Part 13

In England it was once very prevalent. James I. died of ‘a tertian ague’ at Theobalds, near London, and Cromwell succumbed at Whitehall to a ‘bastard tertian ague’ in 1658, a year in which malaria was very widely spread and very malignant; and it is only within recent memory that the fen districts in Cambridgeshire and Lincolnshire, Romney Marsh in Kent, and the marshy districts of Somerset, have lost their evil reputation for ague. The older chemists in the towns in the fen districts still recall the lucrative trade their fathers carried on in opium and preparations of quinine with the fenmen during the first half of last century; but with the improved drainage of the fens this has all disappeared, and at present cases of endemic malaria appear to be unknown in England, though sporadic cases turn up at rare intervals. It was also very prevalent along the estuary of the Thames, both on the Essex and Kentish marshes. Pip in ‘Great Expectations’ says to his convict:

’“I think you have got the ague.” “I’m much of your opinion, boy,” said he. “It’s bad about here,” I told him. “You’ve been lying out on the meshes, and they’re dreadful aguish.”’

Ireland, which appears at first sight peculiarly adapted for the disease, seems to have been remarkably free from it. It may be that the strong antiseptic quality of the peaty bog-water hinders the development of the larval mosquito.

Turning now to the cause of the disease, it is interesting to note that the discovery of the organism which produces all this misery and death took place just about the time when Koch was making his far-reaching investigations into the cause of tuberculosis. In 1880 Koch was at work on the tubercle bacillus; and in the same year a French army surgeon, named Laveran, looking down a microscope in a remote military station in Algiers at a preparation of blood taken from a malarious soldier, recognized for the first time the small organism which has played a larger part in human affairs than the greatest politician or general that ever lived. This small organism is an animal, not a plant. It belongs to the great group of single-celled organisms, mostly microscopic in size, called Protozoa, and it lives as a parasite inside the body of other animals, from which it abstracts what nutriment it needs. Before describing its structure and life-history, a word or two must be said about its surroundings in the body of man.

That blood consists of a fluid in which enormous numbers of cells called blood-corpuscles float is now a matter of common knowledge. These corpuscles are of two main kinds, the red and the white, but the red surpass the white in number, in proportions ranging from 300 up to 700 to 1. A cubic millimetre of blood contains about 5,000,000 red corpuscles; and since these act as the carriers of oxygen from the lungs to the tissues all over the body, and on their return journey carry away the carbon dioxide from the tissues to the lungs, where it is given off, it is obvious that the presence of a parasite in the red corpuscle will have a most serious effect upon the welfare of the body.

Before Laveran’s discovery, Lankester had described a parasitic organism living in the blood-cells of a frog, and within the last twenty years numerous other organisms have been discovered and described by various investigators living in the blood-corpuscles of reptiles, birds, monkeys, and bats. There are at least three species of Hæmatozoa, as they are called, which live in the blood of man, and these three correspond to the three kinds of malaria--the tertian, the quartan, and the æstivo-autumnal, or, as it is often termed, the irregular type of malarial fever, which occurs so frequently in the late summer and autumn in Italy and elsewhere. The hæmatozoön causing the last-named fever has been especially studied by the Italian observers, and it differs more markedly from those causing the tertian and quartan fevers than the latter do inter se. It is not universally conceded that the differences between these three forms of organism are such as to establish a difference of species, but the weight of opinion is in favour of this view. Ross even places the parasite of the æstivo-autumnal fever in a separate genus, and we have throughout this article adopted his nomenclature. Zoologically he groups all the three species infesting man in Wassielevski’s family Hæmamœbidæ, which, besides the human parasites, includes a species found in monkeys, three species in bats, and two in birds. The species causing tertian and quartan fevers are grouped by Ross in the genus Hæmamœba, the former being called Hæmamœba vivax, the latter Hæmamœba malariæ. The parasite causing the æstivo-autumnal fever is called Hæmomenas præcox.

With the exception of a few details the life-history of all these forms is practically identical, although the time which is occupied by different phases of their life-cycle varies in the different species. The account given here applies in the main to them all.

