# Tropical Diseases/Chapter 3

CHAPTER III
MALARIA: DESCRIPTION OF THE PARASITES AND THEIR ASSOCIATED FEVERS
THE different clinical types of malarial disease are associated with different and corresponding species of malaria parasites.
Classification of parasites.—— The different species have been classified according to
    1. The duration of their respective life-cycles inside the human body.
    2. Their morphological characters.
    3. The clinical phenomena they give rise to.
    4. The results of inoculation experiments.
It may be said that, so far as these tests go, there is evidence of plurality of species. That is to say, a particular clinical type of malarial disease is associated with a parasite of definite morphological form and intracorporeal life-cycle, characters which are maintained when the parasite has been inoculated experimentally.
The classification suggested by Mannaberg will here be followed a classification based principally on the investigations of Golgi, Marchiafava, Bignami, Celli, Grassi, and other Italians, as well as on his own most excellent work.
The forms of the malaria parasite, and of the diseases they give rise to, may be divided into two comprehensive groups—— the benign and the malignant. A principal morphological distinction between these two groups is that, whereas the benign parasites never form crescent bodies, the malignant parasites, or at least the most important of them—— the subtertian——form crescents; that is to say, the gamete of the benign parasites is a sphere or disc, that of the malignant parasites a crescent. A principal clinical difference between the two is that, whereas the ​benign parasites rarely give rise to pernicious attacks, the malignant parasites frequently do.
The benign parasites are of two kinds: one, the quartan parasite, having a cycle of seventy-two hours, causing a fever recurring every three days—quartan fever; the other, the tertian parasite, with a cycle of forty-eight hours, causing a fever recurring every two days—tertian fever.
The malignant parasite has three forms, perhaps more: a pigmented parasite, the subtertian, of forty-eight, or approximately forty-eight hours' cycle; a pigmented parasite—pigmented quotidian—of approximately twenty-four hours' cycle; and an unpigmented parasite—unpigmented quotidian—also approximately of twenty-four hours' cycle.
We may arrange them thus:—
| Benign | $\scriptstyle {\left\{{\begin{matrix}\ \\\ \end{matrix}}\right.}$ | Quartan Tertian | $\scriptstyle {\left.{\begin{matrix}\ \\\ \end{matrix}}\right\}\,$ Do not form crescents. |
| Malignant | $\scriptstyle {\left\{{\begin{matrix}\ \\\\\ \ \end{matrix}}\right.}$ | Subtertian: Form crescents. |
| Malignant | $\scriptstyle {\left\{{\begin{matrix}\ \\\\\ \ \end{matrix}}\right.}$ | Quotidian—pigmented Quotidian—unpigmented | $\scriptstyle {\left.{\begin{matrix}\ \\\ \end{matrix}}\right\}\,$ Supposed to form crescents. |
Clinical classification.—Formerly, classification being based entirely on clinical phenomena, malarial diseases were divided into quotidian, ​tertian, and quartan intermittents or agues, and remittents. But since it has been found that what was designated remittent fever is produced by either quartan, tertian, subtertian, or by quotidian parasites—the fact of intermittency or remittency being more or less a matter of accident—it has been considered advisable to expunge the term remittent fever as indicative of a distinct species of malarial disease. Any one of the five kinds of parasites enumerated may cause what was known as remittent fever. The intermittency or the remittency of any given fever depends, in great measure, on the simultaneousness or the reverse of the maturation of the swarm of parasites giving rise to it. If all the parasites present are of nearly the same age, they mature approximately simultaneously and we have an intermittent; if they are of different ages, they mature at different times scattered over the twenty-four hours and we have what was known as a remittent. Further, two generations of tertian parasites maturing on successive days will produce a quotidian fever, Tertiana duplex; two generations of quartan parasites maturing on successive days will produce fever fits on two successive days followed by one day of freedom, Quartana duplex; three generations of quartan parasites will produce what clinically appears to be a quotidian fever, but in reality is a Quartana triplex.
Present classification not final.—The classification adopted is merely provisional. In practice it may be hard, often impossible, to bring the cases met with into exact line with such an arrangement. Moreover, as this classification is based in great measure on observations made in very limited districts, principally in Italy, and principally on Roman fevers, it may not apply to the entire malarial world. That it lies on a substratum of fact there can be no doubt; nor can there be much doubt that it has in many particulars a general application to malarial disease as found all over the world. Still, judging from clinical facts, there seems ground for believing that there are other species or ​varieties of the malaria parasite besides those described by the Italians, and that the list here given will have to be enlarged or recast in the future. Men with extensive experience of malarial disease in their own persons tell us that they can discriminate by their sensations and symptoms between the fevers of different localities. Analogy would incline us to believe that clinical differences of this sort depend on differences in the determining parasites.
CLINICAL PHENOMENA OP MALARIAL FEVER
Before proceeding with a description of the various malaria parasites and their associated fevers, there are certain generalities which, to save repetition, had better be mentioned here.
Intermittent fever or ague.—— Every typical malarial fever is made up of a series of pyrexial attacks which recur at definite intervals of twenty-four, forty-eight, or seventy-two hours. Each attack consists of a stage of rigor, a stage of heat, and a stage of sweating; these are followed by a period, " the interval," of apyrexia -actual or relative. The duration and intensity of the constituent stages vary considerably. On the whole, they observe a certain proportion to each other; as a rule, the more pronounced the rigor, the higher the fever and the more profuse the sweating. Such attacks, with well-marked intervals of apyrexia, are designated intermittent fevers or agues. The expression " ague " is applied only to intermittents having a pronounced rigor stage.
