recourse to indirect procedures in the laboratory diagnosis of chronic or latent malaria HAEMATOLOGICAL FINDI\GS 1 Thick Blood Smear Preparations Thick smears should always be studied on the grounds that it may be possible to demonstrate cither a trophozoite or perhaps a gametocyte 2 The Pigmented Leucocyte While the bulk of the malanal pigment is taken up by the macrophages of the spicen, luser and bone marrow, a certain amount 18 sometimes to be found in the leucocytos of the peripheral blood Especially in the large hyaline monocytes but sometimes in the neutrophiles ·62 MALARIA The pigment appears in the form of coarse yellowish brown or brownish black granulations and is more likely to be found in thick smear preparations than in thin films The presence of this intracellular pigment in the peripheral blood always means that the patient is infected with the malaria parasite 3 The Differential White Cell Count The behaviour of the white blood cells in malaria has already been discussed While it cannot be claimed that an absolutely specific haemogram obtains in chronic malaria there are certain findings which, when taken along with the clinical data, may be said to provide presumptive evidence of the disease The total white cell count usually falls within or just below the normal range, while the percentage of monocytes increases to 15% or over Thus the position may be summarised by saying that where chronic or latent malaria is suspected on clinical grounds a leucopenia with a relative monocytosis provides valuable support to the diagnosis and would justify a course of anti malarial therapy SEROLOGICAL FINDINGS 1 Henry s Serological Test Henry's reaction is based on the assumption that flocculation of melanın or of iron albuminate will be brought about in the presence of the serum antı bodies that develop in response to malarial pig ment The reaction, however, is probably related to the increase in the plasma cuglobulin which flocculates in the presence of distilled water Flocculation may also be induced by lowenng the pH of the plasma hence the reaction conot be regarded as a specific serological test, but the fugh incidence of flocculation occurring 10 plasmodial infections supports the diagnostic validity of the test in the laboratory investigation of the disease The test is positive in the majority of cases of acute and chronic malaria and although a small percentage of positives may be obtained in non malarial conditions recent improvements in technique appear to have reduced the margin of error to between 1 and 3% The chief value of the test lies in the investigation of chronic or latent malaria, but it is clearly of little more than academic interest in acute malaria ·DIAGNOSIS 63 Where a patient is suspected of suffering from chronic malana but in whom no parasites can be found, a negative Henry's reaction may be said to cxclude the disease A positive reaction on the other hand supports a diagnosis of malana Melano flocculation In carrying out the melano-flocculation test melanın is obtained by scraping the choroid from or-eyes and suspending the gelatinous matenal in two volumes of doubly-distilled water The suspension is ground in a mortar containing fine sand and thereafter a little formaldehyde (1 in 200 solution) is added After filtration through loosely packed glass wool the filtrate is centrifuged for eight minutes at 4000 revolutions and is then stored under sterile conditions for a month in a refrigerator The melanın is then standardised in a senes of dilutions to which 02 cc of test serum is added and after two and a quarter hours incubation at 37°C, a final reading is made after a further 15 minutes at room temperature Only definite large floccules are regarded as positive Ferro-flocculation The test consists in adding 02 cc of serum to cach of a series of test tubes containing respectively 1 in 450 methar fer, 1 in 4 800 iron albuminate, 1 in 6,000 iron albuminate with doubly distilled water as the diluent in cach case The control tubes contain doubly distilled water, 1 in 4 800 iron albuminate and i in 1,000 saline solution The suspensions are kept at 37° C for two and a half hours and then at room temperature for another 30 minutes, after which they 3rc examined for flocculation In a positi\c reaction large floccul are seen Wolff's Modification of Chorine s Technique The scrum to be tested is prepared by collecting 30 cc of venous blood which is placed in a dry centrifuge tube until the clot has formed and loosened It is then placed in a refrigerator overnight, after which the serum is separated and if not clear it is centnfuged A series of tubes is prepared each holding 1 0cc of diluted buffer mittures prepared from Baird & Tatlock s Unnersal Buffer Marture vaning from plI 8 4 to 50 in graduated steps of 0 04 Two drops of test scrum are then added to each tube in the sencs The tubes are shaken and left standing for five minutes before readings are talen ·67 MALARIA The reactions are recorded as opalescent, faint cloudiness, cloudı. ness, and marked cloudiness Normal sera rarely show more than faint cloudiness at pH 7 0 and only an opalescence at 74 Strongly positive malarial sera will show cloudiness or marked cloudiness up to 8 0 or 8 4 or beyond, while weakly positive sera show cloudi. ness from 74 These results closely parallel those obtained from the melanoflocculation test 2 THE ICTERUS INDEX A small but significant rise in the icterus index beyond the normal range of four to seven may lead support to a diagnosis of chronic or latent malaria URINARY FINDINGS Urobilinurla Aa tacrease in the urobulin content of the urine is a characteristic of acute malaria, but it may also be found in latent and chronic forms of the disease depending on the degree of haemo lytic activity underlying the non acute forms The tests designed to detect the urobiun increase include 1 The Spectroscopic Test This test has to be carried out on a fresh specimen of urine which has been acıdified with hydrochloric acid In the presence of an increase of urobilin a characteristic absorption band is seen at the junction of the blue and the green Fresh normal urine fails to show any absorption bands 2 The Schlesinger Test This constitutes a highly specific and reliable test for both urobila and its chromogen urobilinogen Its sensitivity is somewhat impaired in the presence of albumin wbuch absorbs small amounts of the pigment The test consists in mising and then filtering 10 cc of urine with the same volume of a well shaken suspension of 10% zinc acetate in absolute alcohol Equal portions of the filtrate are then transferred to narrow testtubes A few drops of HCl are added to one test tube Both tubes are then observed against a black background with lateral illumination ·DIAGNOSIS 65 A greenish fluorescence indicates a positive urobilin reaction A slight bluish tinge-the Tyndall phenomenon--should be ignored Finally, by the addition of N/10 iodine to each tube any urobilinogen present is converted into urobilin STERNAL PUNCTURE Whilst the cramination of the peripheral blood constitutes an integral part of the laboratory diagnosis of acute malaria, the examination of marrow smears obtained by sternal puncture may provide a valuable accessory procedure in the diagnosis of malaria in the chronic phase or modified by chemoprophylaxis Using a sternal puncture needle or a stout lumbar puncture needle, the sternum is punctured at the level of the second intercostal space at a point which lies just below the angle of Louis The skin over the centre of the sternum is anaesthetised The needle is inserted vertically and pressed firmly through the skin and subcutaneous tissue until the bony corter of the sternum is encountered It is then forced into the bone by means of a to and fro rotatory movement or by gentle Lapping with a small mastoid mallet, and in due course a sudden lessening of resistance indicates that the needle point has reached cancellous tissue The stilette is removed, and from 0 5 to 1 0 cc of marrow fluid aspirated The marrow fluid may be oxatsted, centrifuged and examined within 30 minutes, or preferably thick and thin smears are prepared at once, and after drying are stained by Gtemsa's or Field s techrique Great care, patience and experience are necessary in the accurate interpretation of marrow smears on account of the multiplicity of artefacts encountered These include distorted platelets Howell Jolly bodies lying on a shadowy red corpuscle, basophilic red cells or portions of disintegrated myeloid cells The two features which Assist in the identification of a plasmodium are malarial pigment and a containing red cell In acute febrile malaria, marrow smears appear to have no particular advantage over penpheral blood as a means of diagnosis, but in chronic or latent malaru the chances of demonstrating plas. modua are undoubtedly greater in thick marron smcars provided the criminer is fully conversant with the difficulties of identification ·CHAPTER SIX DIFFERENTIAL DIAGNOSIS ACUTE MALARIA It has already been emphasised that acute malaria may simulate practically any acute febrile illness but in discussing the differential diagnosis it is proposed to deal with the common fevers of the Tropics only A careful clinical history, the history of exposure to infection and the season of the year will provide clues to the possible malarial character of the fever, and in the case of Europeans the exclusion of malaria is a primary necessity in all acute febrile states But since the initial phases of so many fevers have so much in common, it may be exceedingly difficult, on clinical grounds alone, to establish a diagnosis hence the importance of blood smear examination in all febrile ills The following conditions merit careful consideration in the differential diagnosis of acute malaria ACUTE PNEUMONIC CONDITIONS In an acute pneumonic attack the onset is abrupt with an initial rigor, but there is usually pain in the side of the chest together with a dry, restrained cough The breathing is rapid and a sticky blood stained sputum soon appears, while the physical signs of consolida tion rapidly develop in the wake of an area of impaired air entry ENTERIC FEVERS While an attack of enteric fever may set in with an abrupt febrile reaction, there is more commonly a steady rise of temperature which will be unaffected by quinine therapy Headache, drowsiness and a gradual slowing of the pulse soon dominate the clinical picture, while tenderness in the night lower segment of the abdomen is common, with a certain amount of persistent gurgling when this area is paipated The abdominal reflex is absent 66 ·67 DIFFERENTIAL DIAGNOSIS At this early stage of the liness, confirmation is obtained by means of blood culture RELAPSIYO FEVER It may be almost impossible to distinguish between relapsing fever and malaria at the onset of the