The organism which Laveran saw living in the blood-corpuscles of his malarious patient was a minute cell of irregular shape whose nucleus can be demonstrated by the use of appropriate reagents. The cell constantly but slowly changes its outline, pushing out and withdrawing blunt rounded processes; in fact, the cell resembles the lobate forms of one of the simplest microscopic animals we know, the Amœba (Fig. 1). The movements and change of shape consequent on them are termed amœboid, and the organism in this stage is known as an amœbula. These amœbulæ whilst in the blood-cell grow rapidly, and in some way they collect the hæmoglobin, or colouring matter of the red corpuscle, within their own bodies, and convert it into a number of dark brown or black pigment granules, which crowd around the nucleus of the parasite. This pigment, the so-called malarial pigment or melanin, had been recognized by Virchow and others about the middle of the nineteenth century as a characteristic product in the blood of malarial patients. The amœbulæ continue to grow rapidly, at the expense of their cell-host, until, after a definite period, which varies from one to several days, they become mature, and by this time they have completely filled up the red corpuscle, whose scanty remains form a tight skin round the fully-grown parasite (Fig. 1, 1-8). When mature, one of two things happens--either they become (1) gametocytes, whose meaning and fate we will consider later, or they become (2) sporocytes. In the latter case the nucleus of the amœbula breaks up into a number of small nuclei, and each surrounds itself by a small mass of protoplasm and forms a spore (Fig. 1, 5-8). The result of this process of division may be roughly realized if we imagine an orange with

Nos. 1, 2, 3, 4, show the growth and the changing shape of the parasite within the blood-corpuscle; Nos. 3, 4, etc., show the aggregation of the pigment, melanin, in the parasite; No. 5 is a sporocyte, which in Nos. 6, 7, and 8, shows the several stages of sporulation; No. 9 shows the spores derived from a single sporocyte, escaped from the blood-corpuscle and free in the blood-plasm, ready to infect new corpuscles; No. 10 is a male gametocyte, removed from the body of man, and either in the stomach of Anopheles or on a microscope-slide, forming there flagella or spermatozoa, a, Parasite; b, red blood-corpuscle; c, spore; d, granules of pigment, melanin; e, flagellum or spermatozoön. (From Thayer.) ]

FIG. 2.--VARIOUS STAGES WHICH THE PARASITE OF THE ÆSTIVO-AUTUMNAL FEVER, HÆMOMENAS PRÆCOX (ROSS), PASSES THROUGH IN THE BODY OF THE MOSQUITO ANOPHELES. MAGNIFIED 2,000 TIMES. AFTER ROSS AND FIELDING-OULD.

No. 1, Flagella or spermatozoa from male gametocyte (see Fig. 1 above); No. 2, flagellum or spermatozoön entering and fertilizing the female gametocyte; No. 3, the fertilized cell or zygote; Nos. 1, 2, 3, are found in the blood in the stomach of the Anopheles; No. 4, the fertilized cell piercing the wall of the stomach of the mosquito to come to rest at No. 5, between the epithelial lining of the stomach and the muscular sheath.

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but one pip in each quarter. Then the skin of the orange will represent what is left of the red blood-corpuscle, the flesh will represent the divided sporocyte, each quarter will represent a spore, and the pip will represent its nucleus.

At this stage the skin to which the red corpuscle has been reduced breaks, and the spores fall into the liquid part of the blood (Fig. 1, 9). The pigment granules which escape at the same time also pass into the liquid of the blood, and are eaten up and removed by those scavengers of the vascular system, the white corpuscles. Each of the spores, after remaining a short time in the fluid of the blood, attaches itself to a new red corpuscle, penetrates its body, and becomes a small amœbula, which repeats the life-history described above. In this way a few organisms will soon produce enough spores to infect a very large number of blood-corpuscles; as many as 60 per cent. are in some cases infected. The severity of the attack naturally depends in a great degree on the number of corpuscles infected. Laveran not only first recognized and described the organism we are dealing with, but he definitely connected its presence with malaria; but it was not until some time later, in 1885, that Golgi described the sporulation of the sporocyte and pointed out that the moment of the escape of the spores from the red corpuscle coincides with the paroxysm of the fever. Since all the amœbulæ of one crop are at about the same stage of growth in any one host, millions of spores in a well-infected patient are thrown into the liquid of the blood at about the same time; and it is clear that this must be accompanied by a profound disturbance of the system. This disturbance manifests itself in a feverish attack. The period when the spores have left the corpuscles and are free in the liquid of the blood is also the time at which the administration of quinine is said to be most effective. Further, it is only at this stage that the disease can be artificially transferred from one man to another. All efforts to transmit the gametocytes have ended in failure.

