# Tropical Diseases/Chapter 4

CHAPTER IV
MALARIA: MORBID ANATOMY AND PATHOLOGY
The blood in malaria.—— As the malaria parasite is a blood parasite, we naturally expect that the primary effect of its presence will be exercised on, and manifested in, the blood; and as the parasite lives in and at the expense of the corpuscles, destroying a certain proportion of them—— in fact, all those attacked ——we look, in the first instance, for a corresponding diminution in the number of the corpuscles—— an oligocythaemia.
Oligocythœmia.—— Accordingly, when in malarial disease we come to measure accurately the corpuscular richness of the blood, we do find a decided oligocythæmia. And not only this, but we find a degree of oligocythæmia greatly in excess of anything we might expect; or which can be accounted for by, or is in correspondence with, the proportion of corpuscles attacked and directly consumed by the parasite, judging by what we see in finger blood —— peripheral blood. If, for example, every hundredth corpuscle contains a parasite we might look for something like a quotidian, tertian, or quartan 1-per-cent. reduction in the total number of blood corpuscles; if every twentieth corpuscle contains a parasite—— a very high and unusual proportion—— we might look for a similarly-timed 5-per-cent. reduction.
Now, this is an amount of hæmolysis which should be easily compensated by the latent physiological hæmogenic margin, and which one would not expect to show as a definite anæmia, or would expect to show only after the recurring drain had been kept up for some considerable time. But what are the clinical facts? One or two paroxysms only, of some malarial fevers, may be immediately followed by an ​anæmia so pronounced as to be discernible to the eye in the intense pallor of the skin and visible mucous surfaces. On counting the corpuscles in such a case we note a regular drop in their number of from 5 to 10 per cent, per paroxysm. Often, after a single paroxysm of some pernicious fever, as many as half a million or even one million corpuscles per c.mm. drop out of the normal five millions; and this reduction may go on, as paroxysm follows paroxysm, until the corpuscular richness has fallen to one million, or even less.
Diminished hœmoglobin value of corpuscles.—— Not only is there in many, in fact in most, cases of malarial disease a pronounced oligocythæmia, but there is, in addition, a marked diminution in the hæmoglobin value of the surviving corpuscles; it may fall 10, 20, or even as much as 50 per cent.
Diminished amount of blood.—— And not only is there this marked diminution in the proportion of the corpuscles to the bulk of the blood and in their hæmoglobin value, but there is, furthermore, in all malarial conditions of any considerable standing a marked diminution in the volume of blood. Thus it comes that at the post-mortem examination of such a case we do not always meet with that congestion of the organs which is so usual a feature in most specific fevers. On the contrary, although in quite recent cases visceral congestion may be marked enough, if a malarial fever has been of any considerable duration the venous system, with the exception of that appertaining to the spleen, liver, and portal system generally, may be markedly empty. And thus it is that often, when we would make a preparation of blood from the living malarial patient, we may find that not only is the blood thin and watery, but that it does not flow freely from the pricked finger.
Destruction and reparation of blood in first attacks and in relapses.—— There appears to be no very definite or manifest law governing the degree, progress, and quality of the anæmia of malarial disease. On the whole, and as rough general rules, it may be laid down that in any given case the anæmia is in pro​portion to the severity of the febrile attacks; that, although the loss of corpuscles following first attacks is usually very marked, this loss is rapidly made good; that, although in relapses the loss of corpuscles is less than in first attacks, the tendency to reparation is also less.
Morbid anatomy: Macroscopic.—— If the body of a patient who has died in the course of an acute attack of malarial disease be dissected, certain appearances are generally found. In the first place, and invariably, the spleen is enlarged often very much enlarged; its surface is dark—— black sometimes—— what is called pigmented. On section, the gland tissue is also found to be dark. Generally the parenchyma of the organ is so much softened as to be almost diffluent, so that the tarry pulp can sometimes be washed away by quite a gentle stream of water. The liver, too, is softened, congested; enlarged, and pigmented. The vessels of the pia mater and brain cortex are full, and the grey matter may present a peculiar leaden hue. The marrow of the spongy bones, such as the sternum and the bodies of the vertebræ, is also dark and congested; and a similar state of pigmentation and perhaps congestion may be discovered in the lungs, alimentary canal, and kidneys.