first febrile parorysm, but the flushed face and congested eyes, together with the photophobia, are more characteristic of relapsing fever than malana However, the only certain means of establishing the diagnosis is by blood smear eraminations during the pyrexial phase In relapsing fever spironemata will be found in the blood THE TYPHUS FEVERS In the tick or mite borne types, a primary eschat with regional lymphangitis and adenitis will indicate the probable nature of the fever, whilst the intense headache, diffuse body pains and later the characteristic rash will distinguish the attack from acute malaria TRYPANOSOMIASIS in acute trypanosomiasis a painless enlargement of the posterior cervical glands (Winterbottom's sign) is a common and valuable sight At the same time a circinate erythematous cruption or the appearance of localısed oedemas of different parts of the body, more especially of the face, legs and feet, will constitute clinical cvidence of the non-malarial character of the infection The diagnosis will test finally with the demonstration of trypanosomes in the peripheral blood or in the juxe from the entarged cervical glands YELLOW FEVER While abortise and incomplete attacks add to the compleuty of the yellow fever syndrome, the salient features of a typical attack include the rapid onset of severe prostration, carly and increasing albuminuns with bradycardia and a gradually deepening icterus Violent fluctuations in temperature, drenching sweats and spicnomegaly are not encountered in yellow fever THE DENGUL-SAND-FLY FEVER GROUP The initial clinical picture in this group of fevers may suggest an acute malarial attack, but the intense headache with pains in ·68 MALARIA the eyes, excruciating pains in the back and joints, and a bradycardia, constitute important clinical clues to the virus nature of the infection Further confirmation is obtained from the blood whuch shows a leucopenia with a relative lymphocytosis and an absence of malaria parasites AMOEBIC HEPATITIS AND AMOEBIC ABSCESS The existence of an amoebic hepatitis gives rise to pain and tenderness over the liver which is usually enlarged The spleen, on the other hand, is not palpable in uncomplicated amoebic hepatitis Blood examinations reveal a neutrophika In amoebic abscess of the liver a more exaggerated clinical picture is obtained, together with heavy sweats, rigors, loss of weight and emaciation There is thus an even closer resemblance to acute malarial attacks, but the presence of hepatic tenderness, the absence of splenomegaly, raising of the right leaf of the diaphragm, with possibly a right basal pleurisy, indicate the probable nature of the ulloess At the same time the blood shows a neutrophilia, and the recurrent rises of temperature fail to respond to quinine therapy grains of HEAT HYPERPYREXIA The acute symptom-complex associated with heat hyperpyrexia is most likely to be confused with cerebral malaria, hence the only satisfactory differential procedure consists in careful examination of blood smears, both thick and thin In the absence of laboratory facilities the only logical procedure to adopt where the two condițions cannot be differentiated with certainty, is to administer 10 quinine (well diluted) intravenously THE DIFFERENTIAL DIAGNOSIS OF THE PERNICIOUS FORMS OF ACUTE MALIGNANT MALARIA Since Pl falciparum infections are capable of giving rise to a massive infection of practically any organ or tissue, it follows that a wide range of grave febnle disorders will be encountered, more especially in the non immune European The clinical grouping of these pernicious forms constitutes the basis of any scheme of differential diagnosis, so that a detailed list of the acute febrile conditions with which malignant malang may be confused becomes necessary ·DIFFERENTIAL DIAGNOSIS 69 It is, therefore, apparent that in the presence of any fulminating fever sa the Tropses, the exclusion of acute malignant malaria should be regarded as an elementary step in the investigation of the primary cause This precaution is especially necessary in the presence of any acute fever in which the presenting features indicate involvement of the central nervous system, abdomen or cardio-vascular system, nor must it be forgotten that malignant malaria may assume an afebrile algd form in which a state of grave collapse dominates the clinical picture So long as the practising physician and surgeon keeps malaria well in mind at all times, dangerous errors of diagnosis will be avoided when dealing with apparent cases of acute meningitis, otius media, heat hyperpyreti3, acute cholecystitus, acute pancreatitis, perforated peptic ulcer, haematemesis, acute bacıllary dysentery and coronary thrombosis It is clearly necessary to observe the greatest precision in the diagnosis of each and every tropical fever and also in every case of collapse for which no obvious cause can be found, if lives are to be saved through the prompt and efficient use of the anti malarial drugs DIFFERENTIAL DIAGNOSIS OF CHRONIC MALARIA In Africa the main tropical disorders with which chronic malaria may be confused are Bilharziasts, Ankylostomiasis Kala azar At the same time any chronic debilitating disease accompanied by splenomegaly may simulate chronic malaria, especially when the syndrome cvolves in relation to a malarial background For this reason it may be necessary to pass in review & varied range of dis orders including leukaemia, lymphadenoma, splenic anaemia, acholunc jaundict, erythraemia, amyloid discase, syphilis, tuber.

·70 MALARIA BILHARZLASIS In the chronic phase of both unnary and intestinal bilharziasis, a rise of temperature occurs at irregular intervals, while splenomegaly and hepatomegaly can usually be demonstrated These findings, together with loss of weight and a state of general debility, may be ascribed to chronic malaria, but in bilharziasis the characteristic ova appear in the stool and urine samples (although prolonged search of repeated specimens may be necessary), and characteristic bilharzial lesions will be demonstrable on cystoscopic examination of the bladder or on sigmoidoscopic examination of the lower bowel The blood findings in chronic bilharziasis generally fail to reveal any significant degree of eosinophilia, but a diagnostic titre will always be obtained with Fairley's complement fixation test ANKYLOSTOMIASIS In this disorder, loss of weight, lassitude and anaemia with icteric tinging of the skin may suggest chronic malaria, but the absence of splenomegaly suggests a non malarial background, and the presence of hookworm ova in the stool will provide the diagnosis, although it may not necessarily constitute the full explanation of the syndrome in view of the frequency with which polyparasitism is encountered in the tropics KALA AZAR This condition bears a very close resemblance to chronic malaria by reason of the intermittent pyrexia, anaemia, splenomegaly and cachexia, all of which the two diseases have in common Consequently the diagnosis rests ultimately on the demonstration of Leishman Donovan bodies in the juice aspirated from the liver or spleen or cultured from the peripheral blood Kala azar will fail to respond to quinine therapy Finally it may be stressed that when dealing with any chronic syndrome for which no adequate explanation can be found, it is always worth while to investigate the patient carefully for evidence of chronic malaria In this way intractable headaches a migrainous syndrome, neuntis, especially a mono neuritis, tachycardias and even certain psychoses may be found to have a malarial background, the elimination of which clears up the complaint ·CHAPTER SEVEN PROGNOSIS AND TREATMENT PROGNOSIS The prognosis in acute malana is determined by the species of the infecting parasite, rapidity of diagnosis and efficiency of treatment, but the outcome of a given attack will also be influenced by such factors as the age, race and state of health of the individual Acute malaria is always a dangerous disease in infants and young children, whether European or African This is especially truc of childhood attacks of acute malignant malaria, which is prone to merge suddenly into a cerebral attack On the other hand the mortality rate from malaria amongst the adult African population living in an endemic area is entirely ncglig able But in the presence of debilitating conditions such as ankylostomiasis, bilharziasis, avitaminosis, syphilis, tuberculosis and so on, acute malaria becomes a more senous disease with a correspond ingly higher death rate in all population groups With these vanous conditions in mind it may be claimed that acute benign malaria (as the name implies) has in the main a good prog nosis, cven though exceptions to the rule can be quoted On the other hand the benign forms show a high relapse rate In acute malignant malaria the danger lies in the onset of pernicious forms such as algd or cerebral malaria which render the outlook grave in the extreme Finally, in the presence of repeated infections with Pl falciparum there is an inherent risk of blackwater fever and with it an entirely new set of adverse prognostic factors With chronic malaria the danger to lfc rests not so much with the malarial infection as such, but with a state of enhanced suscept ability to intercurrent infections such as bronchopneumonia and bacıllary dyscntcry which tend to terminate fatally But both the anaemia and acheria which characterise chronic malaria in Europeans will usually respond well to routine treatment ·72 MALARIA with iron and vitamins once the plasmodial infection has beca eliminated TREATMENT GENERAL MANAGEMENT During an acute attack of malaria the patient should be put to bed and recumbency continued until the temperature has been normal (or more likely subnormal) for a matter of three or four days A mosquito net should always be used from just before sundown until the following morning For the immediate relief of symptoms a tepid (80° F) spongedown of the entire body will have a soothing and refreshing effect and at the same time a tonic effect on the vasomotor system Sponging will also be necessary at the termination of the sweating stage .nant rA of 1000 R it there until specific drug therapy becomes effective For the headache, myalgic pains and general malaise a simple diaphoretic mixture or a combination of five grains of aspirin and five grains of Dover's powder will usually give adequate relief and may be repeated after an interval of four to six hours Restlessness at night and inability to sleep can usually be counteracted by a simple barbiturate, a bromide mixture or even 15 grains of Dover's powder Very occasionally severe pain 10 the splenic region may necessitate a gr 1/6 or gr 1/4 of morphine to ensure a good night's rest at the onset of the attack Nausea and vomiting will usually respond to vigorous antimalarial therapy, but