Hæmamœba vivax, which causes the tertian fever, passes through the various stages of its life-history in man in forty-eight hours; hence the febrile paroxysm occurs every second day. Malaria is usually of the tertian type, and this is certainly the most common form in temperate climates. Occasionally the infection has been repeated, and we may find that there are two groups of the parasite present in the blood, which arrive at the sporulating stage on alternate days; in this case the febrile symptoms manifest themselves every day, and the type of malaria is designated ‘quotidian intermittent fever.’ In this case, if a single dose of quinine be administered at the right time, one group of parasites is killed off and the quotidian fever is reduced to a tertian. There may occasionally be more than two groups present, or the parasites may for some reason have failed to arrange themselves in groups, in which case the fever becomes irregular or continuous.

In the quartan fever the parasite Hæmamœba malariæ takes seventy-two hours to complete its cycle in man, and the paroxysms occur every three days--that is, there are two days without febrile symptoms, followed by a day when there is a paroxysm. This form is common in Sicily and in certain parts of Italy--for instance, around Pavia. Just as in the tertian fever, so in quartan there may be a second infection, in which case paroxysms arise on two successive days, followed by a day of intermission of the fever. If a third group be present, we have a quotidian fever. The æstivo-autumnal fever, due to Hæmomenas præcox, is noted by a marked irregularity in its clinical symptoms. It usually sets in during August, September, or October, and is attended by much more serious results than are the regular intermittent fevers. The pernicious or malignant form of malaria, rarely seen in temperate climates, but common in the tropics, is caused--in many cases, though perhaps not in all--by the same parasite.

From what has been above described, it is evident that when once the parasite has obtained entrance to the blood it may remain and multiply for years. The parasite is, however, very susceptible to the poisonous action of quinine, and this is especially the case at the time when sporulation has just taken place and the spores are being set free in the blood. Quinine seems to have little or no effect on the organisms whilst they are inside the blood-corpuscle, but shortly before the paroxysm is due it should be administered. Quinine is amongst the very few absolutely trustworthy specifics known to medical science. It seems to have been introduced into Europe in the year 1640 by the Countess of Chinchon, a small town south-east of Madrid. The Countess was Vice-Queen of Peru, and in 1638 was cured of a tertian fever by the use of Peruvian bark. Shortly afterwards she started for Europe with a supply of the drug, but unfortunately died on the voyage. About a hundred years later Linnæus named the plant after this lady, but acting on erroneous information omitted the first ‘h’ in the name, and called the plant Cinchona. According to some authorities the word ‘quinine’ is derived from ‘quina,’ the Spanish spelling of the Peruvian word ‘kina,’ which signified bark.

But to come back to the parasite. It was mentioned above that the amœbulæ become either sporocytes or gametocytes. We have followed the fate of the former and must now turn our attention to the latter. In the genus Hæmamœba the gametocyte has a general resemblance to the sporocyte before its nucleus divides and it begins to form spores; and it is impossible to predict which amœbulæ will become sporocytes and which will become gametocytes. In Hæmomenas, however, the gametocyte can be recognized at an early stage. In this genus some of the amœbulæ become globular and ultimately form spores, whilst others become elongated and slightly curved; in fact, they assume the shape of minute sausages. These are the gametocytes. It is on this difference in shape that Ross has founded his new genus for the parasite of the æstivo-autumnal fever, all the essential characters of which had, however, been previously recognized by Italian and American observers.