Premonitory stage.—— Before rigor sets in, and sometimes for several days before the actual disease declares itself, there may or there may not be a premonitory stage marked by lassitude, a desire to stretch the limbs and to yawn, aching of the bones, headache, anorexia, perhaps vomiting, perhaps a feeling as of cold water trickling down the back. If the thermometer be used, it will be found that body temperature has begun to rise, it may be some two or three hours before the other and more striking symptoms which ensue set in; or it may be that the threatened attack will subside spontaneously without ​culminating in the more pronounced phenomena of a fully developed ague.
Cold stage.—— When rigor sets in, the feeling of cold spreads all over the body, becoming so intense that the teeth chatter and the patient shivers and shakes from head to foot. He seeks to cover himself with all the wraps he can lay hands on. Vomiting may become distressing. The features are pinched, the fingers are shrivelled, the skin is blue and cold-looking and may exhibit the condition known as " goose-skin " (cutis anserina). But the feeling of cold is entirely subjective; if the temperature be taken, it is found to be already several degrees above normal and to be rapidly mounting. In young children it is not at all unusual to have a convulsive seizure at this stage a fact that has to be borne in mind, as it is very apt to lead to ideas of epilepsy.
Hot stage.—— After a time the shivering gradually abates, giving place to, or alternating with, waves of warmth and, before long, to persisting feelings of intense heat and febrile distress. The wraps, which before were so eagerly hugged, are now tossed off; the face becomes flushed; the pulse is rapid, full, and bounding; headache may be intense; vomiting frequent; respiration hurried; the skin dry and burning, the thermometer mounting to 104°, 105°, 106° F., or even higher.
Sweating stage.—— After one or more hours of acute distress the patient breaks out into a profuse perspiration, the sweat literally running off him and saturating his clothes and bedding. With the appearance of diaphoresis the fever rapidly declines; headache, vomiting, thirst, and febrile distress giving place to a feeling of relief and tranquillity. By the time the sweating has ceased the patient may feel quite well; a little languid, perhaps, but able to go about his usual occupation. The bodily temperature is now often subnormal, and may remain so until the approach of the next fit, one, two, or three days later.
Duration of the fit.—— The duration of an ague fit and of its constituent stages is very variable. On an average it may be put at six to ten hours, the ​cold stage occupying about an hour, the hot stage from three to four hours, the sweating stage from two to four hours.
The urine in ague.—— During the cold stage the urine is often limpid and abundant, and is passed frequently; but during the hot and sweating stages it is scanty, loaded, sometimes albuminous. The amount of urea is increased, particularly during the cold stage; and so are the chlorides and sulphates. The phosphates, on the contrary, diminished during the rigor and hot stages, are increased during defervescence. The augmentation in the excretion of urea commences several hours before the subjective symptoms of the attack begin, attains its maximum towards the end of rigor, and decreases during the hot and sweating stages, although still continuing above the normal standard. The excretion of carbonic acid follows a corresponding course. Sydney Ringer was the first to point out the interesting fact that, although the return of fever may be prevented by the administration of quinine, yet, for a time, a periodic increase in the excretion of urea occurs on the days on which the fever fit was due. The urine is often deeply coloured, giving with nitric acid the play of colour characteristic of bile pigment, or the brown colour described by Grübler as " hæmapheic." Glycosuria does occur, but is by no means common.
The spleen during the fit.—— The spleen becomes enlarged to a greater or less extent during rigor. At first the swelling disappears in the interval, but it tends to become more or less of a chronic feature if the attacks recur frequently, more especially if they are associated with pronounced cachexia.
Period of the day at which ague commences.——Two-thirds of agues come off between midnight and midday. This is a fact to remember in diagnosis; especially when we have to face the possibility of recurrent pyrexial attacks being dependent on such conditions as liver abscess, tuberculosis, and septic states conditions, be it remarked, in which febrile recurrence takes place almost invariably during the afternoon or evening. ​Atypical agues.—— Cases are frequently met with in which all the above symptoms are very much toned down; in which, perhaps, a periodically recurring feeling of coldness, followed by languor, or a slight headache, or a slight rise of temperature, is the only symptom indicating the presence of the malaria parasite in the blood. In some fevers, and these by no means the least dangerous, the subjective symptoms may at first be of so mild a character that the patient is able to go about his duties with a body temperature of 103° or 104° F.; he may have no severe rigor, no headache, no severe gastric symptoms, no acute febrile distress of a disabling character. Some of the African fevers ——so liable to assume suddenly a pernicious character ——are of this nature. On the other hand, notwithstanding a comparatively slight rise of temperature, headache, prostration, or vomiting may be extremely distressing. There is an infinite variety in this respect. Evidently the toxin—— if toxin there be—— of the malaria parasites is far from being a simple body; probably, like tuberculin, it contains several ingredients arranged in different proportions in the several species and varieties of the parasite. Doubtless, also, the degree of infection, various combinations of the species of parasite, and individual idiosyncrasy play a part in determining the intensity and character of the reaction of the human body to the toxin.
Terms employed.—— Acute malarial attacks which recur daily are called quotidian ague; if they recur every second day, they are called tertian ague; if every third day, they are called quartan ague. As a rule, the attacks tend to occur about the same time every day. In some cases the time of recurrence becomes earlier each day; such fevers are said to anticipate. Or they may occur at a later hour; in which case they are said to postpone. When the individual paroxysms are prolonged, so that one attack has not concluded before the next commences, the fever fits are said to be subintrant. When the fit is prolonged and periodicity is marked by only a slight fall of temperature, a slight sweating, a ​slight feeling of chilliness, the fever is said to remit to be a remittent. Sometimes there is no remission; such a fever is said to be continued. It occasionally happens that two distinct pyrexial attacks come off the same day; such a fever is said to be double. All sorts of blendings of malignant infections, benign tertians, and quartans occur; in such the infection is said to be a mixed infection.