where this has been delayed or has been ineffective an intravenous dnp saline becomes necessary to offset dangerous dehydration acute attack of malaria Since the febrile phase in malaria is of short duration the diet should be restricted to fluids initially Each feed should consist of 5 to 6 oz of fluid administered every two hours Fruit juices are well ·PROGNOSIS AND TREATMENT 73 tolerated when sweetened with glucose, and have a greatly enhanced food value Other fluids include citrated milk (two grains of sodium citrate to the oz.), barley water flasoured with orange or lemon juicc, weak tea or clear soup Jellies and custards may be included in the dictary if desired Barley sugar should be kept by the bedside and taken at any time, while a frec intake of plain water should be en couraged SPECIFIC DRUG THERAPY THE PLASMOCIDAL DRUGS 1 QUININE Cinchona bark, from which quinine is obtained, reached Europe from Peru in 1640, whence it was brought by the wife of the Spanish Viceroy of Peru, the Countess Cinchon It is popularly held though not necessarily historically correct, that the Countess had been rapidly cured of a fever by means of the powdered bark of what came to be known as the Cinchona trec The crude bark continued in use in Europe until carly in the 19th century when Gomez of Portugal isolated a substance he termed cinchoninc (1810 sel 1815) Ten years later cinchonine was shown by the French chemists Pelletier and Cayentou to be made up of two alkalods which they named quinine and cinchonne Upwards of a score of alkaloids have been solated from cinchona bark since then, and although some of them, cg, quinidine, have been shown to be actively piasmocidal they have all been set aside in favour of the crystallizable alkaloid quinine by reason of their greater toxicity or (cg, cinchonidine) lack of therapeutic efficiency The ciochona alkaloids are derived from the bark of the Cinchona tree, originally indigenous to Western South America, but subsequently brought to Ceylon and Java which became the major source of the world's quinine supplics of the various species of Cinchona, succirubra and C calisaju are extensively culuvated in India where they constitute the main sources of quinine, even though the yreld is small (1 5 to 3 50) Ia Java, on the other hand, the dominant species is the more delicate C ledgeriana with a quinine yield of 3 to 80 or more This species is commonly crafted on to C succaruhra, thereby ensuring a hardy plant and a high yield of alkaloid ·74 MALARIA Since the base (quinine alkaloid) is insoluble, quinine is usually administered in the form of a soluble salt The salts most commonly employed include (1) the sulphate and the hydrochloride, both of which have one molecule equivalent of acid and give an almost neutral solution but are not very soluble, and (2) the bisulphate and the bihydrochloride with tho acid equivalents, a high solubility with a resultant strongly acid solution due to the liberation of free sul phuric or hydrochloric acid by hydrolysis, and (3) the dihydro bromide and the ethyl carbonate of quiaine For economic reasons extracts containing the combined alkaloids of cinchona bark have been employed at different times They have been prepared from barks with a low quinine yield, eg, succirubra Thus quinetum was prepared from C succirubra in India, and later "cinchona febrifuge” was evolved from the residual alkaloids after extraction of quinine Since the actual quinine content of these total alkaloid preparations varied widely, the League of Nations Malaria Commission advocated the use of a standardised product termed "Totaquin" in those countnes manufacturing "cinchona febrifuge " It was laid down that Totaquin must contain at least 70% crystallizable alkaloids, of which at least one fifth must be quinine Amorphous alkaloids must not exceed 20%, while mineral substances and water were limited to 5% It is obvious, however, that these crude preparations contain a high percentage of inert matenal, thereby impairing the therapeutic efficiency of the active components THERAPEUTIC ACTION It is probable that the therapeutic value of quinine in malaria is due to its plasmocidal property rather than to any indirect action it may have on the immunity mechanism of the body This view receives support from the rapidity with which quinige acts in acute malaria, especially when administered intramuscularly or intravenously Again, both under experimental conditions in the ape and in naturally occurring infections in man, the plasmocidal action of quinine is in no way impaired by the absence of a spleen, which constitutes an integral part of the immunity mechan ism in malarial infections Unlike undifferentiated protoplasm, the malaria parasite shows ·PROGNOSIS AND TREATMENT 75 important variations in its vulnerability to quiaine The sexual forms are unaflected by ordinary therapeutic doses of the drug while the available evidence suggests that the exo-crythrocytic forms of the parasite are also immune Hence the therapeutic value of quiding in malaria les in its powerful action on the merozoites as they circulate as free bodies in the plasma, and on the developing schizonts within the red corpuscles Quinine is rapidly absorbed and can be demonstrated in the urine within 15 minutes of being taken by mouth The excretion rate a variable quantity, but about a third of that absorbed appears in the urine, with traces in the facces, saliva and milk Just under two-thirds is destroyed in the tissues About tuo-thurds of the quinine absorbed is excreted in the first 12 hours, and most of the remainder within the next 24 hours The amount and rate of excretion is roughly the same whether the quinine is given orally, intramuscularly or intravenously The rapidity with which quinine us ctcreted or destroyed in the tissues necessitates using large doses fairly frequently If an efficient concentration of the drug is to be maintained in the blood stream Methods of Administration Quinine salts may be administered orally, intramuscularly or intrasenously ORAL ADMINISTRATION Quirine is given by the mouth shenever the clinical state permits Although administered either in solution or an tablet form it is always more efficacious and therefore preferable to presenbe quinine in a mixture in the treatment of malana The sulphate of quinine 1s entirely suitable for the purpose, and there is no advantage in prescribing either the bihydrochloride or bisulphate on the ground of their greater solubility The sulphate is readily brought into solu on hy het n 1 mixture of quininc Quinine sulphate Dilute sulphuric acid BP Syrup of ginger Cinnamon water, to half an ounce 10 grains 10 minums ·76 MALARIA 10 grains 30 grains or Quinine sulphate Citric acid Syrup of ginger Cinnamon water, to half an ounce Given as a mixture the quinine is rapidly and completely absorbed with speedy control of the malarial paroxysms (dilute hydrobromic acid is sometimes added to the formulae (1 minım to 1 grain) with the object of reducing tinnitus), whereas tablets may fail to dis integrate and may traverse the intestinal tract unchanged When tablets have been stored for any length of time they must be examined periodically to ascertain their capacity for disintegration in the gastro intestine To this end a tablet should be placed in a glass of lukewarm water and should begin to disintegrate within a few minutes Complete solution is not necessary but failure to disintegrate at all after an hour or so means that the tablet will almost certainly pass unabsorbed through the intestine INTRAMUSCULAR ADMINISTRATION In the treatment of acute malaria, especially acute malignant malaria, It is frequently necessary to administer quinine by the intramuscular route in order to obtain speedy and effective control of the infection Neglect of this procedure may seniously jeopardise the prognosis The main indications for the employment of quinine intra muscularly are as follows - 1 Persistent and violent vomiting 2 A heavy infection of the peripheral blood in Pl falciparum infections, 3 The presence of pernicious forms of acute malignant malaria or a clinically severe attack whatever the species of the infecting plasmodium, 4 Wherever there is reason to suspect ineffective absorption of quinine administered orally, 5 Whenever an attack of malaria complicates the puerperium the post operative state or any illness such as pneumonia which has already guver rise to a state of debility It should be emphasised, however, that it is only necessary to utilise the intramuscular route as a means of bringing the malarial ·PROGNOSIS AND TREATMENT attack under control so that in the majority of cases it should never be necessary to administer more than tho or at most three intra. muscular injections, after which treatment may be continued and completed by means of quinine giren orally The dose given intramuscularly is usually 10 grains of quinine bihydrochlonde dissolved in 1 0 to 20 cc of stenle water, and it should be remembered that a certain amount of pain is expen enced locally during the injection but the pain does not radiate and does not persist The site usually selected for the injection is the upper outer quadrant of the buttock in order to avoid injury to the sciatic nene fibres Once the injection has been given the site is gently massaged to disperse the solution and so avoid extensive muscle necrosis It is obvious, therefore, that the intramuscular administration of quinine is not without danger Some necrosis of muscle tissue 15 always caused by quinine and should infection of the necrosed tissue set in, abscess formation with sive sloughing and a prolonged spell of invalidism will result Gas gangrene, tetanus and general septicaemia have also been listed as complications of intramuscular quinine, but the incidence of such major disasters must be extremely low A more common complication is the gradual formation of a small indurated nodule at the injection site which may last for years and may give rise to a certain amount of local discomfort or even pain from time to time It has sometimes been found necessary to excise the nodule in later years Finally, the injection of quinine into or near the sciatic nene has been responsible for paralysis of the ham strings and all the muscles below the knce with foot drop and inability to for the knec But these potential dangers fade into insignificance when a maximum of care is evercised in the maintenance of a strictly stenic technique and in the selection of the site for injection Thus intramuscular quinine therapy constitutes an important therapeutic weapon in the treatment of acute malang NTRAVENOLS ADMINISTRATION Intravenous quidine therapy is usually reserved for the pernicious vanсlies of acute malignant malaria u bere the urgency of the clinical features demands rapid and immediate control of the infection.