So long as the gametocytes remain in the blood of the patient they undergo no further development; on being liberated from the cell into the fluid of the blood, they degenerate and die; but if they be removed, even only on to a microscope-slide, they begin to develop. They escape from the red corpuscle in which they have hitherto been confined, and some of them--the male gametocytes--are then seen suddenly to emit long filaments (Fig. 1, 10). These filaments can be watched under a high power struggling violently to free themselves from the cell which has given rise to them. Ultimately they succeed, and breaking loose, at once dart away amongst the corpuscles and other debris on the slide. So long ago as 1880 Laveran had seen these bodies, but until 1897 their nature was quite misunderstood. This formation of the filaments or flagella, sometimes called ‘flagellation,’ can only take place at comparatively high temperatures. This has an important relation to the seasonal variation in the prevalence of the disease.

Hitherto in this article we have only studied the malarial parasite inside the body, with the exception that we have just seen that, should it get out, certain cells undergo a further development and produce mobile filaments. It occurred to many that these filaments might be spores, which were in some way carried into the blood of man. Later research showed that this is not their true meaning; but, acting on some such belief, Dr. Patrick Manson propounded the hypothesis that the spores may be conveyed to man by the intervention of some blood-sucking insect; and the brilliant and laborious researches of Major Ross, undertaken with the view of establishing the truth or falsehood of this hypothesis, have within the last few years cleared up the whole question of the transmission of the disease from one patient to another.

It is a well-established belief in many malarious countries that the mosquito plays a part in the infection. The negroes of the Usambara Mountains, who acquire the disease when they descend to the plains, even use the same word to denote the disease and the mosquito. In Assam, in Italy, and in Southern Tyrol, the belief in the mosquito origin of malaria obtains. Experienced travellers, like Livingstone, Emin Pasha, and General Gordon, insisted on the importance of mosquito-nets, thinking that the netting ‘acted as a filter against the malarial poison,’ and knowing by experience that its presence diminished the tendency to the disease. The whole epidemiological evidence was put together in a masterly essay on the mosquito theory, read before the Philosophical Society of Washington in 1883, by Professor A. F. A. King. There was thus a considerable body of opinion in favour of the mosquito-malaria theory, when, in 1894, Manson explained his views to Major Ross, at that time a surgeon in the Indian Medical Service.

Manson’s own epoch-making researches on Filaria--another human parasite whose intermediate host is the mosquito--no doubt strengthened his faith and helped to encourage Major Ross, who in 1895 began in Secunderabad a series of investigations, which, after much weary work, were crowned with brilliant success. The difficulties of the work were very great. Hardly anything was known about the great number of gnats and mosquitoes which are found all over India, and it was often impossible to have them accurately determined. Then no one could predict the appearance of the parasite within the body of the mosquito--if it were there--or in what part of the body it should be looked for. The mosquito had to be searched cell by cell. The difficulty of dissecting a mosquito is great even in temperate climes, and when we recollect that hundreds of all the available species were dissected in the most malarious districts in India, we must recognize that it was only a faith akin to that which moves mountains which sustained the courage and stimulated the perseverance of the tireless worker. For nearly two years and a half Major Ross searched in vain. No matter what species of mosquito he worked at, the results were negative. A less determined man would long ago have abandoned the research; Major Ross only tried new methods. At Sigur Ghat, near Ootacamund, a peculiarly malarious district, he noticed for the first time a mosquito with spotted wings which laid boat-shaped eggs. Shortly afterwards he was able to feed eight specimens of this mosquito on a patient whose blood contained the parasites in the gametocyte stage--and it should have been mentioned above that all mosquitoes dissected were first fed upon the blood of malarious patients. Six of these insects were searched through and through, organ by organ, but without result. The seventh showed certain unusual cells in the outer surface of the stomach, which contained a few granules of the characteristic black pigment or melanin of malarial fever. The eighth and last specimen showed the same characteristic cells with the same characteristic pigment; but the peculiar cells, quite unlike anything hitherto met with in the mosquito’s body, were larger and further developed. ‘These fortunate results practically solved the malaria problem.’