Microscopic: Malarial pigmentation.—— The pigmentation referred to is pathognomonic of malaria. On submitting malarial blood from any part of the body to microscopical examination, it will be found to contain grains of hæmozoin. Particularly is this the case with blood from the organs just mentioned; microscopic sections (Plate II., Figs. 2, 3, 4) will show more or less thickly distributed in the blood, and within the cells of the endothelium of the arterioles and capillaries, minute grains, or actual blocks, of the same intensely black substance. For the most part the hæmozoin grains are enclosed in leucocyte-like bodies which are either clinging to the walls or lying loose in the lumen of the vessels. Here and there the pigmented bodies may be so aggregated together that they form veritable thrombi and occlude the vessels. It is possible that many of ​these bodies are not pigmented leucocytes, but are really dead and breaking-down parasites; for if the preparations were made within two or three hours of death—— that is to say, when the tissues were quite fresh ——it may be possible to see that the capillaries of some of the organs are full not only of hæmozoin but also of parasites, a very large proportion of the blood corpuscles containing them. Particularly is this the case with the spleen and bone marrow; often, too, with the brain, liver, epiploön, and intestinal mucosa. The spleen and bone marrow are further distinguished from the other organs mentioned by the position in which the hæmozoin occurs in them. In all organs the pigment is found in the blood-vessels, but only in these two organs is it found in the cells of the parenchyma as well, and outside and away from the blood-vessels. This extravascular pigment is either free, or it lies in the large cells characteristic of these organs, or in the small cells of the parenchyma.
Nature and source of malarial pigment.—— In colour, in structure, and in chemical reaction this pigment corresponds exactly with the pigment already described as forming so prominent a feature in the malaria parasites themselves. Like this, it is insoluble even in strong acids; it is altered by potash, and is entirely and rapidly dissolved by ammonium sulphide. In recent infections it occurs as minute dust-like grains; in infections of some standing as coarser particles, or as agglomerations of these into irregular, mammillated lumps. So far as the circulation is concerned, such a pigment is found in no other disease whatever. As an extravascular pathological product a similar pigment is found in certain melanotic tumours; but only in the cells of the tumour, never in the blood-vessels. Pigments of several kinds are found in old blood-clots; but such pigments are manifestly different from that of malaria, and yield very different chemical reactions. Intravascular black pigment, therefore, is absolutely pathognomonic of malaria.* Because of ​its physical characters, and of the circumstances in which it occurs, hæmozoin may with confidence be regarded as the specific product of the malaria parasite itself.
Source of the pigment in the pigmented leucocyte.——If further evidence be required of the identity of the intraparasitic pigment and that found in the tissues, it will be supplied by a study of the fate of the pigment grains and clumps set free in the blood on the breaking-up of the segmented parasite.
If malarial blood, drawn during the rigor and early stages of acute attacks, and even at other times, be examined, large mononuclear leucocytes carrying grains or even blocks of black pigment may be encountered. If the observer be fortunate and persevering he will sometimes actually see whence this pigment is derived; he may even detect the leucocytes in the act of taking it up. He may see the pigment set free in the liquor sanguinis by the falling to pieces of a segmenting parasite; and he may then see a phagocyte creep across the field of the microscope and slowly engulf the little block. This undoubtedly is a principal source of the pigment in the leucocytes. Other, though possibly less important, sources are the effete gametes and, especially in the large cells of the spleen, necrosed parasite containing red blood-corpuscles.
Phagocytosis in the spleen.—— The evidence of phagocytosis in the spleen in malaria is very remarkable. Not only are large and small masses of hærnozoin included in the macrophages, in the smaller cells, and in the endothelium, but entire blood- corpuscles, sometimes as many as eight or nine, mostly containing parasites, besides free parasites, free hǣmozoin, and fragmented hæmoglobin, are frequently to be seen in one and the same phagocyte. Sometimes one haemozoin-laden phagocyte may be seen included in another phagocyte, and these perhaps in a third.