·78 MALARIA This is especially the case in cerebral malaria in which the transition to a state of fatal coma may occur with alarming speed It cannot be said, however, that intravenous quinine is desirable in all the pernicious forms of malignant malaria In abdominal and 10 algid malaria, for example, the degree of vasomotor collapse is such that any further depression caused by intravenous quinine therapy is more than likely to bring about fatal syncope In such cases (as will be seen later) it is more profitable to give an intravenous glucose saline to which 10 grains of quinine have been added while at the same time 10 grains have been given intra muscularly When administered intravenously the bihydrochloride of quinine is employed in a dose (for an adult) of 10 grains dissolved in 20 cc of sterile water or 5% glucose saline The injection is given very slowly to obviate an abrupt fall in blood pressure When properly administered the injection is painless and in favour able circumstances a satisfactory clinical response is obtained But It must never be forgotten that a rapid flooding of the circulation with quinine is capable of precipitating a fatal collapse There is too the added danger that an over rapid destruction of parasites may induce a modified Herxheimer reaction However, the dangers inherent in the intravenous administration of quinine are largely offset by a careful assessment of the clinical circumstances combined with meticulous attention to the details of technique Once it is obvious that an attack is coming under control oral therapy should be started TOXIC EFFECTS OF QUININE The administration of quinine in therapeutic doses gives rise to a mild symptom-complex known as cinchonism with deafness and buzzing or ringing in the ears as the main presenting features These symptoms usually appear during the early stages of quinine medica tron, but are temporary la character in that they disappear with the cessation of treatment, and may be said to constitute a useful clinical jodex of quippe absorption Other side effects of a more troublesome nature include nausea, a feeling of dizziness, tremor or palpitation, while the precipitate ·PROGNOSIS AND TREATMENT administration of quinine intravenously may result in an abrupt fall in the blood pressure with the risk of fatal collapse In the ordinary way, howeser, the features of cinchonism do not necessitate suspendrag quiaine therapy Over and above these characteristic side effects some patients ethibit a hyper sensitivity to quinine which may express itself in a variety of ways 1 Cutaneous eruptions These vary from a diffusc erythema or scarlatınıform eruption to an urticaria which may vesiculate In some cases a true allergic eczema develops with extensive oedema of the dermis In such cases the clinical picture bears a close resemblance to exfoliative dermatitis 2 Localised oedemas may desclop in relation to the mucous membranes of the nasopharynx, oral cavity or the bronchial and alimentary tracts, causing acute syndromes characterised by dyspnoca with pulmonary oedema or violent attacks of vomiting or purging accompanied by cardio-vascular collapse 3 Pupuric haemorrhages may develop in relation to the skin or mucous membranes, causing a purpuric eruption which may attain the severity of a purpura haemorrhagica or may be character. used by intractabic haemorrhage from the nose, mouth, bowel or urinary tract 4 Visual disturbances Retinal damage leading to amaurosis may be caused by quinine, but is a relatively rare complication The lesions in the retipa de clop abruptly, are bilateral and are character ised by rapid shrinkage of the visual fields, culminating in complete blindness This complication is liable to be followed by optic atrophy S Permanent deafness This is a rare but possible complication when massive doses of quinine are being given over an unnecessanly long period of time ANTIDOTES TO CINCHOVISV It is claimed that the toxic effects of quinine can be lessened by means of restone orally in 7 grain doses given 30 minutes before cach dose quinine Potassium bromide, cafcinc and adrenalin have also been recommended It is now possible, howeserto male use of alternatic plasmocidal drugs in the presence of quinine intoxication or allergy ·80 MALARIA 2 MEPACRINE (ATEBRIN) Mepacrine is a synthetic acridine derivative with plasmocidal pro perties It was produced in 1930 by Kikuth and his collaborators, Mietzsch and Mauss, at the IG Farbenindustrie, Elberfeld, where it was found to exert a powerful plasmocidal effect on the parasites of bird malaria Shortly afterwards its therapeutic efficacy in all types of human malaria was established and confirmed by workers in all parts of the Tropics The drug is a bright yellow crystalline powder with a bitter taste and sparingly soluble in water, giving a neutral fluorescent solution It is available for oral administration in tablet form, each tablet containing 01 G (14 grains) of the drug A soluble form of the drug known as mepacrine methane-sulpbonate (BP) (Atebrin musonate (Bayer), Quinacrine soluble (Pharmaceutical specialities) ) is suitable for parenteral therapy, and may be given either intra muscularly or, in very urgent cases, intravenously Mepacrine methane sulphonate is a yellow crystalline powder soluble 1 in 3 in water it is put up in ampoules containing 0 375 G of the drug and is equivalent to 0 3G of mepacrine hydro chloride Before administration the powder is dissolved in 50 cc of sterile distilled water and injected immediately Mepacrine is rapidly absorbed, whether given orally or intra muscularly, and is excreted very slowly, unchanged in the unne It appears in the urine about the second day, and persists for two or three weeks after cessation of treatment It is believed that a certain amount of the drug is excreted in the bile, but is subsequently reabsorbed, thereby prolonging its therapeutic action THERAPEUTIC ACTION Mepacrine exerts a powerful plasmocidal action on the asexual forms of all the malaria parasites It has been shown microscopically that vacuolation and fragmentation of the plasmodial cytoplasm occurs, followed by disintegration of the chromatin and complete disappearance of the pigment While it is probable that these changes represent a direct para. sıtıcıdal effect, it does not entirely preclude the possibility of the enhanced action of indirect biological factors ·PROGNOSIS AND TREATMENT 8! Mepactine, hou cycr, has little or no value as 3 gametoade, especially in respect of the crescent forms of Pl falciparum Nor does it appear to have any destructive influeace on the cro-erythrocytic forms of PI rar as revealed by the relapse rate after treatment and the development of an overt attack of berugn malana within a few weeks of discontinuing "suppressive" mopacrine prophylaus Methods of Administration Mepactine may be given (1) orally in the form of mepacrine hydrochloride, or (2) Intramuscularly or Intravenously as mepacrine methane sulphonate ORAL ADMINISTRATION When administered orally mepacrine hydrochloride is given in tablet form, cach tablet containing 0 1G (11 grains) The dose should be taken with plenty of fluid and immediately after food if mcals arc being taken in the case of adults and older children the tablet should always be swallowed whole in view of its intensely bitter taste. but with very young children it may be necessary to crush the tablet and give it in milk or concealed in a spoonful of jelly The average daily dose for an adult is O 3G, but in the case of very heavy patients weighing 12 to 13 stones or over, the daily dose should be increased to 0 4G In the case of children the following daily dosage scheme is recommended Up to one year 005 G (ne, half a tablet) One to four years D-IG Fise to cight years 0-26 Orcr cight years 0-3 G PAREVITRAL ADMINISTRATIOV The circumstances which jusufy and necessitate using quinine either intramuscularly or intravenously in controlling an acute malarial attack will also necessitate parenteral mcpactine therapy when that drug is being used solely in the treatment of an attack Thus intramuscular injections of mopacting are given in the presence of persistent vomiting, pernicious symptoms, & hcary plas. modal infection of the peripheral blood and so on in the case of adults 0-36 G of meparing methane-sulphonate dissolved in 5 cc ·82 MALARIA of sterile distilled water is injected into the gluteal region and the dose repeated in 12 hours If the clinical state permits the treatment course is then completed orally over a period of five days The intramuscular dosage scheme for children is as follows Up to four years 01G From five to eight years 02 G Over eight years 03G The indications for intravenous mepacrine therapy are the same as those listed for intravenous quinine, but there is a fairly general (though not necessarily logical) tendency to use quinine intravenously rather than mepacrine when faced with urgent and dangerous perni cious symptoms While the intravenous dose of mepacrine methane sulphonate is given as 0 3 G for the adult, it is probably safer to use 0 2 G and give 0 15 G intramuscularly at the same time As in all forms of intravenous therapy the injection must be given slowly and may be combined with 0 5 cc of 1 in 1,000 solution of adrenalin Although a temporary fall in blood pressure has been noted both in man and in animals during the intravenous administration of mepacrine, senous collapse has seldom been observed and so far as can be ascertained clinically, mepacrine does not affect the myocardium adversely TOXIC AND SIDE EFFECTS OF MEPACRINE 1 Gastro-intestinal Upsets When taken orally mepacrine may give rise to a certain amount of epigastric discomfort with nausea and possibly vomiting The vomiting may be persistent enough to necessitate abandoning oral in favour of parenteral therapy Abdominal cramps are sometimes experienced, especially when the bowel is constipated They usually disappear after adequate evacuation of the bowel Severe abdominal pain was a frequent occurrence when it was customary to administer mepacrine and plasmoquine simultaneously In a few cases mild diarrhoea persists throughout the course of mepacrine therapy 2 Headaches and Giddiness In a few instances headache and giddiness constitute unpleasant features of a treatment course ·PROGNOSIS AND TREATMENT 3 Psychological Disturbances These disturbances, which fortun ately are not common amongst the Luropean races range from a state of mild cerebral excitement with insomnia or linely dreams to 1 true toxic psychosis which usually assumes the characteristics of an acute confusional insanity of the maniacal type The patient is restless and slecpless talks incessantly in a rambling incoherent manner exhibiting a wild flight of ideas and tends to shout and scream and may even become violent when restrained in any way Fortunately, the psychosis is usually of a temporary nature, but it may be many months before mental stability is regained indeed temporary certification is not infrequently necessary It appears that certain Far Eastern racial groups are especially prone to meracrine psychosis but there can be no question of the European races enjoying complete immunity from this alarming toxic effect Apart from temporary mental derangement transient epilepuforma convulsions havc also been described in Tamils 4 Yellow Staining of the Shin Yellow colouration of the skin is a frequent accompaniment of mopacrine administration whether therapeutic or prophylactic Thc staining appears during or soon after a treatment course and is due to deposition of the acridine pigment in the