Relation of the phenomena of the fever lit to the stages of the parasite.—— All the differences and peculiarities in the clinical phenomena of a malarial attack, complicated and hard to interpret in many cases though they be, are, it is believed, directly correlated to the phases of the intracorporeal life of the parasite; this organism is, in fact, the key to their interpretation. As already mentioned, as the time of rigor approaches, the pigment of the parasite, hitherto scattered throughout the substance of the little animal, becomes concentrated, and segmentation proceeds. Shortly before and during rigor, and as a direct cause of rigor, these segmented parasites are breaking up and, presumably, liberating their toxins. At the end of rigor, during the hot and during the sweating stages, the young parasites of the new generation the small intracorpuscular bodies and the leucocytes carrying the hæmozoin liberated at the breaking up of the segmented bodies—— are in evidence, and the toxins liberated, at the same time are being eliminated. During the interval the intracorpuscular parasites grow, become pigmented, and prepare for maturation. From the fact that parasites are present in the blood during apyrexia, and often in great abundance, it is evident that it is not the mere presence of the parasite in the blood corpuscle that causes the fever; most likely, as suggested, the pyrogenic agent is some toxin which is liberated and becomes free in the liquor sanguinis on the breaking up of the parasite. Consequently, we find that in remittent and continued types of malarial fevers segmenting parasites may be met with at all stages of the fever; and, conversely, that when parasites at all stages of development are ​met with, the associated fever is probably remittent, irregular, or more or less continued in type.
The foregoing are generalities which apply to all the types of malarial infection.
Quartan Infection
The parasite.—The parasite of quartan fever, Plasmodium malariæ (Fig. 20), has a cycle of seventy-two hours. At its earliest stages of epicorpuscular and of early unpigmented intracorpuscular life it takes the form of a small, roundish, clear speck (Plate I., Fig. 1, a), showing up somewhat distinctly against the hæmoglobin of the invaded corpuscle. At this stage, as contrasted with the other species of malaria parasites, it is further
Fig. 20.—Quartan parasite: asexual stage: stained.
distinguished by the feebleness of its amœboid movement. Later, as soon as it becomes pigmented (Fig. 20, b, c, d, e, f), all amœboid movement ceases. (See also Plate I., Fig. 1, b, c, d, e, f.) Relatively to the other malaria parasites, the hæmozoin carried by the quartan is large in amount and coarse in grain, sometimes forming short rods. The segmented or mature parasite (Fig. 20, g, h) is made up of eight to ten elements arranged daisy-fashion and, generally, very symmetrically around the now centrally placed and massive block of very black hæmozoin. About the centre in each of the spherical or pear-shaped segments, which are slightly rough in outline, a shining nucleolus can usually be readily made out.
Malaria parasites. (Compiled from Thayer and Hewetson)
Plate I
quartan parasite does not, as does that next to be described the tertian parasite cause marked enlargement of the blood corpuscle in which it lies; on the contrary, the including corpuscle has often a shrunken appearance with hæmoglobin darker than normal. When mature it completely fills the normal-sized corpuscle, scarcely a rim of hæmoglobin being visible (Fig. 20, f); so that it sometimes looks at this stage as if it were a free and independent body floating about in the liquor sanguinis.* All quartan parasites do not proceed to segmentation, or to gamete formation; some are said to degenerate into the peculiar clear, dropsical-looking spheres, filled with dancing particles (Plate I., Fig. 1, i), which form a striking feature in certain malarial bloods. A considerable proportion of these free, dropsical-looking bodies, with active hæmozoin, are probably male gametocytes which, after being placed on the micro- scope slide, and after escaping from corpuscles, have failed to project their microgamete filaments; others, doubtless, are granular female gametes. The failure to project microgametes, in many instances, is probably not normal, but an effect of mechanical dis- turbance from pressure of the cover-glass, or of other circumstances inherent to the artificial conditions under which we necessarily observe these bodies. In more normal conditions the emission of microgametes may be more frequently effected.
The "daisy"—— as it is sometimes called or segmented phase of the quartan parasite, is more frequently seen in the peripheral blood than is the corresponding phase of the other malarial parasites. ​For this reason, and because of the easy visibility of the parasite at all its stages owing to its size and to the large amount of hæmozoin it carries, and because the entire intracorporeal cycle is completed in the peripheral blood, the quartan is the best form of malaria parasite for the beginner to study.
Geographical distribution.—— The fever which the quartan parasite gives rise to—— single, double, or treble quartan ague is, relatively, much more common in temperate latitudes than in the tropics. Formerly it was common enough in England; it is still far from rare in the malarious districts of north and mid-Europe and, doubtless, elsewhere under similar climatic and telluric conditions. But as we proceed south it becomes, relatively to the other forms of malaria, rarer. In the tropics in some highly malarious places it is unknown. Thus, in a paper read at the Calcutta Medical Congress of 1894, Crombie mentioned that in his large experience he had rarely seen quartan ague. As his experience applied particularly to Calcutta and its environs, it may not hold for the whole country; in fact, Ross and others state that the quartan parasite is common enough in Madras and elsewhere in India. It is the dominating species in certain malarious districts of Ceylon and the Malay States. I have seen it in blood films from Mauritius; Ross mentions it as occurring in Sierra Leone. Doubtless it occurs in limited districts throughout the tropics. Thus, though relatively rare in many of the West India Islands, it is a common form, according to Freeman, in Antigua. The general statements that quartan ague is, relatively to the other forms of malaria, more a disease of the temperate zones than of the tropics, and, further, that both in the tropical and temperate zones it has topographically a very limited distribution, probably express the truth.