Blood of the splenic vein and liver.—— Of all the vessels of the body the splenic vein is that in which malarial pigment is most abundant. Whereas in other vessels it is found to be included in ordinary leucocytes, ​in this vessel it is included, not only in the leucocytes, but also in certain large white cells identical with those occurring in the spleen, and, doubtless, of splenic origin also. Similar cells may be found in the capillaries of the liver, rarely, however, in the blood beyond this organ; that is to say, they are filtered out by the liver from the blood carried to it by the splenic vein. An additional reason for the abundance of hæmozoin in the splenic vein is, that not only is the spleen the physiological destination of many of the hærnozoin-laden leucocytes and effete parasite-infested corpuscles, but it is likewise a favourite nursery for the parasite. In fact, the parasite is present in this organ in greater profusion than elsewhere. Hence it is that the splenic vein, coming direct from a rich breeding- and dumping-ground, contains a large number of hæmozoin-laden leucocytes.
Extravascular pigment.——In the early stages of malarial disease, except in the case of the spleen and the bone marrow, pigment is entirely confined to the lumen of the vessels and to their endothelium. But if we examine tissues from a case which has died at a late period of the disease, the pigment may then be found, not only in the endothelium, but also in the walls of the vessels, and even in the perivascular lymph spaces, whence, it may be inferred, it is subsequently carried to the lymphatic glands to be finally dealt with and broken up. As encouraging this view about the ultimate fate of the malaria pigment, Kelsch has pointed out the significant fact that the lymphatic glands in the hilum of the liver are always markedly pigmented in old-standing malarials; a fact evidently referable to the disposal of the large quantities of hæmozoin which, as we have seen, the liver filters out, more especially from the splenic portion of the portal stream.
These facts explain malarial pigmentation and oligocythœmia.—— The facts just mentioned explain the origin and nature of malarial pigmentation, and also, in part at least, the oligocythæmia of the malarial state, which, as pointed out, is only partially accounted for by the destruction of corpuscles by the ​parasite in the general circulation as represented by finger blood. They show that what is seen in finger blood does not represent anything like the aggregate mortality that is going on among the corpuscles from direct destruction. The principal part of the malarial drama is played out in the spleen, liver, bone marrow, brain, etc., and not in the general circulation. What is seen in finger blood is but an overflow, as it were, of the greater drama going forward in the viscera.
The yellow pigment.—— Besides the pathognomonic black pigment (hæmozoin), there is usually found in the organs a greater or less amount of a yellow or brown pigment (hæmosiderin), the "pigment ochre " of Kelsch and Kiener. This pigment is found not only in the capillaries, but also, and in greatest abundance, in the parenchyma cells of the liver, spleen, pancreas, kidneys, as well as in the bone marrow and in the connective tissues. It is not characteristic of malaria, but occurs in all morbid processes in which there is extensive breaking-up of erythrocytes, as in paroxysmal hæmoglobinuria; in pernicious anæmia, in extensive burns, in poisoning by pyrogallic acid, potassium chlorate, arseniate of hydrogen, and many other toxic agents. It has peculiar chemical properties, being equally insoluble in acids, in alkalis, and in alcohol. At first, when freshly deposited, it gives no evidence, under the usual micro-chemical tests, of containing iron; after it has been in the tissues for some time it appears to be altered in character in this respect, and it then gives a ferrous reaction with ammonium sulphide, and with the double cyanide of iron and potassium.
Polycholia and hœmoglobinœmia.—— Under ordinary conditions of physiological waste the products of the effete blood- corpuscles are converted into bile pigment, and so got rid of. Up to a certain degree of pathological hæmoglobinæmia the liver can deal in a similar way with free hæmoglobin; so it comes about that, when this substance is free in the blood in unusual abundance the secretion and flow of bile become correspondingly increased. If this flow ​of bile be excessive it gives rise to what are called " bilious symptoms "—— bilious vomiting, bilious diarrhœa—— symptoms which are so common in malarial disease, particularly in that variety known as "bilious remittent." Thus, polycholia is a constant and often urgent feature in most malarial fevers, and is good evidence that in malarial infections there is a surcharge of the blood with free hæmoglobin. It is not improbable, although this point is disputed, that the yellowness of the skin and scleræ observed in these fevers is due to tinting by free hæmoglobin, to a hæmoglobinæmia in fact, and not, as is popularly be- lieved, to biliousness or cholæmia from bile absorption.
The yellow pigment is deposited in excessive hœmoglobinœmia.—— As in those other conditions referred to as being attended by rapid hæmolysis, in severe malarial fevers in which there is great and sudden liberation of hæmoglobin which the liver cannot at once deal with, pending its transformation into bile pigment the liberated hæmoglobin is taken up by the protoplasm of the cells of the different tissues and organs of the body, and precipitated in them in a slightly altered form; it is stored up, in fact, waiting to be worked off as bile pigment by the, for the time being, overtaxed liver. The yellow pigment is, in all probability, this precipitated hæmoglobin.