dermis Il persists for three of four weeks or more The staining is usually most pronounced over the front of the chest and abdomen but is not associated either with irtation or photosensitivity Staining of the sclera is also found 3 PAMAQUIN Pamaquin is synthetic quinoline compound prepared in 1934 by Schuleman Schonhofer and Wingler and onginally known as plasmoquine Its plasmocidal cfficacy in avan malaria was demon strated by Rohl in 1926 and soon afterwards the drug was introduced into the treatment of human malaria Pamaquin is a pale yellow granular powder insolublc in aster but readily solubic in alcohol NITRAMLTIC ACTIOY It destroys the asexual forms of Pl tar and P1 malarice but is a poor schizonlide in Pl falciparum infections. On the other hand ·84 MALARIA pamaquin is an active gametocide in all types of infection with a highly selective action on the crescent forms of Pl falciparum It can be shown microscopically that in the presence of pamaquin the crescents become irregular in outline and then rapidly disintegrate, leaving a deposit of granular pigment While the drug may be employed in the treatment of an attack of acute benign malaria, it is valueless in acute malignant malaria In the current therapeutics of malaria, therefore, pamaquin is employed in a supplementary sense after the acute attack has been controlled by means of quinine or mepacrine Its main value lies in its gametocidal properties which render the convalescent patient non-infective to mosquitoes, and in its capacity for reducing the relapse rate in acute benign malaria METHODS OF ADSOINISTRATION While pamaquin may be administered parenterally, the oral route is the only one that need be considered Only in very exceptional circumstances will the intramuscular route be necessary, while intravenous therapy is both useless and dangerous The drug is given in the form of small tablets of 0 01 G and is best given immediately after a meal When given concurrently with Hepacrine the toxic effects of both drugs are sharply enhanced, and attacks of severe abdominal colic are common When given as a follow up to quinine or mepacrine therapy, the usual dosage scheme for pamaquin is 001 G thrice daily for five days TOXIC EFFECTS Pamaquin therapy is complicated by the narrow margin that exists between the therapeutic and the toxic dose, hence when first used in the treatment of malaria toxic symptoms were of frequent occurrence on account of the heavier doses employed at that time On the other hand toxic effects may be induced by extremely small doses of the drug, but usually when treatment has extended over a penod of sıx to nine days The chief toxic effects that may arise dunng pamaquin therapy are as follows | Abdominal pain 22 the form of dull persistent ache in the ·PROGNOSIS AND TRCATMENT $$ epigastriom The underlying cause is probably a state cfpylorospasm, but whatever the cause, the pain is rendered very acute by administer. ing mcpacrine simultaneously (a procedure no longer followed) 2 Cyanosis Cyanosis, especially of the lips, cars and finger nails, tends to occur in susceptible patients or whenever heavy doses are being employed The phenomenon is conditioned by the intracorpuscular formation of methacmoglobin, thereby impeding free oxygenation of the red cells, so that when the attack is at its height the affected areas may look almost black Dyspnoca is not a feature of the attack but a state of weakness together with a severe headache dominates the clinical picture 3 Cardiac Arrhythmia Temporary disturbances in the cardiac rhythm may arise in the course of pamaquin treatment 4 llaemolytie Anaemtia with Methoemoglobinuria A severe form of anacmia has been described in highly susceptible individuals, and 13 usually accompanied by methacmoglobinura. In such circumstances the condition is liable to be confused with blackwater fever Cases which terminate fatally show an acute yellow atrophy of the livet 4 PALUDRINE The discovery of pamaqun and menactine was followed by an ex tensivc study of the qu noline and acridine nuclei but no significant advances have been made on the onginal discoveries More recently, therefore, attention was directed to other hetcro-cyclic ring systems and for a variety of reasons the pyrimidine nucicus was chosen as a new basis in the search for a potent and casily prepared plasmocida drug. The chemistry of its ring structure had already been well studied in relation to sulphapyrimidine, and it had the added advant age that its molecular structure lent itself to the introducuon or chemical groupings of known anu malunal properties Closely linked with these chemical studies was the problem of a bological test of suficient sensitivity to detect traces of anu malamal activity in any given compound, and after careful comparaurt study ! was decided that Pl gallinacrum infecuon in chicks pronded a satisfactory means of detecting these important lesser degrees of See also addendum mage 101 ·86 MALARIA plasmocidal activity By means of this biological test a moderate degree of plasmocidal activity was detected when a dialkylaminoalkylamino side-change was added to the pynmidine nucleus (Compound 2666), but when tested against human malana, the drug was clinically unsuccessful This initial discovery was followed up by a close study of the tautomers of the 2666 molecule, and the conclusion was reached that a central rng system is not essential to anti malarial activity, but that any system presenting the necessary alternation of nitrogen and carbon atoms with the appropriate double bonds could have plasmocidal properties These simplified conditions are fulfilled by the biguanides, and after a series of brilliant chemotherapeutic studies by a group of British chemists a compound now known as Paludrine Hydrochloride was evolved, and probably represents the highest level of plasmocidal activity attainable with the biguanide grouping THERAPEUTIC ACTION The meticulously careful war time studies carried out at the Liverpool School of Tropical Medicine and by Fairley and his team at Cairns in Australia, served to establish the pre-eminence of paludnoe in the therapeutics of human malaria The initial studies in avian malaria had already revealed the interesting fact that the powerful plasmocidal action of the drug is exerted on the schizonts and on the exo erythrocytic forms of the parasite Consequently paludrine was found to exert a causal prophylactic as well as a therapeutic action against Pl gallinaceum (in chicks), Pl cathemerum (in canaries). Pl lophurae (in chicks) and Pl relictum (in canaries) Until the discovery of paludniae, pamaquin had been the only drug capable of destroying pre-erythrocytic forms of the malana parasite, but the toxicity of the drug precluded it from general use in the chemoprophylaxis of malana When the study of the therapeutic properties of paludrine was extended to human malaria, it soon became apparent that the action of the drug was not restricted to the trophozoites alone, but involved the hypothetical pre-erythrocytic forms of the parasite At the same une experimental evidence derived from human volunteers showed ·PROGNOSIS AND TRCAIMENT 1 that paludrine is probably incapable of destroying sporozoites at the time of their inoculation into man so that it becomes necessary to conclude that its prophylactic property is based on its lethal action on the pre-crythrocytic forms of the plasmodium This action is probably the result of arrested nuclear function In the case of PI falciparum infections the systematic administra. tion of paludrine will in due course effect the complete destruction of all the cro-erythrocytic forms so that schizonts fail to appear in the blood and in this way the infection is completely eliminated Thus in Pl falciparum infections paludrine is a true and complete causal prophylactic In P! mhar infections on the other hand, the destruction of the cro-crythrocytic forms of the parasite is endently incomplete, and in consequence, withdrawal of paludrine is followed in due course by the appearance of schizonts in the red cells and the onset of overt malaria as a sequel to uninhibited schizogony in the case of Pl arra infections paludnine must therefore bc classed as a partial causal prophylactic When administered therapeutically in overt malaria, paludnne acts on the young schizonts at the stage of chromatin dispersal and just before division of the cytoplasm takes place The schizont becomes swollen and vacuolated and the chromatın gradually disintegrates in this way merozoites fail to develop and febrile rarorysms are presented The drug has also an important action both on the process of gimctogony and on the gametocytes themselves When gren at the scry onset of a malarial attack the sidespread destruction of trophozoites leads in turn to a relativc failure in famctocyte production in view of the fact that gumciocytes cohe in the walc of the primary schizogony cycles While morphologxcally no significant changes can be seen in gimetocytes exposed to the action of paludrinc, far reaching biological effects have been clearly established. When taken up by the appropriate mosquito the gametocytes of hoth / fru And Pl faktparum undergo ulagellation and fertiliza. tion with the formation of a 71 gote which may develop as far as the ocyst stage but wherever traces of paludnne arrear in the blood- Send the sporogony els fails at this point with complete stenlıza.

·88 MALARIA tion of the gut This phenomena as described persists until all traces of paludrine have been eliminated from the human host in the event of the blood stream containing a high concentration of palu. drine when the mosquito takes up its feed of gametocyte-containing blood, the sporogony cycle is virtually eliminated in that even fusion of the germinal elements fails to occur But in view of the absence of any direct action by paludnine on malarial gametocytes it is important to realise that once the drug has been completely eliminated the gametocytes may regain their infectivity thereby restoring the carrier state" However, it is obvious that the influence of paludnnc on the biology of the gametocyte constitutes a factor of major importance in controlling the spread of malaria METHOD OF ADMINISTRATION Paludrine hydrochlonde is given daily in tablet form, each tablet containing 100 mgms (01 G) In acute malignant malaria due to PI falciparum radical cures have been effected by administenng 100 mgms three times a day for 10 days or 100 mgms twice a day for 14 days In acute benign malaria due either to Pl max, Pl Ovale or Pl malariae the optimum standardcourse has not yet been determined While benign attacks may be cut short and temperatures reduced to normal values by a single dose of 100 mgm of paludrine radical cure cannot be guaranteed, hence a maintenance dose of 100 mgm each week will avert relapses indefinitely It has been suggested that 300 mgm of paludrine daily for 21 days would constitute an overall course for acute benign malaria followed by 100 mgms twice a week for at least six months From the view-point of chemoprophylaxis in malaria paludnnc represents a therapeutic achievement of the first magnitude As mentioned above it constitutes a true causal prophylactic 10 infections with Pl falciparum, but in view of its failure to effect complete elimination of all pre erythrocytic forms in P/ max infections it can only be classed as a partial causal prophylactic In the causal prophylaxis of Pl falciparum infections a dosage of 100 mgms of paludrine hydrochloride is recommended twice a week (every Wednesday and Sunday) throughout the malaria **season".