The fever.—— The ague fit in quartan is generally smart while it lasts, and well defined as regards its constituent stages (Chart 1). It does not tend so markedly, as is the case with the other malarial infections, to the rapid development of cachexia. ​Although the individual attacks are very amenable to quinine, the infection appears to be of a more persistent nature than that of tertian and subtertian malaria; attacks, therefore, are prone to recur during several years.
Tertian Infection
The parasite.—The early stage of the benign tertian parasite, Plasmodium vivax (Plate I., Fig. 2),
Chart 1.—Quartan ague.
resembles that of the quartan inasmuch as it consists of a small pale speck on, or in, the invaded red blood-corpuscle (Plate I., Fig. 2, a); it differs in exhibiting very much greater amœboid activity, changing its form and location in the corpuscle incessantly, besides pushing out and retracting pseudopodia (Plate I., Fig. 2, b). This amœboid activity persists during growth and the formation of hæmozoin, though in a progressively diminishing degree; it gives rise to great and rapidly ​changing irregularities in the contour of the parasite (Plate I., Fig. 2, c, d, e), but is almost entirely suspended by the time hæmozoin-concentration is effected. In the tertian parasite the hæmozoin particles are, on the whole, finer than those of the quartan parasite; and, moreover, are in a state of much more active and incessant movement, constantly changing their position in the peripheral region in which they, for the most part, seem to lie (Plate I., Fig. 2, f). Another, and highly characteristic, accompaniment of tertian infection is the considerable hypertrophy and marked decoloration of the corpuscles containing the parasite (Plate I., Fig. 2, d, e, f , g). Sometimes the affected corpuscles seem nearly twice the diameter of the healthy ones; and nearly always, if the parasite is of any magnitude, the rim of hæmoglobin has a "washed-out" look, sometimes being almost colourless.
In corpuscles invaded by the tertian parasite, deep coloration with Leishman's or Giemsa's stains brings out a feature which does not occur in those attacked by quartan or subtertian parasites. With these stains in tertian-invaded corpuscles the hæmoglobin is speckled with chromophilic particles called " Schüffner's dots." This is a feature of some diagnostic value. In the very young phases of the parasite it is not always present; unfortunately for its diagnostic value, these are just the phases that are difficult to diagnose from quartans and subtertians.
In the tertian parasite, when segmentation is completed, the resulting body, instead of the very symmetrical, daisy-like figure of the quartan, resembles rather a cluster of grapes in some more or less central part of which one or two masses of dark pigment have accumulated among the berries (Plate I., Fig. 2, h; also Figs. 1 and 2, b). The little spherules forming the cluster fifteen to twenty-six in number are smaller, smoother, and more spherical than those of the quartan parasite; seldom, in the unstained condition, exhibiting their nuclei. I believe that in natural, uncompressed conditions the tertian "rosette," as it is called, tends to pass from the disc form, ​impressed on it originally by the shape of the corpuscle, to something more approaching a globular form.
In the tertian, as in the quartan parasite, the gametocyte is a spherical body resembling closely the mature parasite from which the segmented body is evolved (Plate I., Fig. 2, j). It is seen more particularly, just as in the case of the quartan infection, after and not infrequently about the time of rigor. The tertian gametocyte is considerably larger than that of the quartan and subtertian parasite.
Chart 2.—Benign tertian ague.
Geographical distribution.—The tertian parasite, probably the commonest form of malaria parasite, occurs in temperate and tropical latitudes alike. It is often met with as a double infection, and is, perhaps, the most frequent cause of quotidian as well as of tertian agues.
The fever.—The fever it gives rise to, except in the matter of the spacing, which is one of forty-eight ​hours, resembles that caused by the quartan parasite (Chart 2).
MALIGNANT INFECTIONS
Many authorities refuse to recognize more than one species of crescent-forming parasite. On the other hand, carefully conducted observations, both microscopical and clinical, seem to indicate a plurality of species. I shall follow the latter view.
The three parasites (Plate I, Fig. 3, and Plate II., Fig. 1) described by the Italian pathologists in connection with malignant malarial infection, although often associated together as well as with the benign parasites, are each of them occasionally found in what may be termed pure culture. From a study of such cases the morphological and distinguishing characters of the different species, and their special pathological effects, have been more or less satisfactorily made out. Although much remains to be done, enough is already known to enable us, in a measure, to differentiate them from each other as well as from the benign parasites, and to justify their being placed in a group by themselves.
Characters possessed in common by the malignant parasites.—— One notable feature in
Malaria parasites. (Kelsch and Kiener.)
Plate II.
even in severe infections the later pigmented stages are by no means proportionately represented by, or even frequently encountered in, finger blood; the segmenting form (Plate I., Fig. 3, i, j) still less so. To find numerous examples of the more advanced stages of these parasites it is necessary to aspirate splenic blood, or to search in fatal cases in the deeper viscera, or in the bone marrow immediately after death. Owing to this absence of the more advanced forms from the peripheral circulation, the duration of the life span of these parasites is difficult to fix; probably it varies between twenty-four and forty-eight hours, being not very constant even in the same type.
"Brassy bodies."—— Malignant parasites frequently lead to a shrivelling of the invaded corpuscles, many of which, in consequence, are small, crenated, or folded, and very dark. This corpuscle the Italians, from its colour, have designated "brassy body" (Plate I., Fig. 3, e). In the interior of these corpuscles the parasite can generally be made out as a minute pale ring.
The crescent-foody characteristic.—— Most distinctive feature of all, the malignant parasites—— at all events the subtertian—— form crescent gametocytes.