Great excess of hœmoglobinœmia results in hœmoglobinuria.—— Should the liberation of hæmoglobin go beyond this, be too great and too suddenly effected fov the excretory powers of the liver and the storage capacity of the tissues, then the hæmoglobin, little altered in composition, seeks a more speedy way of escape by the kidneys, and hæmoglobinuria is produced. This is what is found in ordinary paroxysmal hæmoglobinuria, and in toxic hæmoglobinuria; and in this way we may account for the peculiar features of the disease to be described later on hæmoglobinuric fever.
Size and shape of the blood-corpuscles.—— On the whole, in malaria, as in most anæmic conditions, the corpuscles are larger than normal particularly those attacked by the parasite, especially the tertian para​site. Occasionally we come across genuine megalocytes, and, not infrequently, certain very minute, darkly- coloured spherical corpuscles, which may be nucleated and of embryonic type. Erythrocytes with basophilic stippling are not uncommon. Some pathologists regard these basophilic granules as evidence of degeneration of the erythrocytes; P. Schmidt, however, considers them as evidences of regeneration, since they are most numerous during recovery. There may be marked irregularity of outline in many of the corpuscles, and an indisposition to form rouleaux.
The leucocytes in malaria.—— The leucocytes, especially the large mononuclear, play a very important part in malaria. In mild attacks their numbers, as observed in peripheral blood, decrease somewhat, both relatively to the red corpuscles and absolutely. In benign tertians and quartans their maximum is attained, according to Billings, two or three hours after the onset of chill. From this time there is a progressive diminution until the minimum is reached at the end of the paroxysm and when temperature has become subnormal. After this the number rises somewhat, and during the interval occupies" a position midway between the maximum and minimum. The large mononuclear elements are increased, both absolutely and relatively. Sometimes the mononuclear are as numerous as the polynuclear leucocytes, especially during apyrexia. A mononuclear leucocytosis of 15 per cent, and upwards, Christophers and Stephens regard as strong evidence of a malarial infection. With regard to the leucocytes in that type of fever which is caused by the crescent-forming small parasites, it is impossible, Billings says, to arrive at so definite a conclusion as in the cases of benign tertian. In the former type of case there appears to be a slight diminution in the number of leucocytes towards the end of the attacks, a diminution which is made good during the interval. Curiously enough, in certain severe pernicious attacks there is a decided increase of the leucocytes in the peripheral blood—— sometimes an ​enormous increase, a positive leucocytosis, the normal 8,000 per c.mm. rising to 10,000, or even to 30,000 the proportion to red corpuscles rising from the normal 1 in 500 or 600 to 1 in 300, or even to 1 in 70.
The cause of fever and of periodicity in malaria.—— The cause of fever in malaria is some toxin or toxins liberated when the segmented parasites break up in the blood. Rosenau and others, by injecting filtered blood-serum procured during the cold stage of an ague, have succeeded in demonstrating the presence in the blood of such a substance.
The cause of the periodicity is doubtless of a two-fold character, the first and most important being the more or less fixed life-span of the parasites, and the second some physiological property in the human body which tends to destroy the parasites. Like so many physiological phenomena, this malaria-destroying principle or force has a tendency to quotidian increase and decrease. Although sometimes almost powerless to cope with the parasites, it usually brings about, especially after repeated infections, a more or less complete immunity.
It might be urged that though such an explanation may be applicable to quotidian periodicity, it could not apply to tertian or quartan periodicity. This cannot be admitted. If there be a regular quotidian occurrence of susceptibility to the malaria germ, this susceptibility must be existent on the second and third day as well as on the first there- fore a tertian parasite, on maturing, will encounter it on the second day, and a quartan on the third, just as certainly as if they were daily-maturing parasites.
This hypothesis may be a wrong one. But it will not be without its use if it impress the importance of placing malarial patients under tonic influences as an aid to specific treatment; and of protecting the subjects of malarial recurrences from debilitating influences. For, just as tonic influences may suffice to cure a fever, so, in many malarials, depressing influences are sufficient to provoke relapse: presumably by weakening the physiological element which holds the infection in check.