·PROGNOSIS AND TREATMENT 19 THE TOXICITY OF PALLDRINE In discussing the toxicity of paludnnc it should be appreciated that the toxic effects so far obsaned have appeared in relation to doses far in cxcess of those normally employed in the chemotherapeutics of malaria There is clearly a wide margin of safety between the therapeutic and potentially toric dose, but it is possible that cases of idiosyncrasy or allergy to the drug will eventually emerge as the drug is used on an cser increasing scale When for experimental purposes, paludrine was being tested in cxtremely high doses in human volunteers, the following toxic cffects nere observed in some cases (1) Vomiting occurred when cases of overt maland received 1,000 mgms of paludnne daily, but in only one case (in which oesophageal spasm occurred) was it found necessary to suspend paludrınc therapy altogether Whenever vomiting has occurred a temporary withdrawal of the drug for 24 to 48 hours or a reduction in the dosage has senied to allay the somiting In two instances the administration of paludnine in a single dose of 1,000 mgms gave rise to abdominal pain. Yomiung and some diarrhoea These symptoms persisted for about 12 hours. (2) Jo the presence of a continued high dosage (es, 1,000 mgons daily for 14 days) evidence of ornitation of the renal tract appears in the form of haematuria accompanied by sheets of epithelial cells, probably denyed from the lower reaches of the renal tract, logether with a few hyalınc and granular casts, So far there is no evidence that paludnne gives rise to an acute parenchymalous nephrus (3) The only obseried effect of plaudnine on the haemopoieuc ussuc consists in the transient appearance of myclocytes in the peripheral blood following the administration of heavy doses This phenomenon is only observed in relation to overt malaria and beats a direct relationship to the dos afe employed It is thought to be due to the direct action of paludrins on the bone marros No tendency to agranulocytosis has so far been obsent ·90 MALARIA OTHER PLASMOCIDAL DRUGS It is not proposed to deal with these drugs 18 any detail, as have httle or no practical value in the current therapeutics of ms METHYLENE BLUE This drug was employed in the treatment of malaria by E and Guttman as far back as 1891 It has little or no action on tions with Pl max or Pl falciparum, but is definitely plasma towards Pl malariae, destroying both the schizonts and the & tocytes The drug is given orally in capsules containing either 3 grains with a total daily dose of 15 graias The urine and the are stained blue, and in some cases strangury occurs as a com] tion ARSENICALS The drugs included in this group are for the most part useful malarial tonics, although in some cases a direct plasmocidal a can be demonstrated NOVARSENOBILLON (NAB) Whittingham claims that NAB not only destroys plasmodia, at the same time exhibits an adrenalin like action whereby the site content of the peripheral circulation is increased, and in circumstances both quinine and mepacrine act with greater efficie However, it will usually be found that relapses occur wherever N. is employed as the sole plasmocidal agent, so that it is wiser to re the drug as a valuable post malarial tonic For this purpose a us dosage scheme consists 10 0 3G to 0 45 G given intravenous weekly intervals for three injections MAPHARSEN It is stated that a single intravenous injection of mapharsen terminate an attack of acute benign malana (Pl max) in 90% cases The dosage employed varies from 0 04 to 0 06 G accor to body weight So far, however, mapharsen therapy appears have been restricted to cases of therapeutic malana ·PROGNOSIS AND TREATMENT 91 STOV ARSOL Here again the preparation constitutes an effective rost malariat tonic, but when combined with quinine as quiniostovarsol acquires moderate plasmoddal properties TITE SLLPHONAMIDES Recent experimental work on the therapeutic range of the sulphona. mides has revealed an activity against Pl gallinaceum in chucks, Pl lophurae in ducks and Pl Anonlesi in monkeys They are inactive against PI inui in monkeys and Pl relictum in canaries and pigeons In regard to human malaria they shou a variable range of plasmocidal activity Recent work has shoan that preparauons such as sulphadiazine sulphamerizine and sulphamethazine are all capable of destroying the asexual forms of Pl falciparum, and could therefore he employed as malanal suppressants with curative potenualties In the case of pl riar infections, however, they have proved incllective as suppressants In view of the variable therapeutic results obtained both in human and in experimental malana in laboratory animals, it is clear that thc plasmocidal value of the sulpha drugs is definitely infenor to that of either quinine or menacnne CERTUNA (CILOVAL) This drug is stated to be dialkylamino-ovyquinolaminobutane, and Iike ramaquin is gametondal, but is much less toxic than pamsquin The douge schemes adiocated so far are as follow's (a) 0-07 G thrie daily for seven days (Suoli) (8) 0-12 G daily for six days (Wiissirobi and Mosua) SPECIFIC TREATMENT OF ACUTE BENIGN MALARIA IN THE EUROPEAN The treatment of acute benign malara aims at the rapid controt of the lebrle parorims, which, though seldom dangerous, neverthe less cause itc patient acute distress and may subsequently are rise to a state of post malanal debility ·92 MALARIA It is generally agreed that the control of the febrile phase is relatively easy even though no standard procedure to this end has ever been laid down The prevention of relapses, however, is much more difficult, and in view of the uncertainty in this regard, most clinicians are content to eliminate the acute attack and simply deal with the relapses when they occur Since the parasites are most vulnerable at the time of their release from the red cells, the plasmocidal efficacy of the drug employed will be greatly enhanced by synchronising its maximum concentration in the blood stream with sporulation in clinical practice, however, this is difficult to accomplish, hence treatment aims at maintaining an adequate concentration of the drug to the blood stream through out the 24 hours As the paroxysms will often be found to occur in the course of the forenoon it will generally be unnecessary to administer the drug during the hours of sleep As aiready stated, absolute uniformity in the treatment of acute malaria has not yet been reached, but the following procedures have been found to constitute a suitable basis for the treatment of acute benign malaria With the diagnosis established and the patient in the grip of an acute febrile paroxysm, one of the following procedures may be adopted -- 1 Quinine sulphate is given in solution in a dosage of 10 grains thrice daily and continued until the patient has remained afebrile for 48 hours, after which the dosage is reduced to 10 grains twice daily for a further five days An alkaline solution consisting of 30 grains of sodium bicarbonate and 30 grains of sodium citrate is given twice daily throughout the period of quinine therapy, but to obrate precipitation of the alkaloid It must never be given together with the quinine solution 2 Where vomiting iaterferes with oral medication 10 grains of quinine are administered intramuscularly and repeated in 12 hours time after which it should be possible to complete the quinine course orally. 3 A very satisfactory procedure consists in controlling the febrile phase by means of quinine as descnbed above and following through with mepacrine 0 IG thrice daily for five days ·PROGNOSIS AND TREATMENT 93 4 Mopactinc may be employed throughout the entre course of treatment as follows (a) Orally 03 G thrice daily for one or tao days. 0-2 G thrice daily the next day, and 0-1 G thrice daily for a further five days, or (6) on initial dose of 375 G of mopacninc methane sulphonate intramuscularly may be considered necessary to cupedite control of the attack, after which the mepacrine course may be completal orally as indicated abore 5 Recent observations on the therapeuties of pl war infec. uons indicate that the lowest relapse rates are obtained when the infection is treated with a combination of quinine and pamaquin in either of the following ways (a) Ten grains of quinine and 001 G of namaquin thrice daily for 10 days (This course calls for constant medical supervision and the immediate withdrawal of ramaquin at the first sign of toxicity) (6) An intermittent course spread over a penod of 31 days as follows 10 grains of quinine and 001 G pamaquin thrice daily for seven days followed by a seven-day rest period The dosage scheme is resumed for a further period of five days and after a further interval of seven days, the five day course is topcated for the last time Toxic manifestations are seldom encountered during the "intermittent" course and recurrences are remarkably fou 6 Paludnine will effect a clinical cure in all forms of acute benign malaria As a suitable overall course 0.3 G daily for 21 days is recommended to prevent relapses a maintenance dosage of 0 1 G (HCC Heckly for at last ut months will be necessary Finally, whx hever procedure has been folloned, after a thoday rest in tuch no drugs are talen, the treatment course is founded oll with pamaquin 0 01 G thne daily for three days ·94 MALARIA THE SPECIFIC TREATMENT OF ACUTE MALIGNANT MALARIA In the treatment of acute malignant malana, speedy control of the attack is of paramount importance of the dangerous pernicious forms are to be averted Indeed it may be said that the occurrence of such forms usually means that treatment has been either delayed or inadequate Consequently the main therapeutic objective in acute malignant malaria is the rapid introduction of an appropriate loading dose of the plasmocidal drug followed by the maintenance of an adequate concentration in the blood stream, throughout the treatment course To this end the procedures laid down for the treatment of acute benign malaria apply, although in malignant malaria it will frequently be found necessary to employ intramuscular medication in the initial phases of the attack Before deciding upon a definite line of therapy in any given caso it is necessary to ascertain 1 Is there a history of blackwater fever? 2 Is there a hustory of hypersensitivity to quinine? 