Time when crescents appear; not a fever form.—— It has been already remarked that these crescent bodies are not to be seen at the very commencement of an infection. A week usually elapses between the first appearance in the peripheral blood of the small intracorpuscular parasites and the first appearance of the crescent bodies.* Once the latter begin to appear, ​they generally tend to increase in number during a few days. They may persist, though after a time in decreasing numbers, in the circulation for one, two, three, or even six weeks after the small fever-causing intracorpuscular parasites and their associated fever have disappeared, whether spontaneously or in consequence of the administration of quinine. Although, when given early in an infection, quinine may prevent the appearance of crescents, yet, when they are once formed, the drug has apparently no influence on these bodies nor on their capacity for emitting microgametes. The crescent body does not cause fever; its presence is usually associated with marked cachexia.
It is a singular fact that in many of the worst types of tropical malaria as that of tropical Africa——crescents are few in number, and in some instances cannot by ordinary examination be found. A. Plehn states that during a period of two years in Africa he only once saw the flagellated body. On the other hand, when we meet with these African infections in England, crescents are frequently encountered, and often in great abundance; at all events, this is my experience.
Characters of the fever.—— It is found that the fevers produced by the malignant parasites are apt to be very irregular in their course. The rigor stage is relatively less marked; the pyrexial stage is more prolonged, and is often characterized by a tendency to adynamic conditions, together with vomiting, intestinal catarrh, pains in the limbs, anorexia, severe headache, and depression. After apparent recovery from the fever there is a great proneness to relapse at more or less definite intervals of from eight to fourteen days. Such fevers are accompanied by rapid destruction of corpuscles, and are usually followed by marked cachexia. At any time in their course symptoms of the gravest character may declare themselves.
QUOTIDIAN INFECTIONS
The quotidian infections are comparatively rare; at all events, they have not been very frequently ​recognized or adequately described. Many regard them as but varieties of the common subtertian infection.
The parasite.—The parasites are said to be of two kinds (very generally in association), the pigmented, Laverania præcox (Plate II., Fig. 1), and the unpigmented, Laverania immaculata. In both the cycle is approximately one of twenty-four hours; in both the young parasites exhibit very active movements, and tend to assume the ring form. Before segmentation they grow so as to occupy from one-fifth
Chart 3.—Quotidian infection.
to one-third only of the corpuscle. Both form little heaps of from six to eight very minute spores.
In the unpigmented parasite hæmozoin is never seen unless it be in the crescent phase—a phase the occurrence of which has not been satisfactorily established; in this phase, however, hæmozoin is never absent. In the pigmented parasite there is a considerable amount of fine hæmozoin, which at the segmenting stage—rarely seen in peripheral blood—collects in the usual way into one or two more or less central clumps.
The fever.—The fever is such as just described, a typhoid-like depression being generally a prominent feature in well-marked cases (Chart 3).
Subtertian Infection
Fig. 21.—Evolution of the subtertian parasite: asexual cycle.
zoin in an irregular heap. The crescent-shaped gametocyte is a characteristic feature.
The fever.—The associated symptoms are, in many respects, very different from those caused by the tertian parasite. In the first place, although rigor is not so marked, the hot stage lasts longer—often exceeding twenty-four hours; in fact, the tendency for the successive paroxysms to overlap, to become subintrant, is very marked. Moreover, where the intermissions are distinct, as Marchiafava and Bignami point out, the crisis is generally unlike that of ordinary tertian. There is frequently what is called a "double crisis"; that is to say, when the fever has attained its apparent fastigium there is a drop of one or more degrees of temperature—the "false crisis"—to be followed by a fresh rise, which is then followed ​by the "true crisis." This peculiar phenomenon the writers referred to attribute to the presence of two swarms of parasites, one of which matures somewhat later than the other. (Chart 4.)
The tendency to the development of pernicious symptoms, to the production of cachexia, and to relapse is similar to what appears to be the case in malignant quotidian infections.
Chart 4.—Subtertian infection.
Geographical distribution.—All these malignant parasites are confined to the warmer regions of the earth, and to the more intensely malarial districts in these; hence the name "tropical" which has been applied to this type of infection. In the sub-tropical zones they occur as first infections only in late summer or early autumn; hence the name "æstivo-autumnal."
​Microscopical examinations in malignant fevers.—In malignant infections the pigmented phase of the fever-causing forms of the parasite is not very frequently met with in peripheral blood. When found, and especially when it is observed that the pigment has become concentrated, it is a sure indication that a paroxysm is impending. On the occurrence of chilliness or of rigor, and at least during the earlier stages of the paroxysm, many small unpigmented parasites, sometimes exhibiting active amœboid movement, sometimes appearing as rings, will be found in finger blood; but towards the end of the fever these unpigmented forms often diminish in number, and all evidence of parasitic infection may even disappear from the blood till the approach or incidence of the next paroxysm. Of course, crescents and pigmented leucocytes may be found during these temporary absences of the intracorpuscular parasites. The segmenting forms of the malignant parasite are best found by aspirating the spleen with a hypodermic needle—hardly a justifiable procedure unless in exceptional circumstances.
Clinical Forms of Malarial Fevers
General statements.—The foregoing account, so far as it goes, and so far as it relates to the clinical manifestations produced by uncomplicated and typical infections, is true enough. But, as there may be an infinite variety as regards the number of the parasites present, individual susceptibility, concurrence of several species (mixed infection being far from uncommon), or of several generations of the same species of parasite maturing at different times, there may be a corresponding variety in the clinical manifestations.
In more temperate climates, and in the winter and spring seasons of warmer latitudes, malarial
​fevers are usually distinct intermittents. Fresh infections occurring in these places and seasons, so far as the subject has been studied, are found to be produced by the tertian and quartan parasites, and are, therefore, of little danger. Relapses, however, of malignant infections, originally contracted during the hot weather, may occur during the cold season in fact, are far from uncommon then.