Without following in detail the various stages of the further investigations carried on by Major Ross, we must endeavour to give an account of the final results obtained by him and later investigators. Being unable to obtain material for the study of malaria in man owing to the scare caused by the outbreak of plague amongst the natives, Ross worked out the life-history of an allied organism which causes malaria in birds. It is to the brilliant researches of the Italian school--prominent among whom are Grassi, Bastianelli, and Bignami--that we owe the first complete accounts of the life-history of the human parasite. It has already been explained that some of the parasites do not form spores, but persist in a more or less unchanged condition whilst in the blood of man as gametocytes. We have also seen that when removed from the human body some of these gametocytes throw off actively mobile filiform bodies. In 1897 MacCallum of Baltimore showed what these filiform bodies really are. Certain of the gametocytes do not produce them, but lie passively still on the microscope-slide, or in the blood within the mosquito’s stomach. These are destined to form the female cell; the filamentous bodies which break off from the first-named gametocyte were seen by MacCallum to fuse with them, and, in fact, to play the part of the male cell or spermatozoön. This, in fact, happens when a mosquito feeds on a malarious patient. The gametocytes, unchanged in the blood of man, as soon as they reach the stomach of the insect, swell and burst from their red corpuscle. The male gametocyte throws off the filiform bodies, which actively swim about seeking a female gametocyte (Fig. 2, 1). When found they fuse with it, and thus produce a fertilized cell or zygote (Fig. 2, 3). This zygote is produced on the microscope-slide, and in the alimentary canal of certain mosquitoes, but so far as is known at present it undergoes further development only in the stomach of the various species of the mosquito genus Anopheles. In all other cases it dies or is digested. In Anopheles, however, the zygote travels to the walls of the stomach, pierces the inner coats and comes to rest underneath the muscular tunic which ensheaths that organ (Fig. 2, 4 and 5).

At first the zygote is very small, about the size of a red blood-corpuscle; but it grows, and in the course of about a week it has, roughly speaking, increased to five hundred times its original bulk (Fig. 3, 1 and 3). Its contents have not only increased, but have divided into some eight or twelve cells, called meres; and each of these meres has given off round its periphery a number of filiform cells, called blasts (Fig. 3, 2). The structure of the mere, with its coating of blasts, may be easily understood by a zoologist when it is mentioned that it very closely resembles that stage in the formation of the spermatozoa of the earth-worm just before the spermatozoa separate themselves from the blastophor; the lay mind may gain a better idea of its appearance by recalling the head of a mop. As the zygote, still resting on the outside of the mosquito’s stomach, matures, the cells which are giving rise to the blasts diminish in size and disappear, leaving the capsule packed with thousands of minute filiform slightly spindle-shaped blasts (Fig. 3, 3). Then the capsule bursts and the blasts make their way into the body-cavity, or space between the stomach and the wall of the mosquito’s body. It is not known whether they have any movement of their

FIG. 3.--FORMATION OF THE BLASTS OF HÆMOMENAS PRÆCOX (ROSS) WITHIN THE BODY OF THE MOSQUITO ANOPHELES. MAGNIFIED 2,000 TIMES. AFTER ROSS AND FIELDING-OULD.

No. 1, The full-grown zygote dividing up into meres; No. 2, an isolated mere which has developed its filiform bodies or blasts; No. 3, the zygote crammed with blasts is bursting; No. 4, the blasts are making their way into the salivary gland of the mosquito a, through it into the œsophagus b, and finally into the proboscis c.

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own, but in some way or another they make their way into the salivary glands of the insect and accumulate in the cells which secrete the saliva. Thence the blasts pass into the salivary duct and down the grooved proboscis of the insect (Fig. 3, No. 4). The next time the mosquito has a meal off a man, some of these blasts will be washed into the man’s blood by the saliva which causes the irritation set up by a mosquito’s bite. It is known that when an infected insect bites a healthy man malaria ensues; and though the blasts have not hitherto been seen to enter the blood-corpuscles, they certainly give rise to the disease, and it can hardly be doubted that they force their way into the red corpuscles and form the young amœbulæ which we described at the beginning of this article.