3 In the appropriate circumstances is there a co-existing pregnancy? Where a positive reply is obtained to any of these questions it is advisable to use mepacrine rather than quinine It must be empha- Sised, however, that there is po hard and fast rule of procedure in the treatment of acute malignant malaria, but the usual lines of approach may be summarised as follows 1. Quinine sulphate is given orally in solution starting with 15 grains and following up with 10 grains thnice daily until the temperature has been normal or subnormal for seven days 2 In the presence of persistent vomitiag, a heavy concentration of plasmodia in the peripheral blood or the threat of pernicious symptoms, 10 grains of quinine are administered intramuscularly, and the dose repeated in 12 hours or earlier if need be If after the second injection the attack appears to be well under control, the treatment course can then be completed orally by means of quinine (10 grains thrice daily as already described) or by means of the mepacrine dosage scheme already described ·PROGNOSIS AND TREATMENT 95 3 Mepacrine may be employed throughout the attack, and in the special circumstances enumerated above it constitutes the drug of choice Where rapidity of action is clearly necessary, mepacrine is given intramuscularly and the dose repeated in sit hours Thereafter it will usually be possible to complete the treatment course orally Where oral treatment is possible from the outset the dosage scheme is the same as that advocated in the treatment of acute benign malatia 4 Paludrine it is claimed, will effect a radical cure in doses of ot G thrice daily for 10 days or 01 G twice daily for 14 days 5 After an interval of two days a course of pamaquin is given (0 01 G thrice daily for three days), where quinine or mepacrine have been employed TREATMENT OF THE MAIN PERNICTOUS FORMS 1 ALGID MALARIA The dangerous state of vasomotor collapse which characterises this variety of malaria calls for prompt and expeditious relief pari passu with the treatment of the malarjal infection Hence the treatment of algid malaria consists in 1 The administration of 5% glucose saline by the intravenous drip technique This procedure is combined with (a) the maintenance of adequate warmth to the body, and (b) 10 mg of desoxycortone daily by injection until the blood pressure has been restored to normal levels 2 Quinine (10 grains) or mepacrine methane-sulphonate (0 373 G) is injected intramuscularly and the dose repeated after sit hours jf after 12 hours no clinical improvement is evident it will then be wiser to give 10 grains of quinine intravenously through the tube of the drop apparatus, and in view of the prevailing vasomotor depression it is important to give 10 minims of 1 in 1,000 adrenalin solution at the same time and by the same route Once the patient has recovered from the algid state the treatment coursc may then be completed by means of mepacrine orally ·94 MALARIA THE SPECIFIC TREATMENT OF ACUTE MALIGNANT MALARIA In the treatment of acute malignant malaria, speedy control of the attack is of paramount importance of the dangerous pernicious forms are to be averted Indeed it may be said that the occurrence of such forms usually means that treatment has been either delayed or inadequate Consequently the main therapeutic objective in acute malignant malaria is the rapid introduction of an appropriate loading dose of the plasmocidal drug followed by the maintenance of an adequate concentration in the blood stream, throughout the treatment course To this end the procedures laid down for the treatment of acute benign malaria apply, although in malignant malana it will frequently be found necessary to employ intramuscular medication up the initial phases of the attack. Before deciding upon a definite line of therapy in any given case it is necessary to ascertain- 1 Is there a history of blackwater fever? 2 Is there a history of hypersensitivity to quinine? 3 In the appropriate circumstances is there a co-eusting pregnancy? Where a positive reply is obtained to any of these questions it is advisable to use mepacrine rather than quinine It must be empha sised, however, that there is no hard and fast rule of procedure in the treatment of acute malignant malaria, but the usual lines of approach may be summarised as follows 1 Quinine sulphate is given orally 10 solution starting with 15 grains and following up with 10 grains thrice daily until the temperature has been normal or subnormal for seven days 2 In the presence of persistent vomiting, a heavy concentration plasmodia in the periphe blood or the threat of pernicious symptoms, 10 grains of quinine are administered intramuscularly, and the dose repeated in 12 hours or earlier of need be If after the second injection the attack appears to be well under control, the treatment course can then be completed orally by' means of quarne (10 grains shrice daily as already described) or by means of the mepacrine dosage scheme already descnbed ·PROGNOSIS AND TREATMENT 95 3 Mepacrine may be employed throughout the attack, and in the special circumstances enumerated above it constitutes the drug of choice Where rapidity of action is clearly necessary, mepacrine is given intramuscularly and the dose repeated in six hours Thereafter it will usually be possible to complete the treatment course orally Where oral treatment is possible from the outset the dosage scheme is the same as that advocated in the treatment of acute benign malaria 4 Paludrine, it is claimed, will effect a radical cure in doses of 0 1 Gthnice daily for 10 days or OI G twice daily for 14 days 5 After an interval of two days a course of pamaquin is given (001 6 thrice daily for three days), where quinine or mepacrine have been employed TREATMENT OF THE MAN PERNICIOUS FORMS 1 ALGID MALARIA The dangerous state of vasomotor collapse which characterises this varot af malam2 c2ll's @ prompt and edu rolul pare passa with the treatment of the malarial infection Hence the treatment of algid malaria consists in 1 The administration of 5° glucose saline by the intravenous drp tochnique This procedure is combined with (a) the maintenance of adequate warmth to the body, and (b) 10 mg of desoxycortone daily by injection until the blood pressure has been restored to normal levels 2 Quinine (10 grains) or meracrine methane sulphonate (0 375 G) is injected intramuscularly and the dose repeated after sit hours If after 12 hours no clinical improvement is evident it will then be wiser to give 10 grains of quinine intravenously through the tube of the drip apratatus, and in vew of the prevailing vasomotor depression it is important to give 10 minims of 1 in 1,000 adrenalin solution at the same time and by the same route Once the patient has recovered from the algıd state the treatment course may then be completed by means of mopactine Grally ·96 MALARIA 2 CEREBRAL MALARIA It may be said that the best treatment of cerebral malaria is centred in the prompt recognition and efficient control of every case of acute malaria But in children especially, or in the case of newcomers to a malarious district cerebral symptoms may set in with alarming rapidity, and in such circumstances a clear concept of the therapeutic procedure is essential Treatment aims at the speedy arrest of sporu lation within the cerebral capillaries, and only by rapidly flooding the entire circulation with a powerful plasmocidal drug can this be achieved Any delay in the absorption of the drug will gravely jeopardise the patient's chances of recovery, hence intravenous therapy constitutes the method of choice in this dangerous form of malaria Various procedures have been advocated, but the following regime has been found sausfactory over a period of several years 1 Ten grains of quinine hydrochloride are given intravenously and repeated in sıx hours if no apparent chnical improvement has taken place 2 Lumbar puncture is performed soon after the intravenous instillation of quinine, and the cerebro-spinal fluid is drained away until a normal rate of flow from the lumbar puncture needle is observed Lumbar puncture may not be deemed necessary in every case of cerebral malaria, but it should always be regarded as an essential therapeutic measure in all cases showing clinical evidence of the onset of coma This procedure probably has the effect of improving the concentration of quinine in the cerebral circulation 3 Glucose saline (5%) is administered intravenously by the slow drip technique Uoder 'field conditions", however, this step may not be possible 4 When clinical improvement sets in, intravenous quinine therapy is replaced by quinine or mepacrine intramuscularly every 6 to 12 hours for two or more injections, and finally the treatment is completed orally It may be noted that some clinicians prefer to employ mepacrine intramuscularly in the treatment of cerebral malaria, giving 0 375G ·PROGNOSIS AND TREATMENT 97 of mepacrinc methane sulphonate every six hours Good results are clamed for this thethod The intravenous technique already desenbed will usually be found effecticia the treatment of cerebral malaria ia the first 24 or 36 hours of the attack, but once this period has elapsed the therapeutic control becomes increasingly difficult and fraught with considerable hazard From the nursing point of view, every case of cerebra) malana must be kept under constant supervision dunng the acute phase The face is kept turned to one side, and it is preferable to keep the head and shoulders slightly raised to give free play to the respiratory muscles 3 ABDOMINAL MALARIA The treatment of abdominal malaria resolves itself into the prompt administration of a specific drug and the prevention of dehydration i The drug of choice in abdominal malaria is mcpacrine in that it does not appear to aggravate the state of vasomotor hypotension which so frequently sets un as the attack develops Mepacrine is given intramuscularly, and the dose is sepeated every six hours until sustained clinical improvement is apparent, when oral treatment can be instituted 2 Intravenous glucose-saline (59) is given at the outset and maintained until all fluid loss has been made good and until the patient can take an adequate amount of fluid orally SPECIFIC TREATMENT OF CHRONIC MALARIA Once a diagnosis of chronic sal3512 has been established, a highly satisfactory response to one of the anti malarial drugs will usually be obtained It is probable that the efficacy of specific drug therapy 15 significantly enhanced by the state of premunity which it is reason able to assume etists to a greater or less degree in all cases of chroruc malana At any rate it is seldom necessary to give a series of courses of drug therapy in chronic malana Mepactine is an invaluable drug in all cases of this kind It is given orally at the rate of three 0 1 G tablets daily for a total of seven days As a follow up measure N A B intravenousfy will always be found of great salue It may be given in three doses of 0 3G at weekly intervats ·98 MALARIA THE SPECIFIC TREATMENT OF MALARIA IN THE AFRICAN When an adult African develops clinical evidence of malaria, an elaborate course of specific therapy is both unnecessary and undesirable The native of the kraals or the native living under conditions which expose him to reinfection is