First attacks, though produced by one of the benign parasites, may assume the characters of a remittent; generally, in temperate latitudes, they are frank intermittents. First attacks of malignant malaria, although they may in a few instances be intermittent, are in the majority of cases remittent in type. So are the attacks resulting from extensive reinforcement by fresh parasites (through fresh infection) of the old stock which a fever subject may carry about him in a latent condition. The first attack experienced by a newcomer to a highly malarious district with a hot climate is, therefore, generally remittent and severe.
It is neither necessary nor desirable to attempt to describe in detail the infinite variety malarial attacks exhibit. It would be impossible in a limited space to do so; and, if done, the result would amount only to an uninteresting and unprofitable ringing of the changes on rigor, pyrexia, diaphoresis, bilious vomiting, bilious diarrhrea, constipation, catarrhal gastritis, headache, bone-ache, prostration, and so forth. The picture would be further confused by the fact that the natural procession of events is generally, nowadays, disturbed by the action of quinine, the use of which is almost universal with Europeans in the tropics; so that it is difficult to say how any given malarial fever would develop, or how it would terminate, if untreated. Sometimes in the case of natives of tropical countries, who may not always command a few grains of quinine, such fevers pass into a typhoid state, with dry brown tongue, sordes in the mouth, and muttering delirium, and may end in collapse and death. In others, untreated remittents and intermittents gradually subside spontaneously in the course of a week or fortnight; or ​the remittent may merge into an intermittent which, in the course of weeks or months, subsides for a time, to recur every now and again at longer or shorter intervals. These recurrences may take place at fairly definite intervals; " long-interval fevers " the Italians have named them. Kelsch and Kiener allowed certain remittents in Europeans to run their course unchecked by quinine; they found that in ten or twelve days the fever gradually expended itself. Under favourable hygienic conditions the parasite and the associated fever frequently disappear together spontaneously. Occasionally the fever forms of the parasite may be present in the blood for days on end without causing acute clinical symptoms.
REMITTENT TYPES
Bilious remittent.—— One type of fever, known as bilious remittent, has long been recognized on account of the bilious vomiting, gastric distress, sometimes bilious diarrhœ, sometimes constipation, which accompany the recurring exacerbations. It is further distinguished by the pronounced icteric or, rather, reddish - yellow or saffron tint of skin and scleræ; a tint derived, probably, not from absorption of bile as in obstructive jaundice, but from modified hæmoglobin (hæmaphein) free in the blood or deposited in the derma and sclerotica. These bilious remittents are very common in the more highly malarious districts of Africa, America, the West Indies, India, and, in fact, in all malarious tropical countries. They are not specially nor directly dangerous in themselves, but they result usually in profound anaemia, and are often but the prelude to chronic malarial saturation, bad health, and invaliding.
Typhoid remittent.—— A modification of the bilious remittent what Kelsch and Kiener call " typhoid remittent " is very much more grave as affecting life than the simple bilious remittent. In the typhoid remittent, typhoid symptoms such as low delirium, prostration, dry tongue, swelling of spleen and liver, subsultus tendinum, marked melanæmia are superadded to the usual symptoms. Though re​covery is the rule, a considerable proportion of such attacks prove fatal.
Adynamic remittent.—— The same writers class by themselves a set of cases they call "adynamic remittent "; cases which are characterized by fatuousness, restlessness, nervous depression, intense muscular and cardiac debility, profound and rapid blood deterioration, icterus, leucocytosis, melanæmia, liability to syncope, occasionally hæmoglobinuria, liability to hæmorrhages, and a marked tendency to local gangrene.
Tuberculosis, syphilis, renal disease, or alcoholism will often be found as factors in determining the two latter types of fever.
PERNICIOUS ATTACKS
Many writers have drawn attention to what are called pernicious attacks or pernicious symptoms —— the French neatly designate them "accès pernicieux " ——a series of phenomena, the possibility of the appearance of which, not only in the course of remittents, but in the course of what is seemingly only an ordinary paroxysm of intermittent fever, should never be lost sight of by the practitioner in tropical climates. These " accès pernicieux " may supervene in apparently mild cases and carry off the patient with horrifying suddenness—— as suddenly as an attack of malignant cholera. The wary practitioner is always on the look-out for them, and is always prepared with measures to meet them promptly when they threaten.
Pernicious attacks are roughly classified into cerebral and algide. The cerebral are divisible into hyperpyrexial, comatose, convulsive, paretic, and so forth; the algide into syncopal, choleriform, dysenteric, hæmorrhagic, etc.
CEREBRAL FORMS
Hyperpyrexial.—— There can be little doubt that many of the cases of sudden death from hyperpyrexia and coma, usually credited to what has been called "ardent fever" or " heat apoplexy," are really malarial. If careful inquiry be made into the ​antecedents of many of these cases, a history of mild intermittent fever will often be elicited; or it will be found that the patient had been living in some highly malarious locality.
In the course of what seemed to be an ordinary malarial attack the body temperature, instead of stopping at 104° or 105° F., may continue to rise and, passing 107°, rapidly mount to 110° or even to 112°. The patient, after a brief stage of wild maniacal or, perhaps, muttering delirium, becomes rapidly unconscious, then comatose, and dies within a few hours, or perhaps within an hour, of the onset of the pernicious symptoms.
Comatose.—— Or the patient, without hyperpyrexia, the thermometer perhaps not rising above 104°, or even lower, may lapse into coma. The coma may pass away with crisis of sweating; on the other hand, an asthenic condition may set in and death from collapse supervene.