largely dependent on a continuing state of premunity to protect him against acute attacks of malarial fever, so that any treatment wuch aims at complete elimination of bis infection is thoroughly unsound from the immunological viewpoint When, therefore, an African native develops an acute malarial pyrexia, a logical and entirely satisfactory therapeutic procedure consists in administering (a) 10 grains of quinine twice daily, or (b) one 0 1 G tablet of mepacrine twice daily until the temperature has been normal for a day When this line of treatment is adopted, the course of specific therapy will rarely last for more than one to two days In the case of infants and young children, however, acute malana may be a serious disease, so that a more vigorous and protracted course of treatment becomes necessary Using appropriately modified doses of quinine or mepacrine, the procedure to be followed is essentially the same as that descnbed for the European ·CHAPTER EIGHT PREVENTION As the wider issues inherent in the problem cf malaria prevention fall outside the scope of what is essentially a clinical monograph, the discussion will be confined to the question of chemoprophylaxis from the view point of the individual Until quite recently the quest for a true causal prophylactic in malana had proved unavailing, but preliminary trials with Paludnine hold out considerable promise of the effective chemical control of the disease in the pre-clinical phase It may be said that wherever Europeans live in an area of endemic malaria it is clearly necessary to supplement all other prophylactic procedures by means of chemoprophylaxis Where the discase per- $15ts in an active form throughout the year, then continuous chemoprophylaxis becomes necessary, but in most parts of Africa at least malaria has a distinct seasonal incidence, so that a more restricted scheme of suppressive treatment becomes possible In such circumstances it will suDice of the treatment is begun immediately ahead of the season" and continued for six weeks after the danger period has passed Furthermore it is important to adhere conscientiously to the dosage scheme adopted particularly in the case of quinine prophylaus, as it is generally held that the erratic quinine taker appears to show an enhanced susceptibility to blackwater fever The following drugs are available in the presention of malaria (1) Quinine, (2) Mepacrine, and (3) Paludnine QUININE PROPJTYLAXIS Two methods of quinine prophylaxis have been evolved (a) the daily small dose of quinine which until quite recently has been the method of choice throughout the tropical beit of the Batish Colonial Empire, and (b) the intermittent metbod onginally advocated by Koch In the case of adults the daily method of quinine prophylaxis consists in taking 5 graias (325 G) of quinine at sunset or preferably s grains night and morning Children from fout to 12 years + ·100 . MALARIA t receive 3 grains (0 2 G) daily Children under four years receive grain (0 05 G) for each year of life For children over 12 years 6 grains (0 4 G) is recommended The intermittent method of quinine prophylaxis originally advocated by Koch consisted in taking a large dose of quinine every tenth day Koch's procedure has since been modified by shortening the interval between doses and now consists in taking 15 grains (16) daily on two consecutive days in each week Nocht advocates five doses of 3 grains (0 2G) or four doses of 0 25 G daily on each of the two days in question, while Ziemann favours 15 grains (1 G) every fourth day Neither method of quinine prophylaxis will prevent infection, nor will it ensure complete freedom from clinical attacks in bad malarious regions, but severe and dangerous attacks will usually be averted, whichever method of prophylaxis is adopted Finally, the clinical evidence available suggests that side effects such as myocardial weakness, defects of hearing or of vision are not encountered in the course of quinine prophylaxis MEPACRINE PROPHYLAXLS Experience during the war years has amply demonstrated the outstanding valuc of mepacrine as a malanal suppressant, together with its great superiority to quinine in this regard The dosage recommended is 01 G daily This dosage scheme is initiated a week or two before the onset of the malana season, to allow time for an effective buld up in plasma mepacrine It is maintained throughout the season and for six weeks after the risk of infection has passed By this means infections with the Pl falciparum will be eliminated and the risk of clinical attacks following the cessation of suppressive treatment virtually removed In the case of infections with Pl max, however, overt clinical attacks will be held in check throughout the period of suppressive treatment, but an acute attack invariably develops within a few weeks of its cessation No toxic symptoms of any signuficance are associated with mepacrine prophylaxis on the dosage scheme outuned above, apart from occasional transient gastric discomfort during the first two or three days of the treatment Yellow tinting of the skin, however, occurs in most cases but varies considerably in depth The pigmentation is ·PREVENTION 101 usually most noticeable in relation to the dorsum of the hands and feet and on the face PALUDRINE PROPHYLAXIS Whde it is not yet possible to make a final assessment of the prophylactic value of paludrine in relation to all varieties of African malana, 1t has been shown above that by reason of its lethal action on the pre erythrocytic forms of the plasmodium it constitutes a complete causal prophylactic in Pl falciparum infections and a partial causal prophylactic in the benign formas The dosage scheme at present recommended for prophylactic purposes is 01 G every Wednesday and Sunday throughout the malaria season ADDENDUM PALUDRIVE Siace the account of the paludnne treatment of malaria was written the drug has become available for the treatment of the disease in Africa, and the experience gained to date has revealed the fact that the drug fails to bring about the rapid control of the febrile paro- Xysms as claimed in the original publications Thus pyrexias condtioned by the Rhodesian strains of Pl falciparum copiipue unabated for three or four days after the introduction of paludrine therapy, while severe attacks of malignant malara bave occurred in spite of systematic paludrine prophylaxis It is clear from these findings that some modification in the descripuon of the therapeutics of paludnine in relation to the African forms of malaria will be necessary ·INDEX PAGE PAGE 26 28 28 haemoglobinaemia plasma bilirubin sedimentation rate serum protein sugar urea Blood Smears fixation of preparation of staining of thick films thin films 57 59 61 58 46 47 A Abdominal Malaria dysenteric syndrome in entenc syndrome in gastric syndrome in treatment of Acute Benign Malarja diagnosis of differential diagnosis of febrile paroxysm in incubation penod physical signs prodromal symptoms prognosis in temperature in treatment of untreated case of Acute Malignant Malaria abdominal form algıd form cerebral forms diagnosis of differential diagnosis of febrile paroxysm in haemorrhagic form incubation period pernicious forms of physical signs of pneumonic form prodromal symptoms prognosis in purpuric form sudoral forn temperature in treatment of untreated case of Algid Malana treatment of Amoebic Abscess of liver Amoebic Hepatitis Ankylostomrases Arsenicals in Malaria Auto-agglutination of red cells 49 50 SO 49 97 37 54 56 66 38 38 40 38 71 41 72 91 41 42 49 46 46 56 66 68 42 SO 42 44 43 50 42 71 50 50 43 72 94 44 46 97 68 68 70 90 21 51 51 с Cerebral Malana encephalitic forms hyperpyrexial form local syndromes 10 meningeal forms treatment of Chronic Malana Clinical features of differential diagnosis of differential white cell count on haematology of icterus Index in physical signs of Pigmented leucocyte in prognosis in serological findings in sternal puocture in treatment of urinary findings in Clinical features of Malaria classification in the African in the European Cinchona Febrifuge Cinchona Species 62 61 64 53 61 71 62 65 97 37 73 S6 57 B Bulharziasis Blood Chemistry in Malaria alkalı reserve cholesterol D Diagnosis of Malana acute forms by laboratory methods chronic forms Dengue fever Differential diagnosis acute malana chronic malana 70 26 27 27 ·Heat Brain Mepachine PAGE E therapeutic action of Entere feners 66 toric effects of Enon 7 Methylene blue 10 malana G P Gametogony 12 Paludrine administration of H chemistry of Haematological findings in Malana 23 therapeutic action of pigmented Icucocyte 26 61 toxicity of red blood cells 23 addendum thrombocytes 26 Pamaquin white blood cells 24 administration or hyperpyrexia 08 chemistry of Henry s serological test 62 02 therapeutic action of Ferro-flocculation 61 toxic effects of melano-f.ccculation 63 Pathology of malara Wolff s modification 63 Bone-marrow 1 Gastro-intestinal tract Immunity in Malaria 28 Heart acquired Kidneys natural Liver Lungs Meninges 70 Pancreas Placenta Spleen Laboratory diagnosis of Maları 57 Supra renal glands examination of blood smears 57 Plasmocidal drugs fication of blood smears 58 Arsenicals preparauon of blood smears 57 scrological tests 62 Mapharsea staining of blood smears 58 sternal puncture 65 blue urinary tests 64 M Malaria 1 Quinine clinical features 37 Stovarsol chirucal pathology 23 Sulphonamudes diagnosis 56 Plasmodia differential diagnosis 66 human species of factors governing distribution life cycle or ecographical disinbution historical review nomenclature or description of imidursty in Plasmodium falciparum in the African and parasttised red cell in the European development of pathology of garnetocytes of prevention uon of 99 Plasmodium malarue prognosts in and parasitised red cell treatment of development of Meractic administration of umetocytes of 81 Plasmodium ovale ុ chemistry of 80 and parasitised red cell synonyms 80 development of Kala azar Novarsenobellon Pamaquin ·S PAGE gametocytes of 18 Plasmodium vivax 14 Sandfly fever and parasitised red cell 16 Schizogony development of 15 ero-crythrocytic phase of gametocytes of 16 Schüffners dots 11 16 17 Pneumonic conditions 66 Sporogony Prevent on of malaria 99 Sternal puncture mepactine in 99 Sulphonamides in malaria paludnde in 101 Totaquin quinine in 99 Treatment of maları3 Prognosis in Malania 71 general management 0 specific drug therapy Quinctum 74 Trypanosomiasis Typhus fevers Quinine 73 antidotes of 79 U intramuscular administration of 76 Unne in malana intravenous administration of 77 Urobilinuria in malaria isolation of 73 oral administration of 75 Schlesinger test for salts of 74 Spectroscopic test for sources of 73 3 therapeutic action of 74 Yellow fever touc cffects of 78 R z Relapsing fever 67 Ziemann's stippling