Other cerebral forms.—— Besides these hyperpyretic and comatose conditions, other forms of cerebral attack may occur in the course of malarial fevers. Thus, there may be sudden delirium ending in coma and, perhaps, death: convulsive seizures of an epileptic or of a tetanic character, with or without delirium or coma forms especially common in children, and too often misdiagnosed and with fatal consequences; conditions simulating cerebro- spinal meningitis; delusional insanity; dementia; various forms of apoplectic-like conditions and of paralysis, complicated, it may be, with aphasia. Seizures of this description, if not fatal, may eventuate in permanent psychical disturbances. Temporary debility, or even complete loss of memory, may succeed severe malarial infection.
Embolism of cerebral capillaries.—— These cerebral attacks are now explained, and it appears to me correctly explained, by the supposition, founded on actual post-mortem observation, that they depend on embolism by the malaria parasite of the capillaries of the various nerve centres involved (Plate II., Fig. 2) ; in hyperpyrexia, the thermic centres; in ​aphasia, Broca's convolution; and so on. By microscopical examination of properly prepared sections of the brain in fatal cases, such a plugging of the vessels can generally be readily observed. The earlier students of malarial melanæmia had remarked the presence of hæmozoin in the cerebral capillaries in many cases of this description, and, overlooking the including parasite, attributed the associated symptoms to thrombosis by the hæmozoin.
Malarial amblyopia.—— In rare instances a comatose pernicious attack eventuates in blindness. The amblyopia is usually transient, lasting for an hour or two only. On the other hand, it may be persistent; in which case, according to Poncet, optic neuritis, peripapillary œdema, extravasation of leucocytes, plugging of retinal and choroidal vessels by parasites or pigmented leucocytes, and consequent multiple hæmorrhages, may be found in the fundus. If the hæmorrhages are minute they are discoverable by the microscope only. These fundus changes differ from those in quinine amblyopia. In the latter, depending on retinal anæmia from toxic spasm of the arterioles, the amblyopia is more persistent; the discs are white and the vessels shrunken; there are no inflammatory symptoms; and central vision is the first to recover. (See Table on p. 76.)
ALGIDE FORMS
The algide forms of pernicious attack, as indicated by the name, are characterized by collapse, extreme coldness of the surface of the body, and a tendency to fatal syncope. These symptoms usually coexist with elevated axillary and rectal temperature.
Gastric form.—— This may be associated with, and in a measure be dependent on, acute catarrhal dyspeptic trouble. It is accompanied by severe epigastric distress, tender retracted abdomen, and incessant vomiting. The vomited matter may contain blood.
Choleraic form.—— Malarial attacks are sometimes accompanied by choleraic symptoms. The stools suddenly become loose, profuse, and numerous. They ​
Table of Diagnostic Points in Quinine and Malarial Amblyopia (see p. 75) :
| Quinine Amblyopia | Malarial Amblyopia |
| History.—Quinine taken in large doses, not less than 30 grains. | History.—Quinine may have been taken, but not necessarily in large doses. |
| Onset.—Sudden, accompanied by deafness; both eyes are affected. | Onset.—Not usually sudden, but it may be so if hæmorrhage has occurred in the macular region. There is no deafness, and both eyes are not necessarily affected. |
| Pupils.—Widely dilated, and whilst loss of vision continues they do not react to light. | Pupils.—React to light. |
| Vision.—Completely lost for a time. | Vision.—Never completely lost. |
| Ophthalmoscopic appearances.—A white haze over fundus; cherry-red spot at macula; optic disc pale; retinal vessels markedly constricted. | Ophthalmoscopic appearances.—There is optic neuritis; optic disc is of characteristic greyish-red colour; retinal hæmorrhages, and sometimes vitreous opacities. |
| Termination.—Usually some permanent defect in the field of vision or in colour vision. Central vision recovers first; optic disc is unusually white, and retinal vessels small. | Termination.—Some cases recover completely; in others greater or less permanent defect of vision remains. |
| Treatment.—Stop quinine. Amyl nitrite has been recommended to induce dilatation of retinal vessels. | Treatment.—Give quinine. |
Dysenteric and hæmorrhagic forms.—— Another form of pernicious attack is characterized by the sudden appearance of dysenteric symptoms; yet another by severe and recurring hæmatemesis, or by hæmorrhage from the bowel or elsewhere. The possibility of a suddenly developed dysentery being of malarial origin must therefore be kept in view; particularly if in what appears to be ordinary dysentery axillary temperature is found to be abnormally high. In every case of dysentery of this kind, or of hæmorrhage from stomach or bowel, in a patient who has recently been exposed to the chance of malarial infection, the possibility of the symptoms being an expression of malarial disease must never be overlooked; an examination of the blood must be made in all such cases before treatment is instituted.
TABULAR STATEMENT OF THE CHARACTER
(Modified from
| | Duration of development | Movement | Hæmozoin | Maximum size | Form of segmentation |
| 1. Quartan parasite, Plasmodium malariæ | Seventy-two hours | Slight movement in the immature forms | Coarse grains; little or no movement | The size of a red blood-corpuscle | Daisy form; the single spores roughish, with distinct nucleolus |
| 2. Tertian parasite, Plasmodium vivax | Forty-eight hours; or less in anticipating types | Active amœboid movement in the immature and also in the middle-aged forms | Finer granules in immature forms; often in the larger actively swarming | Size of a red blood-corpuscle; sometimes even larger | Sunflower or grape-like; single spores small, round; nucleolus rarely seen |
| 3. Pigmented quotidian parasite, Laverania præcox | Twenty-four hours | In the unpigmented immature stage very actively amœboid; less active when hæmozoin accumulates | Very fine; later coalesces in one or two clumps; does not swarm | 1/4-1/3 the size of a red blood-corpuscle | Irregularly formed heap |
| 4. Unpigmented quotidian parasite, Laverania immaculata | Twenty-four hours or less | Very active amœboid movement | None | 1/5-1/4 the size of a red blood-corpuscle | Star-shaped, or in irregular heaps |
| 5. Subtertian parasite. Laveraniamalariæ (Plasmodium falciparum) | Forty-eight hours or less | Active; the movement remains present in the pigmented stage | Fine; often shows oscillatory movement | 1/2-2/3 the size of a red blood-corpuscle | Irregular heaps |
Mannaberg)
| Number of merozoites | Form of gametocyte | Alterations in the infected blood-corpuscles | Relative number of parasites seen in peripheral and visceral blood espectively | Influence of quinine | Liability to reappearance of parasite after leaving infective regions |
| 6-12 | A sphere | The red blood corpuscles are little discoloured, and are not materially altered in size; some appear smaller | Parasites seen in peripheral circulation throughout the whole cycle, and in as great numbers as in visceral blood | Causes disappearance of parasite readily | Liability persists for a very long period. |
| 15-20 (often less) | A sphere | The red blood corpuscles are often hypertrophied, and lose colour, it may be completely. Schüffner's dots in deeply stained specimens | Parasites seen in peripheral blood throughout the whole cycle, but not in such large numbers as in visceral blood | Causes disappearance of parasite readily | Liability persists for long period. |
| 6-8 (even more) | A crescent (?) | The red blood-corpuscles shrink often, and are then either darker-stained (copper colour) or may be completely decolorized | An enormously greater number of parasites present in internal organs as compared with peripheral blood The latter part of the cycle takes place in internal organs only | Causes disappearance of parasite less readily | After a few months, less liability to recurrence. |
| 6-8 | A crescent (?) | The red blood-corpuscles shrink frequently, and are dark | Ditto | Ditto | Ditto. |
| 10-12, rarely 15-16 | A crescent | The red blood-corpuscles shrink frequently; they are dark, or may be perfectly colourless | Ditto | Ditto | Ditto |
The pathology of these various forms of algidity is in all likelihood of a very mixed character. In the gastric, choleraic, hæmorrhagic, and dysenteric types there is probably an accumulation of parasites in the vessels of the intestinal mucosa; such accumulations of parasites have been described. In those attacks in which profuse sweating is the dangerous element, the diaphoresis may be regarded, at all events in part, as symptomatic of excessive blood destruction—— of what is, in reality, equivalent to a sudden and extensive hæmorrhage; or it may be that it is only an excessive reaction to the malarial toxin. The dangerous syncope attending all types of algidity is secondary, and merely an expression of collapse.
A phenomenon occasionally observed in pernicious attacks, especially in those of an algide type, is the flooding of the peripheral blood with vast numbers of parasites, it may be at all stages of development——gametes as well as schizonts. The prognosis in such cases is bad.
A practical experience of these suddenly developed pernicious fevers of the tropics teaches that we should never make light of any malarial attack; particularly if it be of a mild irregular character and imperfectly controlled by quinine, and if small parasites, or the crescent form, be present. The practitioner should be on the alert for any danger signal mental aberration, restlessness, tremor, peculiarity in behaviour, alteration in knee reflexes, and other indications of grave implication of the nervous system. It further teaches that the subjects of such fevers should be particularly careful to guard against chills, fatigue, insufficient and unwholesome food, etc.
* ↑ Many authorities refuse to recognize more than one species of malignant parasite, the differences in length of cycle and pigmentation being regarded merely as variations depending on circumstances and not as specific differences.
* ↑ This parasite has received several names, none of them quite appropriate. Thus the Italians call it "æstivo-autumnal," a term appropriate enough in Italy, where the infection is acquired only during the summer and autumn months, but manifestly inappropriate in the tropics, where it may be acquired at any season. Koch calls it the "tropical parasite," a name equally unsuitable, seeing that the range of the parasite embraces countries far beyond the tropic belt. The term subtertian I have adopted, following Sambon's suggestion. It implies no error either as regards clinical habit, seasonal or geographical range, and it has the additional recommendation of approximating to the name hemitertian, applied by Hippocrates and the ancients to the class of fevers it gives rise to.
* ↑ Several additional species or varieties of malaria parasites have been described lately, e.g. the Plasmodium tenue of Stephens, the Plasmodium falciparum quotidianum of Craig, the Plasmodium vivax minuta of Emin; but as to whether these are valid species or merely varieties it is as yet impossible to pronounce.
* ↑ * In malarial blood the corpuscles are apt to vary in size, as in other anǣmic conditions. A quartan parasite in a megalocyte may therefore simulate a tertian. Usually the including blood corpuscle is, or seems, smaller than normal.
* ↑ * There has been a good deal of speculation as to why certain parasites develop into schizonts, whilst others become gametocytes. The circumstance of the late appearance of the gamete is looked upon by some as evidence that the blood, from repeated development in it of swarms of endogenous parasites, has become exhausted as a pabulum, and that in consequence of this the parasite is directed to a line of development providing for life and growth elsewhere, that is in the mosquito. The analogy of other sporozoa and of the bacteria supports this view.
* ↑ This peculiarity as regards seasonal and geographical distribution of subtertian malaria may be explained, as Grassi, Jancsó, and others have pointed out, by the fact that for its development in the mosquito the subtertian parasite demands a higher atmospheric temperature than suffices for the quartan and tertian parasites. Hence, although these two benign and the subtertian parasites are generally found associated together, and the latter can be acquired at any time in the tropics, it is only in the summer or early autumn that it can be acquired in the sub-tropics and temperate zones. It is stated that if the temperature falls below 15° C. the development of the oöcyst in the mosquito is arrested.